A Phase II Clinical Trial of Tiragolumab in Combination With Atezolizumab in Patients With Non-small Cell Lung Cancer (NSCLC) and Untreated Brain Metastases.
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: Liza Villaruz, MD

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TITLE PAGE  
TITLE:    A phase II clinical trial of tiragolumab in combination with atezolizumab  in patients 
with non-small cell lung cancer (NSCLC) and untreated brain metastases. 
 
HCC #: 
22-045 
Phase: 
II 
Version: 
3.0 
Version Date: 
10/16/2024 
Investigational Agent: 
Tiragolumab 
Commercial Agent: 
Carboplatin 
 
Pemetrexed 
 
Atezolizumab  
 
IND Number: 
161792 
NCT Number: 
NCT05746481  
 
Sponsor-Investigator: 
Liza C. Villaruz, MD 
 
Associate Professor of Medicine 
 
5150 Centre Avenue, 5th Floor 
 
T 412-648-6577 
 
F 412-648-6579 
 
villaruzl@upmc.edu 
 
Biostatistician: 
Hong Wang, PhD 
 
Research Associate Professor of Biostatistics  
 
UPMC Hillman Cancer Center Biostatistics Facility 
 
UPMC Cancer Pavillon POB2, Suite 4C 
 
5150 Centre Avenue 
 
Pittsburgh, PA 15232 
 
T 412-383-1588 
 
how8@pitt.edu 
 
Source of Support: 
Genentech 
 
Study Monitor:  
     Clinical Research Services 
University of Pittsburgh 
3500 Fifth Avenue, Suite 205 
Pittsburgh, PA 15213 
 
 
 
 
 
 

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Table of Contents 
Title Page .........................................................................................................................................1 
i. PROTOCOL SUMMARY ............................................................................................................4 
ii. SCHEMA .....................................................................................................................................7 
1. 
BACKGROUND .................................................................................................................9 
1.1 
Lung Cancer .............................................................................................................9 
1.2 
Tiragolumab and Atezolizumab .............................................................................10 
1.3 
Rationale ................................................................................................................13 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................14 
2.1 
Objectives ..............................................................................................................14 
2.2 
Endpoints ...............................................................................................................15 
3. 
PATIENT SELECTION AND ELIGIBILITY CRITERIA ..............................................15 
3.1 
Inclusion Criteria ...................................................................................................15 
3.2 
Exclusion Criteria ..................................................................................................17 
4. 
REGISTRATION PROCEDURES ...................................................................................19 
4.1 
General Guidelines .................................................................................................19 
4.2 
Registration Process ...............................................................................................19 
5. 
TREATMENT PLAN ........................................................................................................20 
5.1 
Agent Administration .............................................................................................20 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................21 
5.3 
Duration of Therapy ...............................................................................................23 
5.4 
Duration of Follow-up ...........................................................................................24 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................24 
6.1 
Atezolizumab and Tiragolumab Dosing ................................................................24 
6.2 
Carboplatin and Pemetrexed Dosing .....................................................................25 
7. 
Management Guidelines for Immune-Related Adverse Events .........................................25 
7.1 
Pulmonary Events ..................................................................................................25 
7.2 
Hepatic Events .......................................................................................................26 
7.3 
Gastrointestinal Events ..........................................................................................27 
7.4 
Endocrine Events ...................................................................................................29 
7.5 
Ocular Events .........................................................................................................31 
7.6 
Immune-mediated Myocarditis ..............................................................................32 
7.7 
Infusion-related Reactions .....................................................................................33 
7.8 
Cytokine-release Syndrome ...................................................................................34 
7.9 
Pancreatic Events ...................................................................................................37 
7.10 
Dermatologic Events ..............................................................................................38 
7.11 
Neurologic Disorders .............................................................................................39 
7.12 
Immune-mediated Meningoencephalitis ................................................................41 

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7.13 
Renal Events ..........................................................................................................41 
7.14 
Systemic Immune Activation ................................. Error! Bookmark not defined. 
7.15 
Immune-mediated Myositis ...................................................................................42 
7.16 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation 
Syndrome ...............................................................................................................44 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................45 
8.1 
Tiragolumab ...........................................................................................................45 
8.2 
Atezolizumab .........................................................................................................46 
8.3 
Carboplatin and Pemetrexed ..................................................................................46 
9. 
STATISTICAL CONSIDERATIONS...............................................................................46 
9.1 
Study Design/Endpoints.........................................................................................46 
9.2 
Statistical Analysis Plan .........................................................................................46 
9.3 
Sample Size/Accrual Rate ......................................................................................48 
9.4 
Stopping Rule for Excess Toxicity ........................................................................48 
9.5 
For Phase 2 Protocols Only: Reporting and Exclusions ........................................49 
10. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................49 
10.1 
Adverse Events ......................................................................................................49 
10.2 
Recording/Reporting requirements ........................................................................53 
10.3 
Reporting of Serious Adverse Events .................... Error! Bookmark not defined. 
10.4 
Review of Safety Information: Sponsor-Investigator Responsibilities ......... Error! 
Bookmark not defined. 
10.5 
IND safety reports .................................................. Error! Bookmark not defined. 
10.6 
Submission of IND safety reports .......................... Error! Bookmark not defined. 
10.7 
Follow-up ............................................................... Error! Bookmark not defined. 
10.8 
Disclaimer .............................................................. Error! Bookmark not defined. 
10.9 
Reporting adverse events to the responsible IRB .. Error! Bookmark not defined. 
11. 
STUDY CALENDAR .......................................................................................................65 
12. 
MEASUREMENT OF EFFECT........................................................................................66 
12.1 
Antitumor Effect – Solid Tumors ..........................................................................66 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................74 
13.1 
Data Safety Monitoring Plan .................................................................................74 
13.2 
Quality Control and Quality Assurance .................................................................75 
13.3 
Data Handling and Record-Keeping ......................................................................76 
13.4 
Institutional Review Board (IRB) Approval ..........................................................76 
13.5 
Ethical and Scientific Conduct of the Clinical Study ............................................77 
13.6 
Informed Consent...................................................................................................77 
14. 
REFERENCES ..................................................................................................................78 
15. 
APPENDICES ...................................................................................................................83 
15.1 
APPENDIX A: PERFORMANCE STATUS CRITERIA .....................................83 
16.2 
APPENDIX B: Anaphylaxis Precautions ..............................................................84 

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15.3 
APPENDIX C: Safety Reporting Fax Cover Sheet ...............................................85 
15.4 
APPENDIX D: Administration of Atezolizumab and Tiragolumab 
infusions .................................................................................................................86 
 
 
 
 
i. PROTOCOL SUMMARY 
 
Title 
A phase II clinical trial of tiragolumab in combination with 
atezolizumab in patients with non-squamous non-small cell lung 
cancer (NSCLC) and untreated brain metastases 
Short Title 
Tiragolumab and atezolizumab in NSCLC with untreated brain 
metastases 
Protocol Number 
HCC 22-045 
Phase 
Phase II 
Study Design 
While the current trial was originally designed to investigate the 
activity of carboplatin, pemetrexed, atezolizumab and tiragolumab in 
patients with non-squamous NSCLC and untreated brain metastases, 
in response to the SKYCRAPER-06 interim analysis, the protocol has 
been amended after the enrollment of the first three patients to an 
investigation of atezolizumab with or without tiragolumab in patients 
with newly diagnosed metastatic PD-L1 selected NSCLC and 
untreated brain metastases. The first three patients accrued on 
Version 2.0, Version Date: 05/17/2023, will continue to be treated 
and included in study as cohort one, and the remaining patients will 
be included as cohort two. 
 
The three patients in cohort one will continue to be treated according 
to the Version 2.0, Version Date: 05/17/2023 schema due to ongoing 
clinical benefit and tumor response to the four-drug regimen. These 
three patients have CNS disease that has improved and there have 
been no unanticipated toxicity or safety signals. The patients have 
been made aware of the results of SKYSCRAPER-06 and intend to 
be treated per the cohort one schema. This was discussed with 
Genentech and agreed upon.  
 
Patients with at least one untreated evaluable brain metastasis of 5 
mm or more will be enrolled. Lesions previously treated with SRS 
may not be used as target lesions. Patients will be required to undergo 
an on-treatment brain MRI at three weeks for safety purposes. 
Additional restaging will occur at nine-week intervals. PD-L1 tumor 
proportion score (TPS) will be determined utilizing an FDA-

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approved test by local testing.  
Study Duration 
36 months 
Study Center(s) 
Multi-center with 2-3 external sites  
Objectives and Endpoints 
Primary  
Objective: To estimate the rate of initiation of salvage radiation 
therapy to the CNS in patients with NSCLC and untreated brain 
metastases treated with the combination of tiragolumab and 
atezolizumab with or without chemotherapy.   
Endpoint: Proportion of patients that require salvage radiation 
therapy to the CNS within 18 weeks of study initiation 
Secondary 
Objectives:  
1. To characterize the safety and tolerability of the combination 
of tiragolumab and atezolizumab with and without 
chemotherapy in patients with NSCLC and untreated brain 
metastasis, particularly Grade ≥ 2 (symptomatic) CNS related 
adverse event.  
 
2. To estimate the brain metastasis response rate (BMRR; 
response assessment in neuro-oncology brain metastases 
[RANO-BM]). 
3. To estimate the overall response rate (ORR), assessed using 
RECIST v1.1. 
4. To estimate progression-free survival (PFS). 
5. To estimate overall survival (OS). 
6. To estimate progression-free survival 2 (PFS2) after initiation 
of salvage XRT 
7. To estimate PD-L1 tumor proportion score (TPS) as a 
potential predictive biomarker of response. 
Endpoints:  
1. Frequency of Grade ≥ 2 (Symptomatic) CNS related adverse 
events per CTCAE v5.0 
2. Brain Metastasis Response Rate (BMRR) (per RANO-BM) 
3. Objective Response Rate (ORR) 
4. Progression-free Survival (PFS) 
5. Overall Survival (OS) 
6. Progression-free Survival after initiation of salvage XRT 
(PFS2) 
7. PD-L1 TPS 
Number of 
Participants 
Approximately 35 participants 
Main Inclusion and 
Exclusion Criteria 
 Key Inclusion 
• Patients must have histologically or cytologically confirmed 

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NSCLC.  
• In patients treated with the combination of tiragolumab and 
atezolizumab, patients must have PDL1 TPS >50%, as 
determined by an FDA-approved test. 
• Patients must have asymptomatic brain metastases with at 
least one untreated evaluable (per RANO-BM) brain 
metastasis of 5 mm or more. A growing lesion previously 
treated with whole brain radiotherapy is acceptable given the 
lower incidence of radiation necrosis. Lesions previously 
treated with SRS may not be used as target lesions.  
• Patients are not required to have measurable disease outside 
the CNS per RECIST 1.1. 
• Prior chemotherapy, immunotherapy or radiation given with 
curative intent in early stage or locoregionally advanced 
NSCLC is permitted, if completed more than 12 months prior 
to initiation of study treatment.  
• Prior radiation with palliative intent in the metastatic setting 
to non-CNS lesions is permitted (no washout).  
• Age ≥18 years. 
• ECOG performance status ≤ 1.  
• Patients must have normal organ and marrow function. 
 
Key Exclusion 
• Symptoms related to brain metastases requiring CNS 
radiation, steroids greater than prednisone 10 mg/d or 
equivalent, or anti-epileptic therapy ≤ 2 weeks of treatment 
initiation are exclusionary. 
• Prior systemic therapy for metastatic disease is not allowed. 
• Active or history of autoimmune disease or immune 
deficiency, requiring systemic therapy ≤ 12 months of study 
enrollment. 
Investigational 
Product  
 
Cohort 1: Tiragolumab 600 mg intravenously (IV) for induction 
treatment will be administered on Day 1 of each 21-day cycle for 4 
cycles (in combination with atezolizumab plus pemetrexed and 
carboplatin). Maintenance therapy will continue with tiragolumab in 
combination with atezolizumab and pemetrexed on Day 1 of each 21-
day cycle.  
 
Cohort 2: Tiragolumab 600 mg intravenously (IV) for induction 
treatment will be administered on Day 1 of each 21-day cycle for 4 
cycles (in combination with atezolizumab). Maintenance therapy will 
continue with tiragolumab in combination with atezolizumab on Day 
1 of each 21-day cycle. 

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Duration of 
administration 
For up to 2 years on therapy until loss of clinical benefit, 
unacceptable toxicity, death, or withdrawal of consent. 
Reference therapy 
Carboplatin AUC 5 Day 1 
Pemetrexed 500 mg/m2 Day 1 
Atezolizumab 1200 mg IV Day 1 
Statistical Methods 
Patients in cohort 1 and cohort 2 will be pooled for all safety and 
efficacy analyses. 
 
For the primary endpoint of whether or not the patient requires 
salvage radiation therapy to the CNS within 18 weeks, an exact 
binomial test will be used for the null hypothesis Ho:  P (salvage 
therapy)>0.5 at α=0.05. The sample size of 35 patients will provide 
80% power if the true P (salvage therapy) is less than or equal to 
0.27. 
For binary endpoints (including the primary endpoint), the proportion 
will be calculated with a 95% exact (Clopper-Pearson) confidence 
interval. Each survival endpoint will be characterized by the product-
limit (Kaplan-Meier) method with a 95% Greenwood confidence 
region. Median survival will be estimated from the survival function 
with a 95% Brookmeyer and Crowley confidence interval. 
Data and Safety 
Monitoring Plan  
Principal Investigator, Sub-investigators, regulatory, CRS 
management, clinical research coordinators, clinical research 
associates, data managers, and clinic staff meet monthly in disease 
center Data Safety Monitoring Boards (DSMB) to review and discuss 
study data to include, but not limited to, the following: 
• Serious adverse events 
• Subject safety issues 
• Recruitment issues 
• Accrual 
• Protocol deviations 
• Unanticipated problems 
• Breaches of confidentiality 
Minutes from the DSMB meetings are available to those who are 
unable to attend the disease center DSMB in person or through 
conference call. 
 
 
 
ii. SCHEMA 
 
This is a phase II clinical trial aimed at the evaluation of the safety and clinical activity of 
tiragolumab and atezolizumab with or without chemotherapy in the first line treatment of 

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metastatic NSCLC patients with asymptomatic, untreated brain metastases. Patients must have 
asymptomatic brain metastases with at least one untreated evaluable brain metastasis of 5 mm or 
more. Lesions previously treated with SRS may not be used as target lesions. Patients will be 
required to undergo an on-treatment brain MRI at three weeks for safety purposes while on trial, 
and additional restaging will occur at nine-week intervals. PD-L1 tumor proportion score (TPS) 
will be determined utilizing an FDA-approved test by local testing.  
 
Cohort 1 (accrued to protocol Version 2.0, Version Date: 05/17/2023): 
 
 
 
 
Induction treatment with tiragolumab in combination with atezolizumab plus pemetrexed and 
carboplatin will be administered on Day 1 of each 21-day cycle for 4 cycles. Following the 
induction phase, maintenance therapy will continue with tiragolumab in combination with 
atezolizumab and pemetrexed on Day 1 of each 21-day cycle.  
 
 
Cohort 2 (Version 3.0, Version Date 10/16/2024): 
 
 
Treatment with tiragolumab in combination with atezolizumab will be administered on Day 1 of 
each 21-day cycle for up to 2 years of therapy until loss of clinical benefit, unacceptable toxicity, 
death or withdrawal of consent. Patients with progressive brain metastases (based on RANO-BM 
and/or clinical progression) will be allowed to undergo salvage local therapy, e.g. radiotherapy 
and be allowed to continue on trial, if they are clinically stable, as deemed by the treating 
investigator. 
Patients will continue up to 2 years on therapy until loss of clinical benefit, unacceptable 
toxicity, death or withdrawal of consent. Patients with progressive brain metastases (based on 
RANO-BM and/or clinical progression) will be allowed to undergo salvage local therapy, e.g. 
Newly diagnosed metastatic non-
squamous NSCLC 
At least one untreated brain 
metastasis (≥5mm)
Mandatory archival tumor tissue
N = 35
Carboplatin AUC 5 Day 1
Pemetrexed 500 mg/m2 Day 1
Atezolizumab 1200 mg IV Day 1
Tiragolumab 600 mg IV Day1
Cycle length = 21 days
MRI brain at 3 weeks to assess safety 
Restaging (CT/MRI brain) every 9 weeks 

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radiotherapy and be allowed to continue on trial, if they are clinically stable, as deemed by the 
treating investigator. 
 
1. 
BACKGROUND 
 
1.1 
Lung Cancer 
 
Lung cancer remains the leading cause of cancer deaths worldwide; it is the most common 
cancer in both men and women and accounted for approximately 13% of all new cancers in 2008 
(Jemal et al. 2011). In 2012, it was estimated that there were 313,000 new cases of lung cancer 
and 268,000 lung cancer deaths in Europe (GLOBOCAN 2012). In the United States, there were 
an estimated 221,200 new cases of lung cancer and 158,040 lung cancer deaths in 2015 (Siegel et 
al. 2015). 
Non-small cell lung cancer (NSCLC) is the predominant subtype of lung cancer, accounting for 
approximately 85% of all cases (Molina et al. 2008; Howlader et al. 2014). NSCLC can be 
divided into two major histologic types:  adenocarcinoma and squamous cell carcinoma (Travis 
et al. 2011). Adenocarcinoma histology accounts for more than half of all NSCLC, while 
squamous cell histology accounts for approximately 25% (Langer et al. 2010) of NSCLC. The 
remaining cases of NSCLC are represented by large cell carcinoma, neuroendocrine tumors, 
sarcomatoid carcinoma, and poorly differentiated histology. 
Genetic changes that have prognostic and/or predictive significance in NSCLC include mutations 
in the EGFR gene and rearrangement in the ALK gene. The rates of these mutations differ 
between squamous cell carcinoma and adenocarcinoma. For example, EGFR mutations have 
been reported in 10%-40% of patients with adenocarcinoma NSCLC but are infrequently 
observed in squamous NSCLC (Herbst et al. 2008). Rearrangement in the ALK gene is very rare 
in the squamous histology but observed in approximately 7% of patients with adenocarcinoma 
(Herbst et al. 2008; Langer et al. 2010). 
 
In patients without actionable oncogenic drivers, platinum-based chemotherapy regimens 
without the addition of immunotherapy reached a plateau in overall response rate (approximately 
15%-22%) and median overall survival (OS) (7-10 months). The addition of bevacizumab to 
carboplatin and paclitaxel resulted in an increased response rate of 35% and an increased median 
OS of 12 months. Further benefit has been demonstrated with pemetrexed maintenance therapy 
when administered to patients with a response of stable disease or better following four cycles of 
cisplatin plus pemetrexed (median PFS of 4.1 months with pemetrexed maintenance vs. 2.8 
months with placebo maintenance) (Paz Ares et al. 2012).    
 
In previously treated advanced NSCLC patients, unprecedented survival gains have been 
demonstrated with pembrolizumab, nivolumab and atezolizumab. These survival gains have 
extended into the 1st line setting in patients with high PD-L1 expressing (tumor proportion score; 
TPS ≥ 50%) tumors with superior OS with pembrolizumab, compared with chemotherapy. 
Pembrolizumab in combination with carboplatin and pemetrexed was approved in the 1st line 
treatment of non-squamous NSCLC regardless of TPS, based on superior response rates, 
progression-free survival and overall survival, compared with chemotherapy alone.  
 

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The IMPower150 clinical trial demonstrated the addition of atezolizumab to carboplatin, 
paclitaxel, and bevacizumab resulted in superior PFS and OS compared with carboplatin-based 
chemotherapy alone in the 1st line treatment of an all-comer (with regard to TPS) non-squamous 
NSCLC population. As first line therapy, carboplatin, paclitaxel and bevacizumab has been 
associated with equivalent survival to carboplatin, pemetrexed, and bevacizumab (Patel et al. 
2013). Combinations of a platinum agent with pemetrexed have been used more widely because 
of a better tolerability and safety profile. Thus, carboplatin, pemetrexed and bevacizumab have 
been chosen as the platinum backbone in the current clinical trial.  
 
1.2 
Tiragolumab and Atezolizumab 
 
1.2.1 Tiragolumab 
 
Tiragolumab is a fully human IgG1/κ mAb that binds T cell immunoreceptor with Ig and ITIM 
domains (TIGIT), an immune inhibitory receptor that is expressed on the surface of activated T 
cell and natural killer (NK) cell subsets and interacts with high affinity with CD155 (also known 
as poliovirus receptor [PVR]) (Yu et al. 2009). Genetic ablation of TIGIT in T cells in mice 
results in exacerbated T cell responses, demonstrating the role of TIGIT in inhibiting T cell 
responses (Joller et al. 2011; Johnston et al. 2014). Therapeutic blockade of TIGIT by 
tiragolumab represents an attractive strategy for cancer therapy and is expected to enhance the 
magnitude and quality of tumor specific T cell responses, which may result in improved 
meaningful anti tumor activity when tiragolumab is combined with other CIT and chemotherapy. 
The available nonclinical and clinical data provide a strong rationale for evaluating the potential 
clinical benefit of tiragolumab in patients with cancer. 
Refer to the Tiragolumab Investigator’s Brochure for details on the nonclinical and clinical 
studies for tiragolumab. 
 
1.2.2 Atezolizumab 
 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets PD-L1 
and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as 
CD80), both of which function as inhibitory receptors expressed on T cells. Therapeutic 
blockade of PD-L1 binding by atezolizumab has been shown to enhance the magnitude and 
quality of tumor specific T cell responses, resulting in improved anti-tumor activity 
(Fehrenbacher et al. 2016; Rosenberg et al. 2016). Atezolizumab has minimal binding to Fc 
receptors, thus eliminating detectable Fc effector function and associated antibody-mediated 
clearance of activated effector T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is 
being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab will be administered at a fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 
21-day cycle), which is the approved dosage for atezolizumab (see U.S. Package Insert). Anti-
tumor activity has been observed across doses ranging from 1 mg/kg to 20 mg/kg Q3W. In Study 
PCD4989g, the maximum tolerated dose of atezolizumab was not reached and no DLTs were 

11 
 
observed at any dose. The fixed dose of 1200 mg Q3W (equivalent to an average body weight-
based dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical studies (Deng et al. 
2016) and available clinical pharmacokinetic, efficacy, and safety data (refer to the 
Atezolizumab Investigator's Brochure for details). 
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical studies. 
 
1.2.3 Background on Blockade of the TIGIT Pathway in Cancer as a Potential Anticancer 
Therapy 
 
TIGIT is a novel immune inhibitory receptor that is a member of the Ig super family (Yu et al. 
2009; Manieri et al. 2017). TIGIT expression is elevated in the tumor microenvironment in many 
human tumors, is coordinately expressed with other checkpoint immune receptors such as PD-1, 
and is associated with impaired T-cell function and anti-tumor immunity (Johnston et al. 2014). 
Activation of TIGIT on T-cells and NK-cells limits cellular proliferation, effector cytokine 
production, and killing of target tumor cells (TCs) (Stanietsky et al. 2009; Yu et al. 2009; 
Johnston et al. 2014; Wang et al. 2015; Manieri et al. 2017). 
TIGIT is expressed in a wide variety of human tumors, including NSCLC, and is highly 
correlated with Tcell infiltration and PD1 expression (Johnston et al. 2014). Fluorescence 
activated cell sorting analysis of fresh tumor samples showed that TIGIT and PD1 are also co-
expressed on tumor infiltrating T cells. TIGIT expression ranges from 30% to 80% and from 
50% to 80% on tumor infiltrating CD4+ and CD8+ T cells, respectively (Johnston et al. 2014). It 
has also been reported that tumor infiltrating lymphocytes from early stage primary NSCLCs co-
express TIGIT with PD-1, suggesting that TIGIT expression may be important throughout the 
development of NSCLC (Tassi et al. 2017). 
Therefore, TIGIT is a potential target for therapeutic intervention aimed at restoring the immune 
response against the tumor, especially in NSCLC. Agents that inhibit the activity of TIGIT may 
relieve an important source of tumor associated immune suppression and may enhance the 
activity of other immune based therapies, such as atezolizumab, an inhibitor of PD-L1. Early 
nonclinical results using genetically deficient mice and blocking antibodies reveal a key role for 
TIGIT in regulating Tcell responses. Together the data support the hypothesis that anti-TIGIT in 
combination with anti-PD-L1 may reactivate antitumor immunity in NSCLC to provide clinical 
benefit to patients.  
 
1.2.4 Combined Inhibition of the TIGIT and PD-L1/PD-1 Pathways as Potential 
Anticancer Therapy 
 
The inhibitory immunoreceptor TIGIT has been shown to limit the effector function of tumor 
associated lymphocytes. Activation of TIGIT on T cells and NK cells limits proliferation, 
effector cytokine production, and killing of target TCs. Therefore, in the context of the tumor 
microenvironment, TIGIT acts to limit antitumor immune responses. Interference with 
TIGIT/PVR interaction may enhance the magnitude and quality of the tumorspecific Tcell 
responses through increased expansion of T cells as well as improved Tcell priming and/or 
effector function. Because TIGIT and PD1 are co-expressed by infiltrating T cells in several 
human tumors, inhibition of the TIGIT/PVR pathway may complement and potentiate the 

12 
 
antitumor activity of a PDL1 pathway inhibitor such as atezolizumab. 
The combined inhibition of the TIGIT and PD-L1/PD-1 pathways by tiragolumab and 
atezolizumab, respectively, has demonstrated promising clinical activity in the Phase I study 
GO30103 and the Phase II study GO40290 (hereafter referred to as CITYSCAPE). Study 
GO30103 is a first-in-human, combined Phase Ia/Phase Ib, open-label, dose escalation, 
multicenter study. The study evaluated the safety, tolerability, immunogenicity, 
pharmacokinetics, exploratory pharmacodynamics, and preliminary evidence of biologic activity 
of tiragolumab administered as a single agent (Phase Ia) or in combination with atezolizumab 
(Phase Ib) to patients with locally advanced or metastatic malignancies. As of December 2, 2019, 
171 patients with multiple tumor types, including NSCLC, had been enrolled in the Phase Ib 
portion of the study. Objective responses, including complete responses (CR) in 4 patients, and 
partial responses (PR) in 23 patients, have been observed. 
No maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no clear dose-
related trends in the incidence or severity of adverse events have been determined for single-
agent tiragolumab or tiragolumab in combination with atezolizumab in Study GO30103. 
Tiragolumab was further evaluated in patients with PD-L1 selected advanced NSCLC (tumor 
proportion score [TPS] ³  1%) in the Phase II, global, randomized, double-blind, placebo-
controlled CITYSCAPE study. As of the clinical cutoff date of Dec 2, 2019, the confirmed 
objective response rate (ORR) in the intent-to-treat (ITT) population was higher in the 
tiragolumab combined with atezolizumab arm (37%) than in the placebo combined with 
atezolizumab arm (21%). Investigator assessed progression-free survival (PFS) was also 
improved with a stratified hazard ratio (HR) of 0.58 (95% confidence interval (CI): 0.38 to 0.89), 
with a median PFS not estimable and 3.9 months in the tiragolumab combined with atezolizumab 
arm compared to the placebo combined with atezolizumab arm, respectively. Responses to 
tiragolumab in combination with atezolizumab were observed in patients with both squamous 
and non-squamous histology (Rodriguez-Abreu et al, 2020). 
As of the clinical cutoff date of December 2, 2019 in the CITYSCAPE study, there were 135 
safety evaluable patients. The safety profile was comparable between the tiragolumab combined 
with atezolizumab arm and the placebo combined with atezolizumab arm for all grades of 
adverse events (99% vs 96%), Grade ≥ 3 adverse events (48% vs 44%), Grade 5 adverse events 
(4.5% vs 7.4%), serious adverse events (37% vs 35%), and adverse events leading to study 
treatment withdrawal (10.4% vs 8.8%). Study treatment related adverse events occurred at a 
higher frequency in the tiragolumab combined with atezolizumab arm (82%) compared to the 
placebo combined with atezolizumab arm (72%). 
Using a comprehensive medical concepts strategy, immune-mediated adverse events were 
reported with a higher frequency in the tiragolumab combined with atezolizumab arm (69%) 
compared to the placebo combined with atezolizumab arm (47%). The difference (> 10% 
difference between arms) was predominantly attributed to events of immune mediated rash 
(preferred terms of rash, rash maculopapular, dermatitis, erythema, eczema, pruritic rash, 
folliculitis and skin ulcer) (40% vs 15%) and infusion related reactions (preferred term of 
infusion related reaction) (30% vs 10%). 
Tiragolumab is being investigated in clinical studies as a potential therapy against various tumor 

13 
 
types. Refer to the Tiragolumab Investigator’s Brochure for details on the nonclinical and 
clinical studies for tiragolumab. 
 
1.2.5 Combined Inhibition of TIGIT and PD-L1/PD-1 Pathways in Combination with 
Chemotherapy  
Several Phase III metastatic studies, including MK-3475-189 (KEYNOTE-189), MK-3475-407 
(KEYNOTE-407), GO29436 (IMpower150), and GO29537 (IMpower130), have documented 
that, when co-administered with chemotherapy, the efficacy benefit of PD-L1/PD-1 inhibitors 
extends across all PD-L1 expression subgroups (Gandhi et al. 2018; Paz-Ares et al. 2018; 
Socinski et al. 2018; Gadgeel et al. 2019; West et al. 2019). 
 
The data are consistent with the known effects of chemotherapy on the tumor microenvironment 
that may potentiate the effects of immunotherapies. In addition to direct cytotoxicity, which 
increases release of tumor antigens and enhances immunogenicity, chemotherapy has been 
shown to increase expression of PD-L1 (Zhang et al. 2008) and increase levels of CD155 (PVR), 
the ligand for TIGIT (Yoshida et al. 2019). The expectation that tiragolumab will further enhance 
atezolizumab efficacy in the context of chemotherapy is supported by nonclinical evidence that 
the TIGIT pathway is associated with immune dysfunction and chemoresistance (Blake et al. 
2016; Burugu et al. 2018). In lung cancer models, TIGIT expression on T cells contributed to 
carboplatin chemoresistance through the upregulation of CD155 and subsequent T-cell 
dysfunction (Anestakis et al. 2020). 
Furthermore, an exploratory study in gastric cancer has shown that after treatment with platinum 
chemotherapy, patients with a higher percentage of CD8 + TIGIT + T cells had increased rates of 
cancer relapse and shorter disease-free survival (DFS) (Tang et al. 2019). Because the TIGIT 
pathway is associated with immune dysfunction and chemoresistance, these findings suggest that 
TIGIT blockade to restore T-cell function could potentially improve outcomes for patients 
undergoing chemotherapy. In support of this hypothesis, in vitro studies have shown that TIGIT 
blockade countered the suppression of T-cell proliferation and activation following 
chemotherapy (Tang et al. 2019). 
Collectively, the data and preliminary results of the Phase I GO30103 and Phase II CITYSCAPE 
studies have led to the hypothesis that anti-TIGIT treatment (tiragolumab) in combination with 
anti-PD-L1 treatment (atezolizumab) plus chemotherapy may result in enhanced and more 
durable responses. This combination is currently under evaluation in other indications. 
 
1.3 
Rationale 
 
Multiple PD1 and PD-L1 directed therapies have been approved as monotherapy (in PD-L1 
selected patients) and in combination with chemotherapy (in PD-L1 unselected patients) in the 
treatment of newly diagnosed metastatic NSCLC. Patients with untreated brain metastases have 
been excluded from the registrational trials leading to the approval of these agents.  
 
In a single arm phase II clinical trial of carboplatin, pemetrexed, and atezolizumab in patients 
with metastatic non-squamous NSCLC and untreated brain metastases (ATEZO-BRAIN, Nadal 
et al., WCLC 2021), this combination was safe and tolerable and associated with a systemic 

14 
 
median PFS of 8.9 months (95% CI 6.7-13.8) and intracranial PFS by RANO-BM of 6.9 months 
(95% CI 4.7-12.1). The intracranial response by RANO-BM was 40%. This study demonstrated 
proof of concept that a chemoimmunotherapy regimen is safe and potentially efficacious in 
newly diagnosed NSCLC patients with untreated brain metastases.  
 
The anti-TIGIT antibody tiragolumab in combination with atezolizumab in the 1st line treatment 
of metastatic NSCLC with a PD-L1 TPS ≥ 1% was associated with an ORR of 37% and median 
PFS of 5.6 months compared with an ORR of 21% and median PFS of 3.9 months in patients 
treated with atezolizumab and placebo (HR for PFS 0.58; 95% CI 0.38-0.89) (CITYSCAPE, 
Rodriguez-Abreu et al., ASCO 2020).  
 
At initial accrual of this phase II trial, the ongoing SKYSCRAPER-06 clinical trial was 
evaluating the combination of platinum, pemetrexed, and atezolizumab with or without 
tiragolumab in patients with newly diagnosed metastatic non-squamous NSCLC patients and 
excluded patients with untreated brain metastases. This phase II trial aimed at the evaluation of 
the safety and clinical activity of tiragolumab in combination with carboplatin, pemetrexed and 
atezolizumab in the first line treatment of metastatic non-squamous NSCLC patients with 
asymptomatic untreated brain metastases. 
 
At its first interim analysis, the SKYSCRAPER-06 trial did not meet its primary endpoints of 
progression free survival and overall survival, and the study was halted.  
 
The ongoing SKYSCRAPER–01 clinical trial is investigating tiragolumab in combination with 
atezolizumab compared with placebo in combination with atezolizumab in patients with 
previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell 
lung cancer. In this study, patients with brain metastases are excluded. 
 
While this trial was originally designed to investigate the activity of carboplatin, pemetrexed, 
atezolizumab and tiragolumab in patients with non-squamous NSCLC and untreated brain 
metastases, in response to the SKYCRAPER-06 interim analysis, the protocol has been amended 
after the enrollment of the first three patients to an investigation of atezolizumab with or without 
tiragolumab in patients with newly diagnosed metastatic PD-L1 selected NSCLC and untreated 
brain metastases. The first three patients will be included in study as cohort one, and the 
remaining patients will be included as cohort two. 
 
The three patients in cohort one will continue to be treated according to the cohort one schema 
due to ongoing clinical benefit and tumor response to the four-drug regimen. These three patients 
have CNS disease that has improved and there have been no unanticipated toxicity or safety 
signals. The patients have been made aware of the results of SKYSCRAPER-06 and intend to be 
treated per the cohort one schema. This was discussed with Genentech and agreed upon.  
 
 
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
 

15 
 
2.1.1 Primary Objective 
•  To estimate the rate of initiation of salvage radiation therapy to the CNS in patients with 
NSCLC and untreated brain metastases treated with the combination of tiragolumab  and 
atezolizumab with and without chemotherapy.  
 
2.1.2 Secondary Objectives 
1.  To characterize the safety and tolerability of the combination of tiragolumab and 
atezolizumab with and without chemotherapy in patients with NSCLC and untreated 
brain metastasis, particularly Grade ≥ 2 (symptomatic) CNS related adverse event. 
 
2. To estimate the brain metastasis response rate (BMRR; response assessment in neuro-
oncology brain metastases [RANO-BM]). 
3. To estimate the overall response rate (ORR), assessed using RECIST v1.1. 
4. To estimate progression-free survival (PFS). 
5. To estimate overall survival (OS). 
6. To estimate PFS2 after initiation of salvage XRT.  
7. To estimate PD-L1 tumor proportion score (TPS) as a potential predictive biomarker of 
response. 
 
2.2 
Endpoints 
2.2.1 Primary Endpoint 
• Rate of initiation of salvage radiation therapy to the CNS (proportion of patients that 
require salvage radiation therapy to the CNS (within 18 weeks from study initiation)   
2.2.2 Secondary Endpoints 
1. Adverse Events and Serious Adverse Events per CTCAE v5.0 
2. Brain Metastasis Response Rate (BMRR) (per RANO-BM) 
3. Objective Response Rate (ORR) 
4. Progression-free Survival (PFS)  
5. Overall Survival (OS)  
6. Progression-free Survival after initiation of salvage XRT (PFS2) 
7. PD-L1 TPS 
 
3. 
PATIENT SELECTION AND ELIGIBILITY CRITERIA 
3.1 Inclusion Criteria  
• Patients must have histologically or cytologically confirmed NSCLC.  
• In patients treated with the combination of tiragolumab and atezolizumab, patients must 
have PDL1 TPS >50%, as determined by an FDA-approved test. 
• Patients must have asymptomatic brain metastases with at least one untreated evaluable 
(per RANO-BM) brain metastasis of 5 mm or more. A growing lesion previously treated 
with whole brain radiotherapy is acceptable given the lower incidence of radiation 
necrosis. Lesions previously treated with SRS may not be used as target lesions.  
o Patients are not required to have measurable disease outside the CNS per RECIST 

16 
 
1.1. 
• Prior chemotherapy, immunotherapy or radiation given with curative intent in early stage 
or locoregionally advanced NSCLC is permitted, if completed more than 12 months prior 
to initiation of study treatment.  
• Prior radiation with palliative intent in the metastatic setting to non-CNS lesions is 
permitted (no wash-out period).  
• Age ≥18 years.  
• ECOG performance status ≤ 1. 
• Life expectancy ≥12 weeks. 
• Patients must have normal organ and marrow function as defined below within 14 days 
prior to initiation of study treatment: 
o Absolute neutrophil count ≥1,500/mcL without granulocyte colony-stimulating factor 
support 
o Platelets ≥100,000/mcL without transfusion 
o Hemoglobin ≥ 90 g/L (9 g/dL) 
Patients may be transfused to meet this criterion. 
o Total bilirubin ≤1.5x institutional upper limit of normal (ULN) with the following 
exception: 
 Patients with known Gilbert disease:  total bilirubin ≤ 3 × ULN 
o AST(SGOT)/ALT(SGPT) and ALP ≤2.5 × institutional ULN  
o Creatinine Clearance (CrCl) ≥45 mL/min/1.73 m2 (calculated using the Cockcroft-
Gault formula) 
o Serum albumin ≥ 25 g/L (2.5 g/dL) 
o For patients not receiving therapeutic anticoagulation:  INR and aPTT ≤ 1.5 × ULN 
o For patients receiving therapeutic anticoagulation:  stable anticoagulant regimen 
• Negative HIV test at screening 
• Negative hepatitis B surface antigen (HBsAg) test at screening. If positive, an HBV DNA 
test must also be performed to determine if the patient has an HBV infection, which 
would render the patient ineligible. Patients receiving treatment with anti-viral therapy 
for HBV are excluded. 
• Negative hepatitis C antibody. If positive, an HCV RNA test must also be performed to 
determine if the patient has an HCV infection, which would render the patient ineligible. 
• Availability of a representative tumor specimen for exploratory biomarker research. 
• For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraception: 
• Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for 90 days after the final dose of 
tiragolumab, 5 months after the final dose of atezolizumab, and 6 months after the final 
dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin. 
o A woman is considered to be of childbearing potential if she is postmenarchal, has 
not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman 

17 
 
with a tubal ligation is considered to be of childbearing potential. The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
o Examples of contraceptive methods with a failure rate of < 1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. 
o The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not adequate methods of contraception. If required per local 
guidelines or regulations, locally recognized adequate methods of contraception and 
information about the reliability of abstinence will be described in the local Informed 
Consent Form. 
• Women who would like to become pregnant after study treatment discontinuation should 
seek advice on oocyte cryopreservation prior to initiation of study treatment because of 
the possibility of irreversible infertility due to treatment with cisplatin and carboplatin.  
• For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below: 
o With a female partner of childbearing potential, men who are not surgically sterile 
must remain abstinent or use a condom plus an additional contraceptive method that 
together result in a failure rate of < 1% per year during the treatment period, for 90 
days after the final dose of tiragolumab, and for 6 months after the final dose of 
paclitaxel, pemetrexed, gemcitabine, carboplatin or cisplatin. Men must refrain from 
donating sperm during this same period. 
o With a pregnant female partner, men must remain abstinent or use a condom during 
the treatment period for 90 days after the final dose of tiragolumab, and for 6 months 
after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin to 
avoid exposing the embryo.  
o The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not adequate methods of contraception. If required per local 
guidelines or regulations, locally recognized adequate methods of contraception and 
information about the reliability of abstinence will be described in the local Informed 
Consent Form. 
• Men who would like to father a child after study treatment initiation should be advised 
regarding the conservation of sperm prior to treatment because of the possibility of 
irreversible infertility resulting from chemotherapies used in this study. 
• Women of childbearing potential must have a negative serum pregnancy test result within 
14 days prior to initiation of study treatment. 
• Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
• Symptoms related to brain metastases requiring CNS radiation ≤ 2 weeks of treatment 
initiation are exclusionary. Steroids greater than prednisone 10 mg/d or equivalent, or 
anti-epileptic therapy ≤ 2 weeks of treatment initiation are exclusionary. 

18 
 
• Prior systemic therapy for metastatic disease is not allowed.  
• Patients whose tumors harbor oncogenic drivers with an approved 1st line therapy (e.g. 
EGFR, ALK, and ROS1 alterations) are excluded.  
• Patients who are receiving any other investigational agents. 
• Active or history of autoimmune disease or immune deficiency, including, but not limited 
to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, 
granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or 
multiple sclerosis, with the following exceptions: 
o Patients with a history of autoimmune-related hypothyroidism who are on thyroid 
replacement hormone are eligible for the study. 
o Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are 
eligible for the study. 
o Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) 
are eligible for the study provided all of following conditions are met: 
 Rash must cover < 10% of body surface area 
 Disease is well controlled at baseline and requires only topical corticosteroids 
 No occurrence of acute exacerbations of the underlying condition requiring 
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, 
oral calcineurin inhibitors, or high potency or oral corticosteroids within the 
previous 12 months. 
• Positive Epstein-Barr virus (EBV) viral capsid antigen immunoglobulin M (IgM) test at 
screening  
• An EBV polymerase chain reaction (PCR) test should be performed as clinically 
indicated to screen for acute infection or suspected chronic active infection.  Patients 
with a positive EBV PCR test are excluded. 
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active 
pneumonitis on screening chest computed tomography (CT) scan. History of radiation 
pneumonitis or fibrosis in a radiation field is permitted. 
• History of leptomeningeal disease. 
• Active tuberculosis. 
• Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 
months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of 
study treatment, or anticipation of need for a major surgical procedure during the study.  
• History of malignancy other than NSCLC within 2 years prior to screening, with the 
exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS 
rate ≥ 90%). 
• Severe infection within 2 weeks prior to initiation of study treatment, including, but not 
limited to, hospitalization for complications of infection, bacteremia, or severe 
pneumonia. 
• Prior allogeneic stem cell or solid organ transplantation. 
• Any other disease, metabolic dysfunction, physical examination finding, or clinical 

19 
 
laboratory finding that contraindicates the use of an investigational drug, may affect the 
interpretation of the results, or may render the patient at high risk from treatment 
complications. 
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or 
within 5 months after the final dose of atezolizumab. 
• Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids in excess of prednisone 10 mg/d or equivalent, cyclophosphamide, 
azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to 
initiation of study treatment, or anticipation of need for systemic immunosuppressive 
medication during study treatment, with the following exceptions: 
o Patients who received acute, low-dose systemic immunosuppressant medication or a 
one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contrast allergy) are eligible for the study. 
o Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for 
chronic obstructive pulmonary disease (COPD) or asthma, or low-dose 
corticosteroids for orthostatic  
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to atezolizumab, tiragolumab or other agents used in study. 
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or 
fusion proteins. 
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of 
the atezolizumab or tiragolumab formulation. 
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, 
within 90 days after the final dose of tiragolumab, 5 months after the final dose of 
atezolizumab, or 6 months after the final dose of pemetrexed, gemcitabine, paclitaxel, 
carboplatin, or cisplatin 
o Women of childbearing potential must have a negative serum pregnancy test result 
within 14 days prior to initiation of study treatment. 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally by the Study Team.  
Following registration, patients should begin protocol treatment within 7 days.  
Issues that would cause treatment delays should be discussed with the Investigator. The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
• 
Once the signed informed consent has been obtained, all pretreatment evaluations 
have been performed, and patient’s eligibility has been confirmed by the coordination 
team and the treating physician investigator, central site will be notified and a patient 
ID number will be assigned. The patient will be registered at this time. To register a 
patient, the Coordinating Center team must complete the eligibility/registration form 

20 
 
and review the signed Informed Consent and HIPAA authorization form, in addition 
to reviewing all supporting source documentation.number. 
 
5. 
TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential 
risks are described in Section 10. Appropriate dose modifications are described in Section 7.  
 
Regimen Description per cohort assignment 
(To be administered in the order listed below) 
Agent 
Premedications* 
Dose 
Route* 
Schedule 
Cycle 
Length 
Atezolizumab 
See below 
1200 mg in 
250 cc NS 
IV over 60 minutes 
(+/- 15 min.) for 
the 1st infusion, 
over 30 minutes 
(+/- 10 min.) for 
subsequent 
infusions, as 
tolerated 
Day 1 
 
Tiragolumab 
See below 
600 mg  
IV over 60 minutes 
(+/- 15 min.) for 
the 1st infusion, 
over 30 minutes 
(+/- 10 min.) for 
subsequent 
infusions, as 
tolerated 
Day 1 
21 days 
 
 
 
 
Pemetrexed 
Recommended: 
Dexamethasone 4 mg po 
BID day before, day of, 
and day after 
Folic acid 1 mg po daily 
B12 1000 mcg IM q9 
weeks +/-1 week 
500 mg/m2 in 
100 cc NS 
IV over 10 minutes 
Day 1 
Carboplatin 
Granisetron 1 mg IV  
X 1 dose 
AUC 5 in 
250 cc NS 
IV over 30 minutes 
Day 1 
*May be modified based on institutional standards. 
 
5.1.1 Atezolizumab 
Atezolizumab will be administered in a monitored setting where there is immediate access to 
trained personnel and adequate equipment and medicine to manage potentially serious reactions. 
For anaphylaxis precautions, see Appendix B. Atezolizumab infusions will be administered per 
the instructions in Appendix D. 
 

21 
 
Refer to the Investigators Brochure for detailed instructions on drug preparation, storage, and 
administration. 
 
Guidelines for medical management of infusion-related reactions (IRRs) are provided in Section 
7. 
 
5.1.2 Tiragolumab 
Tiragolumab will be administered in a monitored setting where there is immediate access to 
trained personnel and adequate equipment and medicine to manage potentially serious reactions. 
For anaphylaxis precautions, see Appendix B.  
Tiragolumab is to be administered by IV infusion either neat, after dilution in 0.9% NaCl, or 
after dilution in both 0.9% NaCl and manufacturer-provided tiragolumab diluent (Phase I Study 
GO30103 only). In the co-infusion cohort in the Phase Ib portion of Study GO30103, both 
tiragolumab and atezolizumab are added to a single 0.9% NaCl bag for administration. Refer to 
the Pharmacy Manual for additional details. A 0.2 µm in line filter must be used with the 
infusion set during administration. 
Tiragolumab must be prepared for dosing under appropriate aseptic conditions as it does not 
contain antimicrobial preservatives. The dose solution should be used immediately. If not used 
immediately, the total storage time of the dose solution prior to administration should not exceed 
24 hours to limit the risk of microbial growth in case of accidental contamination. The 
recommended storage condition for the dose solution is 2°C–8°C, but dose solutions may be 
stored at room temperature for up to a maximum of 4 hours. 
The compatibility of tiragolumab with diluents other than described is unknown. Tiragolumab 
must not be infused into the same line or cannula concomitantly with other drug infusions, 
including parenteral nutrition. Infusions of blood products and any electrolyte supplementation 
must not occur simultaneously with infusion of tiragolumab. 
5.1.3 Carboplatin and Pemetrexed 
 
Refer to the full prescribing information and labeling for these individual agents. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Patients are permitted to use the following therapies during the study: 
 
• 
Oral contraceptives 
• 
Hormone-replacement therapy 
• 
Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or 
low-molecular-weight heparin) 
• 
Inactivated influenza vaccinations 
• 
Megestrol acetate administered as an appetite stimulant  
• 
Mineralocorticoids (e.g., fludrocortisone) 
• 
Corticosteroids administered for COPD or asthma   

22 
 
• 
Low-dose corticosteroids administered for orthostatic hypotension or adrenocortical 
insufficiency (prednisone >10 mg/d or equivalent ≤ 2 weeks of treatment initiation are 
exclusionary.) 
• 
Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief 
of pain). Treatment with atezolizumab may be continued during palliative radiotherapy.  
• 
Local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency 
ablation). Target lesions treated with local therapy are no longer evaluable for 
radiographic response. 
 
Premedication with antihistamines, antipyretics, and/or analgesics may be administered for the 
second and subsequent atezolizumab infusions only, at the discretion of the investigator. 
 
In general, investigators should manage a patient's care (including preexisting conditions) with 
supportive therapies other than those defined as cautionary or prohibited therapies as clinically 
indicated, per local standard practice. Patients who experience infusion-associated symptoms 
may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-
receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard 
practice. Serious infusion associated events manifested by dyspnea, hypotension, wheezing, 
bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be 
managed with supportive therapies as clinically indicated. 
 
Systemic corticosteroids, immunosuppressive medications, and TNF-a inhibitors may attenuate 
potential beneficial immunologic effects of treatment with atezolizumab.  Therefore, in situations 
in which systemic corticosteroids, immunosuppressive medications, or TNF- a inhibitors would 
be routinely administered, alternatives, including antihistamines, should be considered.  If the 
alternatives are not feasible, systemic corticosteroids immunosuppressive medications, and TNF- 
a inhibitors may be administered at the discretion of the investigator. 
 
Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion 
of the investigator, for the treatment of specific adverse events when associated with 
atezolizumab and/or tiragolumab therapy (refer to Section 7). 
 
Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety 
profiles, and potential drug drug interactions are generally unknown.  However, herbal therapies 
not intended for the treatment of cancer may be used during the study at the discretion of the 
investigator. 
Use of the following concomitant therapies is prohibited as described below: 
Concomitant therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), whether 
health authority approved or experimental, is prohibited for various time periods prior to starting 
study treatment, depending on the agent, and during study treatment, until disease progression is 
documented, and the patient has discontinued study treatment. 
Investigational therapy within 42 days prior to initiation of study treatment and during study 
treatment. 

23 
 
Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of 
study treatment, during study treatment, for 90 days after the final dose of tiragolumab, and for 5 
months after the final dose of atezolizumab. 
Patients being treated with chemotherapy (i.e., carboplatin, cisplatin, pemetrexed, paclitaxel, or 
gemcitabine) should not receive live vaccines. 
Systemic immunostimulatory agents (including, but not limited to, interferons and IL 2) are 
prohibited within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to 
initiation of study treatment and during study treatment because these agents could potentially 
increase the risk for autoimmune conditions when given in combination with atezolizumab and 
tiragolumab. 
 
5.3 
Duration of Therapy 
 
Treatment may continue for 24 months or until one of the following criteria applies: 
 
• 
Intolerable toxicity related to study treatment, including development of an immune 
mediated adverse event determined by the investigator to be unacceptable given the 
individual patient’s potential response to therapy and severity of the event.  
• 
Grade ≥ 2 intracranial hemorrhage, where grade 2 was defined as symptomatic CNS 
hemorrhage or for which medical intervention is indicated 
• 
Any medical condition that may jeopardize the patient’s safety if he or she continues 
study treatment. 
• 
Investigator determines discontinuation is in the best interest of the patient. 
• 
Pregnancy. 
• 
Radiographic disease progression per RECIST v1.1 or RANO-BM and symptomatic 
deterioration attributed to disease progression.  
o 
Patients may continue past objective progression of disease if, in the opinion of the 
treating investigator with consultation of Principal Investigator, the patient 
continues to benefit clinically from therapy.  
o 
Patients with progressive brain metastases will be allowed to undergo salvage local 
therapy, e.g. radiotherapy, and be allowed to continue on trial, if they are clinically 
stable, as deemed by the treating investigator. 
o 
Patients with progressive disease outside the CNS will be allowed to undergo 
salvage local therapy, e.g. radiotherapy, and be allowed to continue on trial, if they 
are clinically stable, as deemed by the treating investigator. 
• 
Loss of clinical benefit as determined by the investigator after an integrated assessment 
of radiographic and biochemical data, local biopsy results (if available), and clinical 
status (e.g., symptomatic deterioration such as pain secondary to disease) 
 
The primary reason for study treatment discontinuation should be documented in the patient’s 
medical records. Patients who discontinue study treatment prematurely will not be replaced. 
 
Patients will return to the clinic for a treatment discontinuation visit ≤ 30 days after the last dose 
of study treatment. The visit at which response assessment shows progressive disease may be 
used as the treatment discontinuation visit. Patients who discontinue study treatment for any 

24 
 
reason other than progressive disease or loss of clinical benefit will continue to undergo tumor 
response assessments as outlined in the schedule of activities. 
 
Patients have the right to voluntarily withdraw from the study at any time for any reason. In 
addition, the investigator has the right to withdraw a patient from the study at any time. Reasons 
for withdrawal from the study may include, but are not limited to, the following: 
• 
Withdrawal of consent 
• 
Study termination or site closure 
• 
Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the Investigator 
 
Every effort should be made to obtain information on patients who withdraw from the study. The 
primary reason for withdrawal from the study should be documented in the patient’s medical 
records. If a patient requests to be withdrawn from the study, this request must be documented in 
the source documents and signed by the investigator. Patients who withdraw from the study will 
not be replaced. 
 
If a patient withdraws from the study, the study staff may use a public information source (e.g., 
county records) to obtain information about survival status. 
 
5.4 
Duration of Follow-up 
 
After treatment discontinuation, information on survival follow-up and new anti-cancer therapy 
will be collected via telephone calls, patient medical records, and/or clinic visits approximately 
every 3 months until death (unless the patient withdraws consent or the Investigator terminates 
the study). 
 
Patients will be followed for a minimum of 30 days after removal from study and, whenever 
possible, until death. Patients removed from study for unacceptable adverse event(s) will be 
followed until resolution or stabilization of the adverse event. 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Atezolizumab and Tiragolumab Dosing 
 
There will be no dose reductions for tiragolumab and/or atezolizumab in this study. 
 
Study treatment may be temporarily suspended as appropriate for management of toxicity. On 
the basis of the available characterization of mechanism of action, tiragolumab may cause 
adverse events similar to but independent of atezolizumab, may exacerbate the frequency or 
severity of atezolizumab related adverse events, or may have non overlapping toxicities with 
atezolizumab. In addition, given the evolving knowledge about the proposed regimen, 
investigators must assume that all components of the study treatment may have caused or 
contributed to the observed AE, without making inference of causality between the observed AE 
and a particular drug(s) composing the investigational regimen. As such, dose interruptions or 
treatment discontinuation in response to immune mediated adverse events should be applied to 

25 
 
all components of the study regimen, carboplatin, pemetrexed, tiragolumab and atezolizumab.  
 
Study treatment may be held for a maximum of approximately 12 weeks (or approximately 4 
cycles). If study treatment is interrupted for approximately longer than 12 weeks (or 
approximately 4 cycles), the patient must permanently discontinue all components of the study.  
 
Study treatment may be suspended for reasons other than toxicity (e.g. surgical procedures) with 
Principal Investigator approval. The investigator and the Principal Investigator will determine the 
acceptable length of treatment interruption.  
 
6.2 
Carboplatin and Pemetrexed Dosing  
 
For adverse events associated with carboplatin and pemetrexed, refer to guidelines in the 
applicable prescribing information.  
 
7. 
Management Guidelines For Immune-Related Adverse Events 
 
Toxicities associated or possibly associated with atezolizumab or tiragolumab treatment should 
be managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology, when 
clinically indicated. 
Although most immune-mediated adverse events observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications. Discontinuation of atezolizumab and/or tiragolumab may 
not have an immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents.  
The investigator should consider the benefit-risk balance for a given patient prior to further 
administration of atezolizumab and/or tiragolumab.  
 
7.1 
Pulmonary Events 
 
Pulmonary events may present as new or worsening cough, chest pain, fever, dyspnea, fatigue, 
hypoxia, pneumonitis, and pulmonary infiltrates.  Patients will be assessed for pulmonary signs 
and symptoms throughout the study.    
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. COVID-19 
evaluation should be performed per institutional guidelines where relevant. Management 
guidelines for pulmonary events are provided in Table 1. 
 
Table 1 
Management Guidelines for Pulmonary Events, Including Pneumonitis 

26 
 
7.2 
Hepatic Events 
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be monitored 
throughout study treatment. Management guidelines for hepatic events are provided in Table 2. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of 
the next dose of study drugs. 
Event 
Management 
Pulmonary 
event, Grade 1 
• Continue atezolizumab and tiragolumab and monitor closely. 
• Re-evaluate on serial imaging. 
• Consider patient referral to pulmonary specialist. 
• For Grade 1 pneumonitis, consider withholding atezolizumab and tiragolumab. 
Pulmonary 
event, Grade 2 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset. a 
• Refer patient to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL with or without transbronchial biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab 
and tiragolumab, permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator.  
• For recurrent events or events with no improvement after 48-72 hours of 
corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4 
• Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• Oral or IV broad-spectrum antibiotics should be administered in parallel to the 
immunosuppressive treatment. 
• Bronchoscopy or BAL with or without transbronchial biopsy is recommended. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
BAL = bronchoscopic alveolar lavage. 
a  Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., > 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an assessment of benefit-
risk by the investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day 
oral prednisone before atezolizumab and tiragolumab can be resumed. 
 

27 
 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Table 2 
Management Guidelines for Hepatic Events 
Event 
Management 
Guidelines for patients  
Hepatic event, Grade 
1 
• 
Continue atezolizumab and tiragolumab. 
• 
Monitor LFTs until values resolve to within normal limits or to baseline 
values. 
Hepatic event, Grade 
2 
All events: 
• 
Monitor LFTs more frequently until return to baseline values.  
Events of > 5 days’ duration: 
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. 
b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator.  
Hepatic event, Grade 
3 or 4 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 
Consider patient referral to gastrointestinal specialist for evaluation and 
liver biopsy to establish etiology of hepatic injury.  
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
LFT = liver function test. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be based on an assessment of benefit-risk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
 
 
7.3 
Gastrointestinal Events 
Management guidelines for diarrhea or colitis are provided in Table 3. 
 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or 
bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy to 

28 
 
check for inflammation and lymphocytic infiltrates to confirm colitis diagnosis.  
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
• 
Continue atezolizumab and tiragolumab. 
• 
Initiate symptomatic treatment. 
• 
Endoscopy is recommended if symptoms persist for > 7 days. 
• 
Monitor closely. 
Diarrhea or 
colitis, Grade 2 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset. a 
• Initiate symptomatic treatment. 
• If strong clinical suspicion for immune-mediated colitis, start empiric IV steroids while 
waiting for definitive diagnosis. 
• Patient referral to GI specialist is recommended. 
• For recurrent events or events that persist > 5 days, initiate treatment with 
corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.  If the event does not 
improve within 48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
Diarrhea or 
colitis, Grade 3 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset. a 
• Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement.  If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
Diarrhea or 
colitis, Grade 4 
• 
Permanently discontinue atezolizumab and tiragolumab.  
• 
Refer patient to GI specialist for evaluation and confirmation biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
GI: gastrointestinal. 
 a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The acceptable length 
of the extended period of time must be based on an assessment of benefit-risk by the investigator and in alignment 
with the protocol requirements for the duration of treatment and documented by the investigator. 

29 
 
Event 
Management 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
 
7.4 
Endocrine Events 
Management guidelines for endocrine events are provided in Table 4. 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies. The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine and 
thyroxine levels should be measured to determine whether thyroid abnormalities are present. 
Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing hormone, 
follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone [ACTH] 
levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain (with 
detailed pituitary sections) may help to differentiate primary pituitary insufficiency from primary 
adrenal insufficiency. 
 
Table 4 
Management Guidelines for Endocrine Events 
 
Event 
Management 
Grade 1 hypothyroidism • Continue atezolizumab and tiragolumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
Grade 2 
hypothyroidism 
• Consider withholding atezolizumab and tiragolumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab and tiragolumab when symptoms are 
controlled, and thyroid function is improving. 
Grade 3 and 4 
hypothyroidism 
• Withhold atezolizumab and tiragolumab. 
• Initiate treatment with thyroid replacement hormone. 
• Monitor TSH closely. 
• Refer to an endocrinologist. 
• Admit patient to the hospital for developing myxedema 
(bradycardia, hypothermia, and altered mental status). 
• Resume atezolizumab and tiragolumab when symptoms are 
controlled, and thyroid function is improving. 
• Permanently discontinue atezolizumab and tiragolumab and contact 
the principal investigator for life-threatening immune-mediated 
hypothyroidism. c 
Grade 1 
hyperthyroidism 
TSH ≥ 0.1 mU/L and < 0.5 mU/L: 
• Continue atezolizumab and tiragolumab. 

30 
 
Event 
Management 
• Monitor TSH every 4 weeks. 
• Consider patient referral to endocrinologist. 
TSH < 0.1 mU/L: 
• Follow guidelines for Grade 2 hyperthyroidism. 
• Consider patient referral to endocrinologist. 
Grade 2 
hyperthyroidism 
• Consider withholding atezolizumab and tiragolumab. 
• Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
• Consider patient referral to endocrinologist. 
• Resume atezolizumab and tiragolumab when symptoms are 
controlled, and thyroid function is improving. 
Grade 3 and 4 
hyperthyroidism 
• Withhold atezolizumab and tiragolumab. 
• Initiate treatment with anti-thyroid drugs such as methimazole 
or carbimazole as needed. 
• Refer to an endocrinologist. 
• Resume atezolizumab and tiragolumab when symptoms are 
controlled, and thyroid function is improving. 
• Permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator for life-threatening immune-
mediated hyperthyroidism.  
Symptomatic adrenal 
insufficiency, 
Grade 2-4  
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks 
after event onset. a 
• 
Refer patient to endocrinologist. 
• 
Perform appropriate imaging. 
• 
Initiate treatment with corticosteroids equivalent to 1-
2 mg/kg/day IV methylprednisolone and convert to 1-
2 mg/kg/day oral prednisone or equivalent upon improvement. 
• 
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab and tiragolumab. b 
• If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab and tiragolumab, permanently discontinue 
atezolizumab and tiragolumab and contact the principal 
investigator.  
Hyperglycemia, 
Grade 1 or 2  
• 
Continue atezolizumab and tiragolumab. 
• 
Investigate for diabetes. If patient has Type 1 diabetes, treat as 
a Grade 3 event. If patient does not have Type 1 diabetes, treat 
as per institutional guidelines. 
• Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
• 
Withhold atezolizumab and tiragolumab. 
• 
Initiate treatment with insulin. 
• 
Evaluate for diabetic ketoacidosis and manage as per 
institutional guidelines. 

31 
 
Event 
Management 
• 
Monitor for glucose control. 
• Resume atezolizumab and tiragolumab when symptoms 
resolve and glucose levels are stable. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3  
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks 
after event onset. a 
• 
Refer patient to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with corticosteroids equivalent to 1-
2 mg/kg/day IV methylprednisolone and convert to 1-
2 mg/kg/day oral prednisone or equivalent upon improvement. 
• 
Initiate hormone replacement if clinically indicated. 
• 
If event resolves to Grade 1 or better, resume atezolizumab 
and tiragolumab. b 
• 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab and tiragolumab, permanently 
discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4  
• 
Permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator.  
• 
Refer patient to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with corticosteroids equivalent to 1-
2 mg/kg/day IV methylprednisolone and convert to 1-
2 mg/kg/day oral prednisone or equivalent upon improvement. 
• Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., ≥ 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an assessment of 
benefit-risk by the investigator and in alignment with the protocol requirements for the duration of 
treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 
mg/day oral prednisone before atezolizumab and tiragolumab can be resumed. 
 
 
7.5 
Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). Management 
guidelines for ocular events are provided in Table 5. 
 
Table 5 
Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
Continue atezolizumab and tiragolumab. 
Patient referral to ophthalmologist is strongly recommended. 

32 
 
Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive 
therapy. 
If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset. a 
Patient referral to ophthalmologist is strongly recommended. 
Initiate treatment with topical corticosteroid eye drops and topical immunosuppressive 
therapy. 
If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
If event does not resolve to Grade 1 or better while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
Ocular event, 
Grade 3 or 4 
Permanently discontinue atezolizumab and tiragolumab.  
Refer patient to ophthalmologist. 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral prednisone.  
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., ≥ 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit-risk by the investigator 
and in alignment with the protocol requirements for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
 
7.6 
Immune-Mediated Cardiac Events 
 
Management guidelines for cardiac events are provided in Table 6. 
Immune-Mediated Myocarditis 
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope.  Myocarditis may also be a clinical manifestation of 
myositis or associated with pericarditis (see section on pericardial disorders below) and should 
be managed accordingly.  Immune-mediated myocarditis needs to be distinguished from 
myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent 
history of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 6. 
 
Immune-Mediated Pericardial Disorders 

33 
 
Immune-mediated pericarditis should be suspected in any patient presenting with chest pain and 
may be associated with immune-mediated myocarditis (see section on myocarditis above). 
Immune-mediated pericardial effusion and cardiac tamponade should be suspected in any patient 
presenting with chest pain associated with dyspnea or hemodynamic instability.  
Patients should be evaluated for other causes of pericardial disorders such as infection 
(commonly viral), cancer related (metastatic disease or chest radiotherapy), cardiac injury related 
(post myocardial infarction or iatrogenic), and autoimmune disorders, and should be managed 
accordingly. 
All patients with suspected pericardial disorders should be urgently evaluated by performing an 
ECG, chest X-ray, transthoracic echocardiogram, and cardiac MRI as appropriate per 
institutional guidelines.  A cardiologist should be consulted.  Pericardiocentesis should be 
considered for diagnostic or therapeutic purposes, if clinically indicated. 
Patients with signs and symptoms of pericarditis, pericardial effusion, or cardiac tamponade, in 
the absence of an identified alternate etiology, should be treated according to the guidelines in 
Table 6.  Withhold treatment with atezolizumab and tiragolumab for Grade 1 pericarditis and 
conduct a detailed cardiac evaluation to determine the etiology and manage accordingly. 
Table 6 
Management Guidelines for Immune-Mediated Cardiac Events 
Event 
Management 
Immune-mediated 
myocarditis, Grades 2-
4 
 
Immune-mediated 
pericardial disorders, 
Grades 2-4 
• Permanently discontinue atezolizumab and tiragolumab and contact 
the principal investigator. 
• Refer patient to cardiologist. 
• Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, VAD, or 
pericardiocentesis as appropriate. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥ 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
 
7.7 
Infusion-related Reactions 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab or tiragolumab. 
However, patients who experience an infusion-related reaction (IRR) with Cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited in treating 
atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 

34 
 
 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with tiragolumab and atezolizumab. These reactions, which are thought to be due to 
release of cytokines and/or other chemical mediators, occur within 24 hours of atezolizumab or 
tiragolumab administration and are generally mild to moderate in severity. Guidelines for 
medical management of IRRs during Cycle 1 are provided in Table 7. For subsequent cycles, 
IRRs should be managed according to institutional guidelines. 
 
Table 7 
Management Guidelines for Infusion-related Reactions 
Event 
Management 
IRR, Grade 1  
• 
Reduce infusion rate to half the rate being given at the time of event onset. 
• 
After the event has resolved, the investigator should wait for 30 minutes while 
delivering the infusion at the reduced rate. 
• 
If the infusion is tolerated at the reduced rate for 30 minutes after symptoms 
have resolved, the infusion rate may be increased to the original rate. 
IRR, Grade 2 
• 
Interrupt infusion. 
• 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic medication, glucocorticoids, epinephrine, bronchodilators, oxygen, 
IV fluids). 
• 
After symptoms have resolved to baseline, resume infusion at half the rate 
being given at the time of event onset. 
• 
For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics and monitor closely for IRRs. 
IRR, Grade 3 or 4 
• 
Stop infusion. 
• 
Administer aggressive symptomatic treatment (e.g., oral or IV antihistamine, 
anti-pyretic medication, glucocorticoids, epinephrine, bronchodilators, oxygen, 
IV fluids). 
• 
Permanently discontinue atezolizumab or tiragolumab and contact the 
principal investigator.  
IRR: infusion-related reaction. 
 
7.8 
Cytokine-release Syndrome 
No premedication is indicated for the administration of Cycle 1 of atezolizumab or tiragolumab. 
However, patients who experience CRS with atezolizumab or tiragolumab may receive premedication 
with antihistamines, anti pyretics, and/or analgesics (e.g., acetaminophen) for subsequent infusions. 
CRS is defined as a supraphysiologic response following administration of any immune therapy that 
results in activation or engagement of endogenous or infused T cells and/or other immune effector 
cells. Symptoms can be progressive, always include fever at the onset, and may include hypotension, 
capillary leak (hypoxia), and end-organ dysfunction (Lee et al. 2019). CRS has been well documented 
with chimeric antigen receptor T-cell therapies and bispecific T-cell engager antibody therapies but 
has also been reported with immunotherapies that target PD-1 or PD-L1 (Rotz et al. 2017; Adashek 
and Feldman 2019), including atezolizumab. 
Severe COVID-19 is associated with a CRS involving the inflammatory cytokines interleukin (IL)-6, 
IL-10, IL-2, and IFN-γ (Merad and Martin 2020). If a patient develops suspected CRS during the 

35 
 
Event 
Management 
study, a differential diagnosis should include COVID-19, which should be confirmed or refuted 
through assessment of exposure history, appropriate laboratory testing, and clinical or radiologic 
evaluations per investigator judgment. If a diagnosis of COVID-19 is confirmed, the disease should 
be managed as per local or institutional guidelines. 
Guidelines for medical management of CRS are provided in Table 8. 
Table 8 
Management Guidelines for Cytokine-Release Syndrome 
Event 
Management 
Grade 1 a  
Fever b with or without 
constitutional 
symptoms 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
• If the infusion is tolerated at the reduced rate for 30 minutes, the infusion rate 
may be increased to the original rate. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment, c including maintenance of IV fluids for 
hydration. 
• In case of rapid decline or prolonged CRS (> 2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per Grade 2. 
• For subsequent infusions, consider administration of oral premedication with 
antihistamines, anti-pyretics, and/or analgesics, and monitor closely for CRS. 
Grade 2 a 
Fever b with at least one 
of the following: 
• Hypotension not 
requiring 
vasopressors 
• Hypoxia requiring 
low-flow oxygen d by 
nasal cannula or 
blow-by 
• Immediately interrupt infusion. 
• Upon symptom resolution, wait for 30 minutes and then restart infusion at half 
the rate being given at the time of event onset. 
• If symptoms recur, discontinue infusion of this dose. 
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus as needed. 
• Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate). Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and 
symptoms of HLH or MAS as described in this appendix. 
• Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  
• Consider hospitalization until complete resolution of symptoms. If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize patient 
(monitoring in the ICU is recommended), permanently discontinue atezolizumab 
or tiragolumab and contact the principal investigator.  
• If symptoms resolve to Grade 1 or better for 3 consecutive days, the next dose of 
atezolizumab or tiragolumab may be administered. For subsequent infusions, 

36 
 
Event 
Management 
consider administration of oral premedication with antihistamines, anti-pyretics, 
and/or analgesics and monitor closely for CRS. 
• If symptoms do not resolve to Grade 1 or better for 3 consecutive days, contact 
the principal investigator. 
Grade 3 a 
Fever b with at least one 
of the following: 
• Hypotension 
requiring  a 
vasopressor (with or 
without vasopressin) 
Hypoxia requiring 
high-flow oxygen d by 
nasal cannula, face 
mask, non-rebreather 
mask, or Venturi mask 
• Permanently discontinue atezolizumab or tiragolumab and contact the principal 
investigator.  
• Administer symptomatic treatment. c 
• For hypotension, administer IV fluid bolus and vasopressor as needed. 
• Monitor cardiopulmonary and other organ function closely; monitoring in the 
ICU is recommended. Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms 
of HLH or MAS as described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy.  
• Hospitalize patient until complete resolution of symptoms. If no improvement 
within 24 hours, manage as per Grade 4, that is, admit patient to ICU and initiate 
hemodynamic monitoring, mechanical ventilation, and/or IV fluids and 
vasopressors as needed; for patients who are refractory to anti-cytokine therapy, 
experimental treatments may be considered at the discretion of the investigator. 
Grade 4 a 
Fever b with at least one 
of the following: 
• Hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
• Permanently discontinue atezolizumab or tiragolumab and contact the principal 
investigator.  
• Administer symptomatic treatment. c 
• Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed. Monitor other organ 
function closely. Manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• Rule out other inflammatory conditions that can mimic CRS (e.g., sepsis). If no 
improvement within 24 hours, initiate workup and assess for signs and symptoms 
of HLH or MAS as described in this appendix. 
• Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• Consider anti-cytokine therapy. For patients who are refractory to anti-cytokine 
therapy, experimental treatments e may be considered at the discretion of the 
investigator. 
• Hospitalize patient until complete resolution of symptoms. 
 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway pressure; 
CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; CRS = cytokine-release syndrome; 
CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report Form; 
HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care unit; MAS = macrophage activation syndrome; 
NCCN = National Cancer Comprehensive Network; NCI = National Cancer Institute. 
The management guidelines have been adapted from NCCN guidelines for management of CAR T-cell-related 
toxicities (Version 2.2019). 

37 
 
Event 
Management 
a Grading system for management guidelines is based on the ASTCT CRS Consensus Grading Scale. NCI CTCAE 
v1.1 and the ASTCT CRS Consensus Grading Scale should be used when reporting severity of CRS on the Adverse 
Event eCRF. NCI CTCAE v1.1 should be used when reporting severity of organ toxicities associated with CRS on 
the dedicated Cytokine Release Syndrome eCRF. Organ toxicities associated with CRS should not influence overall 
CRS grading. 
b Fever is defined as temperature ³ 38°C not attributable to any other cause. In patients who develop CRS and then 
receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when subsequently 
determining event severity (grade). In this case, the grade is driven by the presence of hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, and/or 
oxygen. For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per institutional 
practice. 
d Low flow is defined as oxygen delivered at £ 6 L/min, and high flow is defined as oxygen delivered at > 6 L/min. 
e Refer to Riegler et al. (2019) for information on experimental treatments for CRS. 
 
7.9 
Pancreatic Events 
 
The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate 
workup should include an evaluation for ductal obstruction, as well as serum amylase and lipase 
tests. Management guidelines for pancreatic events, including pancreatitis, are provided in 
Table 9. 
 
Table 9 
Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase > 1.5-2.0 x ULN: 
• 
Continue atezolizumab and tiragolumab. 
• 
Monitor amylase and lipase weekly. 
• 
For prolonged elevation (e.g., > 3 weeks), consider treatment with 
corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase > 2.0-5.0 x ULN: 
• 
Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
• 
Refer patient to GI specialist. 
• 
Monitor amylase and lipase every other day. 
• 
If no improvement, consider treatment with corticosteroids equivalent to 
1-2 mg/kg/day oral prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue and tiragolumab 
atezolizumab and contact the principal investigator.  
• 
For recurrent events, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator.  
Immune-mediated 
pancreatitis, Grade 2 or 3 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
• Refer patient to GI specialist. 

38 
 
Event 
Management 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator. 
• For recurrent events, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator.  
Immune-mediated 
pancreatitis, Grade 4 
• Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• Refer patient to GI specialist. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.  
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
GI = gastrointestinal. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., 
≥ 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on an assessment of benefit-risk by the investigator and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab and tiragolumab can be 
resumed. 
 
7.10 Dermatologic Events 
 
The majority of cases of rash reported with the use of atezolizumab and/or tiragolumab were 
mild in severity and self-limiting, with or without pruritus. Although uncommon, cases of severe 
cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis 
have been reported with atezolizumab. A dermatologist should evaluate persistent and/or severe 
rash or pruritus. A biopsy should be considered unless contraindicated. Management guidelines 
for dermatologic events are provided in Table 10. 
 
Table 10 Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
• 
Continue atezolizumab and tiragolumab. 
• 
Consider treatment with topical corticosteroids and/or other symptomatic therapy 

39 
 
(e.g., antihistamines). 
Dermatologic 
event, Grade 2  
• 
Continue atezolizumab and tiragolumab. 
• 
Consider patient referral to dermatologist. 
• 
Initiate treatment with topical corticosteroids. 
• 
Consider treatment with higher-potency topical corticosteroids if event does not 
improve.  
• 
If unresponsive to topical corticosteroids, consider oral prednisone 0.5 mg/kg/day. 
Dermatologic 
event, Grade 3  
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset.a 
• 
Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 10 mg/day oral prednisone, 
increasing dose to 1-2 mg/kg/day if event does not improve within 48-72 hours. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and contact the principal 
investigator.  
Dermatologic 
event, Grade 4 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the principal 
investigator.  
Stevens-Johnson 
syndrome or toxic 
epidermal 
necrolysis (any 
grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal necrolysis: 
• Withhold atezolizumab and tiragolumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis. 
• Confirm diagnosis by referring patient to a specialist (dermatologist, ophthalmologist 
or urologist as relevant) for evaluation and, if indicated, biopsy. 
• Follow the applicable treatment and management guidelines above. 
If Stevens-Johnson syndrome or toxic epidermal necrolysis, permanently discontinue 
atezolizumab and tiragolumab. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., 
≥ 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of ≤ 10 mg/day oral prednisone.  The acceptable length of the extended 
period of time must be based on an assessment of benefit-risk by the investigator and in alignment with the 
protocol requirements for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab and tiragolumab can be 
resumed. 
 
7.11 Neurologic Disorders 
 
Patients may present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic 
workup is essential for an accurate characterization to differentiate between alternative 
etiologies. Management guidelines for neurologic disorders are provided in 11, with specific 
guidelines for myelitis provided in Table 12. 
 
Table 11 Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-
• 
Continue atezolizumab and tiragolumab. 

40 
 
mediated 
neuropathy, 
Grade 1 
• 
Investigate etiology. 
• 
Any cranial nerve disorder (including facial paresis) should be managed as per 
Grade 2 management guidelines below. 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 2 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset. a 
• Investigate etiology and refer patient to neurologist. 
• Initiate treatment as per institutional guidelines. 
• For general immune-mediated neuropathy: 
– 
If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
– 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator. c 
• For facial paresis: 
– 
If event resolves fully, resume atezolizumab and tiragolumab b 
• 
If event does not resolve fully while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator. c 
Immune-
mediated 
neuropathy, 
including facial 
paresis, Grade 3 
or 4 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of corticosteroids equivalent to 1-2 mg/kg/day oral or IV 
prednisone. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The acceptable 
length of the extended period of time must be determined by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
 
 
Table 12 Management Guidelines for Immune-Mediated Myelitis 
 
Event 
Management 
Immune-mediated myelitis, 
Grade 1 
• 
Continue atezolizumab and tiragolumab unless symptoms worsen 
or do not improve. 
• 
Investigate etiology and refer patient to a neurologist.  
Immune-mediated myelitis, 
Grade 2 
• 
Permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator. 
• 
Investigate etiology and refer patient to a neurologist. 

41 
 
• 
Rule out infection. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day 
oral prednisone. 
Immune-mediated myelitis, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator. 
• 
Refer patient to a neurologist. 
• 
Initiate treatment as per institutional guidelines. 
 
7.12 Immune-mediated Meningoencephalitis 
 
Immune-mediated meningoencephalitis should be suspected in any patient presenting with signs 
or symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, 
neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of 
consciousness. Encephalopathy from metabolic or electrolyte imbalances needs to be 
distinguished from potential meningoencephalitis resulting from infection (bacterial, viral, or 
fungal) or progression of malignancy, or secondary to a paraneoplastic process.  
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed and a neurologist should 
be consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in 13. 
 
Table 13 Management Guidelines for Immune-Mediated Meningoencephalitis 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 
Refer patient to neurologist. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 
1 month. 
 
 
7.13 Renal Events 
 
Eligible patients must have adequate renal function, and renal function, including serum 
creatinine, should be monitored throughout study treatment. Patients with abnormal renal 
function should be evaluated and treated for other more common etiologies (including prerenal 
and postrenal causes, and concomitant medications such as non-steroidal anti-inflammatory 

42 
 
drugs). Refer the patient to a renal specialist if clinically indicated. A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment. 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in 14. 
 
Table 14 Management Guidelines for Renal Events  
Event 
Management 
Renal event, Grade 1 
• 
Continue atezolizumab and tiragolumab. 
• 
Monitor kidney function, including creatinine, closely until values resolve 
to within normal limits or to baseline values.  
Renal event, Grade 2 
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event 
onset.a 
• 
Refer patient to renal specialist. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab and 
tiragolumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab and tiragolumab, permanently discontinue atezolizumab and 
tiragolumab and contact the principal investigator.  
Renal event, Grade 3 
or 4 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator.  
• 
Refer patient to renal specialist and consider renal biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day oral 
prednisone. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 
month. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., 
> 12 weeks after event onset) to allow for corticosteroids (if initiated) to be reduced 
to the equivalent of ≤ 10 mg/day oral prednisone.  The acceptable length of the 
extended period of time must be based on the investigator’s benefit-risk assessment and in 
alignment with the protocol requirements for the duration of treatment and documented 
by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the 
equivalent of ≤ 10 mg/day oral prednisone before atezolizumab and tiragolumab can 
be resumed. 
 
 
7.14 Immune-mediated Myositis 
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders. Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 

43 
 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy. Patients with possible 
myositis should be referred to a rheumatologist or neurologist. Patients with possible myositis 
should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 15. 
 
Table 15 Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, 
Grade 1 
• 
Continue atezolizumab and tiragolumab. 
• 
Refer patient to rheumatologist or neurologist.  
• 
Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, 
Grade 2 
• 
Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset a 
and contact the principal investigator. 
• 
Refer patient to rheumatologist or neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or equivalent 
upon improvement. 
• 
If corticosteroids are initiated and event does not improve within 48 hours after 
initiating corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
• 
If event does not resolve to Grade 1 or better while withholding atezolizumab 
and tiragolumab, permanently discontinue atezolizumab and tiragolumab and 
contact the principal investigator.  
Immune-
mediated 
myositis, 
Grade 3 
• Withhold atezolizumab and tiragolumab for up to 12 weeks after event onset a and 
contact the principal investigator. 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely compromised 
(e.g., cardiac or respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, resume atezolizumab and tiragolumab. b 
• If event does not resolve to Grade 1 or better while withholding atezolizumab and 
tiragolumab, permanently discontinue atezolizumab and tiragolumab and contact 
the principal investigator.  
• For recurrent events, treat as a Grade 4 event. 
Immune-
mediated 
myositis, 
• Permanently discontinue atezolizumab and tiragolumab and contact the principal 
investigator.  

44 
 
Grade 4 
• Refer patient to rheumatologist or neurologist. 
• Initiate treatment as per institutional guidelines. 
• Respiratory support may be required in more severe cases. 
• Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely compromised 
(e.g., cardiac or respiratory symptoms, dysphagia, or weakness that severely 
limits mobility); convert to 1-2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• If event does not improve within 48 hours after initiating corticosteroids, consider 
adding an immunosuppressive agent. 
• If event resolves to Grade 1 or better, taper corticosteroids over ≥ 1 month. 
a Atezolizumab and tiragolumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤ 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on the investigator’s benefit-risk assessment and 
in alignment with the protocol requirements for the duration of treatment and documented by the investigator.  
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤ 10 mg/day oral 
prednisone before atezolizumab and tiragolumab can be resumed. 
7.15 Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are considered 
to be potential risks for atezolizumab.  
Clinical and laboratory features of severe CRS overlap with HLH, and HLH should be 
considered when CRS presentation is atypical or prolonged.   
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
• Fever ≥ 38.5°C 
• Splenomegaly 
• Peripheral blood cytopenia consisting of at least two of the following: 
o Hemoglobin < 90 g/L (9 g/dL) (< 100 g/L [10 g/dL] for infants < 4 weeks old) 
o Platelet count < 100 x 109/L (100,000/µL) 
o ANC < 1.0 x 109/L (1000/µL) 
• Fasting triglycerides > 2.992 mmol/L (265 mg/dL) and/or fibrinogen < 1.5 g/L 
(150 mg/dL) 
• Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• Low or absent natural killer cell activity 
• Ferritin > 500 mg/L (500 ng/mL) 
• Soluble IL-2 receptor (soluble CD25) elevated ≥ 2 standard deviations above age-
adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 

45 
 
having MAS if the following criteria are met: 
• Ferritin > 684 mg/L (684 ng/mL) 
• At least two of the following: 
o Platelet count ≤ 181 x 109/L (181,000/µL) 
o AST ≥ 48 U/L 
o Triglycerides > 1.761 mmol/L (156 mg/dL) 
o Fibrinogen ≤ 3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in Table 16.  
 
Table 16 Management Guidelines for Suspected Hemophagocytic Lymphohistiocytosis or 
Macrophage Activation Syndrome 
Event 
Management 
Suspected HLH 
or MAS 
• 
Permanently discontinue atezolizumab and tiragolumab and contact the 
principal investigator. 
• 
Consider patient referral to hematologist. 
• 
Initiate supportive care, including intensive care monitoring if indicated 
per institutional guidelines. 
• 
Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• 
If event does not respond to treatment within 24 hours, contact the 
principal investigator and initiate treatment as appropriate according to 
published guidelines (La Rosée 2015; Schram and Berliner 2015; 
La Rosée et al. 2019). 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
8. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 10.1. 
 
8.1 
Tiragolumab 
 
Tiragolumab is provided in two configurations: 
• The initial formulation and vial configuration (RO709-2284/F01-01), supplied in single-
dose 20 mL glass vials containing 20 mL of tiragolumab drug product and buffered in 
histidine solution containing polysorbate 20, sucrose, and water for injection (WFI). The 
approximate concentration of tiragolumab antibody in the vials is 20 mg/mL. This 
formulation and configuration is currently being used in ongoing trials. A matching 
placebo is provided in single-dose 20 mL glass vials containing 20 mL of histidine 
solution containing polysorbate 20, sucrose, and WFI. 
• A subsequent formulation and vial configuration (RO709-2284/F03-01), supplied in 
single-dose 15 mL glass vials containing 10 mL of tiragolumab drug product and 
buffered in histidine solution containing polysorbate 20, sucrose, L-methionine, and WFI. 

46 
 
The approximate concentration of tiragolumab antibody in the vials is 60 mg/mL. This 
formulation and configuration is currently being used in ongoing trials. A matching 
placebo is provided in single-dose 15 mL glass vials containing 10 mL of histidine 
solution containing polysorbate 20, sucrose, L-methionine, and WFI. 
8.2 
Atezolizumab 
 
The atezolizumab 1200 mg drug product will be supplied in a single-use, 20-mL USP/Ph. Eur. 
Type 1 glass vial as a colorless to slightly yellow, sterile, preservative-free clear liquid solution 
intended for IV administration. The vial is designed to deliver 20 mL (1200 mg) of atezolizumab 
solution but may contain more than the stated volume to enable delivery of the entire 20-mL 
volume. 
 
8.3 
Carboplatin and Pemetrexed 
 
Carboplatin and pemetrexed will be supplied commercially. Refer to the full prescribing 
information and labeling for these individual agents. 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
Study Design/Endpoints 
 
This is a phase II clinical trial aimed at the evaluation of the safety and clinical activity of 
tiragolumab in combination with atezolizumab with or without chemotherapy in the 1st line 
treatment of non-squamous NSCLC patients with untreated brain metastases. Patients in cohort 1 
and cohort 2 will be pooled for all safety and efficacy analyses. 
 
 
Primary Endpoint: 
• Proportion of patients that require salvage radiation therapy to the CNS (within 18 weeks 
from treatment initiation) 
 
Secondary Endpoints:  
• Adverse Events and Serious Adverse Events per CTCAE v5.0. 
• Brain Metastasis Response Rate (BMRR, per RANO-BM) 
• Objective response rate (ORR), assessed using RECIST v1.1 
• Progression-free survival (PFS) 
• Intracranial PFS 
• Overall Survival (OS) 
• PFS2 after initiation of salvage XRT 
• PD-L1 TPS 
 
9.2 
Statistical Analysis Plan 
 
Response-evaluable patients (i.e., evaluable for salvage radiation therapy, and ORR) are those 
who receive at least one dose of all four components of the combination therapy and have at least 

47 
 
one post-treatment scan. For safety endpoints (intracranial hemorrhage and adverse events) and 
survival endpoints (PFS, PFS2 and OS), participants must have received at least one dose of the 
combination therapy in order to be regarded as evaluable.  
 
9.2.1 Primary Aim 
 
The primary endpoint is whether or not the patient requires salvage radiation therapy to the CNS 
within 18 weeks. The proportion of participants requiring salvage therapy will be calculated with 
a 95% exact (Clopper-Pearson) confidence interval. An exact binomial test will be used for the 
null hypothesis Ho:  P(salvage therapy)>0.5 at α=0.05. Patients who do not reach week 18 of 
treatment and who have no salvage radiation to the brain before dropping out will not be 
included in the primary analysis.  
 
9.2.2 Secondary Aims 
 
• To characterize the safety and tolerability of the combination of tiragolumab and 
atezolizumab with or without chemotherapy in patients with NSCLC and untreated brain 
metastasis, particularly Grade ≥ 2 (symptomatic) CNS related events. Adverse events will be 
tabulated by type, grade and relatedness to treatment. The proportion of patients experiencing 
Grade ≥ 2 (symptomatic) CNS related events will be calculated with a 95% exact (Clopper-
Pearson) confidence interval.  
 
• To estimate the brain metastasis response rate (BMRR; response assessment in neuro-
oncology brain metastases [RANO-BM]). The proportion of participants experiencing 
response by RANO-BM will be calculated with a 95% exact (Clopper-Pearson) confidence 
interval.  
 
• To estimate the objective response rate (ORR), assessed using RECIST v1.1 (detailed in 
Section 12.1.5.1). The proportion of participants experiencing response by RECIST v1.1 will 
be calculated with a 95% exact (Clopper-Pearson) confidence interval. 
 
• To estimate progression-free survival (PFS). PFS, defined in Section 12.1.6, will be 
characterized by the product-limit (Kaplan-Meier) method with a 95% Greenwood 
confidence region. Median PFS will be estimated from the survival function with a 95% 
Brookmeyer and Crowley confidence interval. 
 
• To estimate intracranial PFS. Intracranial PFS, defined in Section 12.1.7, will be 
characterized by the product-limit (Kaplan-Meier) method with a 95% Greenwood 
confidence region. Median Intracranial PFS will be estimated from the survival function with 
a 95% Brookmeyer and Crowley confidence interval. 
 
• To estimate overall survival (OS). OS (months from first study treatment to death or last 
contact) will be characterized by the product-limit (Kaplan-Meier) method with a 95% 
Greenwood confidence region. Median OS will be estimated from the survival function with 
a 95% Brookmeyer and Crowley confidence interval. 
 

48 
 
• To estimate progression-free survival 2 (PFS2, defined in Section 12.1.8) after initiation of 
salvage XRT. PFS2 will be estimated by the product-limit (Kaplan-Meier) method with a 
95% Greenwood confidence region. Median PFS2 will be estimated from the survival 
function with a 95% Brookmeyer and Crowley confidence interval. 
 
• To explore PD-L1 tumor proportion score (TPS) as potential predictive biomarkers of 
response. Logistic regression and proportion hazards (Cox) regression will be used to 
investigate the relationships between PD-L1 TPS and response (RECIST and RANO-BM, as 
above) and OS, PFS and PFS2. 95% likelihood ratio confidence intervals will be determined 
for odds and hazard ratios. 
 
9.3 
Sample Size/Accrual Rate 
 
Figure 1 displays the power of the hypothesis test of the primary 
endpoint for true values of P(salvage therapy) ranging from 0.01 to 
0.5 for n=35 participants evaluable for efficacy. It is seen that the 
power is in excess of 80% if the true P(salvage therapy) is less than 
or equal to 0.27. 
 
9.4 
Stopping Rule for Excess Toxicity 
 
A stopping rule for excess toxicity will be checked after every five 
participants have received four cycles of treatment.  
 
Stopping rule for excess toxicity 
# Participants 
# Toxicities 
5 
3 
10 
5 
15 
7 
20 
9 
25 
11 
30 
13 
35 
15 
 
The trial will be halted if the number of participants experiencing 
Grade 2 or worse CNS adverse events equals or exceeds the number 
in the second column. The table goes to 35 participants because 
more than 35 participants may be enrolled to accrue 35 participants 
evaluable for efficacy. The table is generated by a beta-binomal 
stopping rule:  Stop trial if P(P(toxicity)>0.35)>0.75, where the 
uninformative beta(1,1) prior is employed. Figure 2 shows the 
expected sample size as a function of the true probability of toxicity. 
 
In addition, the trial will be halted if any of the following criteria are 
met: 
 
 
Figure 2  Expected sample 
size as a function of True 
P(Toxicity) 
 
Figure 1  Power of hypothesis 
test on the primary endpoint 

49 
 
Any death(s) that is not clearly due to disease progression or extraneous causes. 
Two or more Grade 4 AEs that are at least possibly related to any component of the study 
treatment. 
 
9.5 
For Phase 2 Protocols Only: Reporting and Exclusions 
 
9.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with tiragolumab, 
carboplatin, pemetrexed, and atezolizumab. 
 
9.5.2 Evaluation of Response 
 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of 
the following categories:  1) complete response, 2) partial response, 3) stable disease, 4) 
progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early 
death because of other cause, or 9) unknown (not assessable, insufficient data). [Note:  By 
arbitrary convention, category 9 usually designates the “unknown” status of any type of data in a 
clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. 
Patients in response categories 4-9 should be considered to have a treatment failure (disease 
progression). Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be 
protocol specific.  
 
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major 
protocol violations, etc.). However, these subanalyses may not serve as the basis for drawing 
conclusions concerning treatment efficacy, and the reasons for excluding patients from the 
analysis should be clearly reported.  
 
10. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  
 
10.1 Adverse Events 
 
10.1.1 Tiragolumab 
 
Because tiragolumab is a therapeutic mAb and targets immune cells, IRRs associated with 
hypersensitivity reactions, and/or target-mediated cytokine release may occur. Infusion reactions 
may be mild in nature or may be severe. Most of the IRRs associated with tiragolumab have been 

50 
 
Grade 1 and 2, and have most commonly presented with pyrexia and pruritus, but have also 
included hypertension, chills, nausea, anxiety, joint stiffness, dyspnea, wheezing, rash, and 
temperature intolerance. In Study GO30103 where tiragolumab was given either as a single-
agent (Phase Ia) or in combination with atezolizumab, but given prior to atezolizumab (Phase 
Ib), IRR events related to tiragolumab occurred roughly 60 to 90 minutes after infusion began. 
Please refer to the Investigator’s Brochure for additional detailed information on adverse events.  
 
10.1.2 Atezolizumab 
 
Atezolizumab has been associated with risks such as the following:  IRRs and immune related 
hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, hyperthyroidism, 
adrenal insufficiency, hypophysitis, Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, facial paresis, myelitis, meningoencephalitis, myocarditis, pericardial 
disorders, and nephritis. In addition, systemic immune activation is a potential risk associated 
with atezolizumab when given in combination with other immunomodulating agents. Refer to 
Section 6 of the Atezolizumab Investigator's Brochure for a detailed description of anticipated 
safety risks for atezolizumab.  
 
10.1.3 Adverse Event Lists for Carboplatin and Pemetrexed 
 
Please refer to the package inserts for the comprehensive list of adverse events. 
 
10.1.4 Definitions 
 
Adverse event (AE) means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction is considered "life-
threatening" if, in the view of the sponsor-investigator, its occurrence places the patient or 
subject at immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
Serious adverse event or serious suspected adverse reaction is considered "serious" if, in the 
view of the sponsor-investigator, it results in any of the following outcomes: 
• Results in death 
• Is a life-threatening adverse event 
• Requires inpatient hospitalization or prolongation of existing hospitalization. The 
following hospitalizations are NOT considered to be SAEs: 
o A visit to the emergency room or other hospital department < 24 hours, that does 
not result in admission (unless considered an important medical or life-threatening 
event) 
o Elective surgery, planned prior to signing consent 

51 
 
o Admissions as per protocol for a planned medical / surgical procedure 
o Routine health assessment requiring admission for baseline / trending of health 
status (eg, routine colonoscopy) 
o Medical / surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases. 
o Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical / surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
o Admission for administration of anticancer therapy in the absence of any other 
SAEs 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or a congenital anomaly/birth defect 
• Is an important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in the 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Unexpected adverse event or unexpected suspected adverse reaction is considered "unexpected" 
if it is not listed in the investigator brochure or is not listed at the specificity or severity that has 
been observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the current 
application, as amended. 
 
For example, under this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. “Unexpected,” as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under investigation. 
 
Pregnancy 
If a female subject becomes pregnant while receiving the study drug or within 90 days after the 
final dose of tiragolumab, 5 months after the final dose of atezolizumab, or if the female partner 
of a male study subject becomes pregnant while the study subject is receiving the Tiragolumab or 
within 90 days after the final dose of tiragolumab, whichever is later, a report should be 
completed and expeditiously submitted to Genentech, Inc. Pregnancies will be followed-up until 
the outcome of the pregnancy is known, whenever possible, based upon due diligence taken to 
obtain the follow-up information. Abortion, whether accidental, therapeutic, or spontaneous, 
should always be classified as serious, and expeditiously reported as an SAE. Similarly, any 

52 
 
congenital anomaly/birth defect in a child born to a female subject exposed to the study drug 
should be reported as an SAE. 
 
10.1.5 AEs of Special Interest (AESIs) 
Adverse events of special interest for this study are as follows: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's Law: 
o Treatment-emergent ALT or AST > 3 x ULN in combination with total bilirubin 
> 2 x ULN 
o Treatment-emergent ALT or AST > 3 x ULN in combination with clinical 
jaundice 
• 
Suspected transmission of an infectious agent by the study drug (STIAMP), as defined 
below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting transmissible 
spongiform encephalopathy), pathogenic or non-pathogenic, is considered an infectious 
agent.  A transmission of an infectious agent may be suspected from clinical symptoms 
or laboratory findings that indicate an infection in a patient exposed to a medicinal 
product.  This term applies only when a contamination of the study drug is suspected. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, 
and hypophysitis 
• 
Hepatitis, including AST or ALT > 10 x ULN 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or myasthenia 
gravis, and meningoencephalitis 
• 
Systemic lupus erythematosus 
• 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine release syndrome, 
hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS) 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥ 2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis bullous, toxic 
epidermal necrolysis)    

53 
 
• 
Myelitis 
• 
Facial paresis 
• 
Post-Study Adverse Events  
o For studies involving collection of survival data, the investigator after the end of 
the adverse event reporting period (defined as 90 days after the last dose of study 
drug) should report all deaths, (regardless of cause), and any serious adverse event 
including development of cancer or a congenital anomaly in a subsequently 
conceived offspring of a female subject who participated in the study that is 
believed to be related to prior exposure to study drug. 
o Case Transmission Verification will be performed by both parties during this 
period half-yearly to ensure successful transmission of single case reports.  
 
10.2 Recording/Reporting requirements 
 
10.2.1 Eliciting AE Information 
 
Research subjects will be routinely questioned about AEs at study visits. 
 
10.2.2 Recording Requirements 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) will be recorded in 
the subjects’ case histories. For all adverse events, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the event (i.e., whether 
the event should be classified as a serious adverse event) and; 2) an assessment of the casual 
relationship between the adverse event and the study drug(s). 
 
Adverse events will be followed until resolution while the patient remains on-study. Once the 
patient is removed from study, events thought to be related to the study medication will be 
followed until resolution or stabilization of the adverse event, or until the patient starts a new 
treatment regimen, or death, whichever comes first. Subjects will be followed for AEs/SAEs for 
30 days after their last dose of study drug(s). 
 
AEs or abnormal test findings felt to be associated with the investigational drug or study 
treatment(s) will be followed until the event (or its sequelae) or the abnormal test finding 
resolves or stabilizes at a level acceptable to the Principal Investigator. 
 
10.2.2.1 Abnormal Test Findings 
 
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met: 
• 
The test finding is accompanied by clinical symptoms. 
• 
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy. 
Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not 

54 
 
constitute an AE. 
• 
The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical study. 
• 
The test finding is considered an AE by the Sponsor-Investigator of the IND application. 
 
10.2.2.2 AE Evaluation  
  
The investigator or designee is responsible for ensuring that all AEs (both serious and non-
serious) observed by the clinical team or reported by the subject which occur after the subject has 
signed the informed consent are fully recorded in the subject’s medical records. Source 
documentation must be available to support all AEs.   
  
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study, requiring treatment or causing apparent clinical manifestations, result 
in a delay or dose modification of study treatment, or judged relevant by the investigator), should 
be reported as an AE.    
  
The investigator or sub-investigator (treating physician if applicable) will provide the following 
for all AEs (both serious and non-serious):  
  
• Event term (as per CTCAE version 5)  
• Description of the event  
• Date of onset and resolution  
• Expectedness of the toxicity  
• Grade of toxicity   
• Attribution of relatedness to the investigational agent- (this must be assigned 
by an investigator, sub-investigator, or treating physician)  
• Action taken as a result of the event, including but not limited to; no changes, 
dose interrupted, reduced, discontinued, etc. or action taken with regard to the 
event, i.e. no action, received concomitant med or other intervention, etc.  
• Outcome of event  
  
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) version 5.0 will be utilized for AE reporting.   
 
The following grading scale should be used to assess AE/SAE severity for events not specifically 
listed in CTCAE version 5.0. 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 

55 
 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. Examples of self-care activities of daily living include bathing, dressing and undressing, feeding oneself, using 
the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event  
d. Grade 4 and 5 events must be reported as serious adverse events  
 
An expected AE is an event previously known or anticipated to result from participation in the 
research study or any underlying disease, disorder, or condition of the subject. The event is 
usually listed in the Investigator Brochure, consent form or research protocol.   
  
An unexpected AE is an AE not previously known or anticipated to result from the research 
study or any underlying disease, disorder, or condition of the subject.   
  
Attribution is the relationship between an AE or serious AE and the study drugs. Attributions are 
required for each drug administered as part of the treatment regimen. Attribution will be assigned 
as follows:  
  
• Definitely Related – The AE is clearly related to the study drug. There is a reasonable 
causal relationship between study treatment and the AE. The event responds to 
withdrawal of study treatment (dechallenge) and recurs with rechallenge when clinically 
feasible.  
• Probably Related – The AE is likely related to the study drug. There is a reasonable 
causal relationship between study treatment and the AE. The event responds to 
dechallenge.  
• Possibly Related – The AE may be related to the study drug. There is a reasonable 
possibility that study treatment caused the adverse event. The investigator can provide a 
rationale or evidence to suggest a causal relationship between study treatment and the AE 
other than just a temporal relationship.  
• Unlikely Related– The AE is doubtfully related to the study drug. There is only a 
temporal relationship to study treatment, but not a reasonable causal relationship between 
study treatment and the AE.  
• Unrelated – The AE is clearly NOT related to the study drug. There is no temporal 
relationship to study treatment. There is a reasonable causal relationship to another drug 
product, concurrent disease, or circumstance.  
  
10.3 Reporting of Serious Adverse Events  

56 
 
  
10.3.1 Reporting Requirements  
  
All events meeting the definition of a serious adverse event should be reported according to the 
departmental SAE checklist and SAE form. Serious adverse events are collected from the date of 
the subject’s first dose of treatment until 90 days after the final dose. The initial SAE form 
should be sent to the following within 24 hours of the Principal Investigator becoming aware of 
the event:  
  
1. Liza Villaruz @villaruzl@upmc.edu 
2. crssafetysubmissions@upmc.edu  
3. Local Institutional Review Board when reporting requirements are met (completed by 
CRS Safety with input from the Principal Investigator).  
4. Genentech, as outlined in Section 10.3.2  
  
In addition to completing appropriate patient demographic and suspect medication information, 
the report should include as applicable the following information that is available at the time of 
report within the departmental SAE form:  
  
• CTCAE term(s) and grade(s)   
• Current status of study drug  
• All interventions to address the AE (testing and result, treatment and response)  
• Hospitalization and/or discharge dates  
• Event relationship to study drug(s)  
 
Follow-up reports:    
  
All SAEs should be followed to resolution or stabilization. Additional information may be added 
to a previously submitted report by adding to the original departmental SAE form and submitting 
it as follow-up or creating supplemental summary information and submitting it as follow-up 
with the original departmental SAE form. All follow-up forms must include the date the form is 
revised and should be submitted to the contacts listed above within 24 hours of the Principal 
Investigator becoming aware of the new information.  
  
10.3.2 
Reporting to Genentech  
  
Investigators must report all SAEs to Genentech within the timelines described below. The 
completed form should be faxed immediately upon completion to Genentech Drug Safety at:  
  
(650) 2254682  
OR  
(650) 2254630  
Email: usds_aereporting-d@gene.com  
  
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available.  

57 
 
  
Serious AE reports and AEs of Special Interest, whether related or unrelated to atezolizumab, 
will be transmitted to Genentech within one (1) business day of the Awareness Date.  
  
Additional reporting requirements to Genentech include the following:  
  
Any reports of pregnancy following the start of administration with atezolizumab and within the 
follow-up period (for female patients within 90 days after the last dose of atezolizumab or the 
partner of a male patient within 90 days of completing therapy) will be transmitted to Genentech 
within one (1) business day of the Awareness Date.  
  
• Pregnancies will be followed up until the outcome of the pregnancy is 
known, whenever possible, based upon due diligence taken to obtain the 
follow-up information.  
• All non-serious atezolizumab AEs originating from the study will be 
forwarded to Genentech quarterly.  
 
In addition to SAEs, pregnancy reports and AESIs, the following Special Situations Reports 
should be collected and transmitted to Genentech/Roche even in the absence of an Adverse 
Event within thirty (30) calendar days:  
  
• Data related to product usage during pregnancy or breastfeeding  
• Data related to overdose, abuse, misuse, inadvertent/erroneous 
administration, medication error or occupational exposure, with or without 
association with an AE/SAE unless otherwise specified in the protocol  
• Data related to a suspected transmission of an infectious agent via a 
medicinal product (STIAMP)  
• Lack of therapeutic efficacy  
 
In addition, reasonable attempts should made to obtain and submit the age or age group of the 
patient, in order to be able to identify potential safety signals specific to a particular population  
  
Exchange of Single Case Reports with Genentech 
 
PI will be responsible for collecting all protocol-defined Adverse Events (AEs)/Serious Adverse 
Events (SAEs), pregnancy reports (including pregnancy occurring in the partner of a male study 
subject), other Special Situation reports, AESIs and Product Complaints with an AE where the 
patient has been exposed to the Product. The completed Genentech approved reporting forms 
should be sent to the Genentech contact specified below. Transmission of these reports (initial and 
follow-up) will be either electronically via email or by fax and within the timelines specified 
below: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
[This requirement, based on European Medicines Agency’s (EMA) Good Pharmacovigilance 

58 
 
Practices (GVP) Module VI Section B.3, applies to Genentech because it is part of the larger 
Roche organization that operates in EU territories] 
 
For ALL events that are unexpected based on the drug safety profile in the Investigator’s 
Brochure and/or Informed Consent Form, the Batch ID/lot ID for biologics associated with 
AE/SSR/PC/AESI must be included when submitting the case reports to Genentech. 
 
All Product Complaints without an AE should call via: 
PC Hotline Number: (800) 334-0290 (M-F: 5 am to 5 pm PST) 
 
Investigators must report all the above-mentioned single case reports adequately to Genentech on 
Genentech approved SAE form within one (1) business day of the awareness date. 
 
PI /UPMC will forward quarterly listings of non-serious AEs originating from the Study to 
Genentech/Roche  
 
Transmission of these reports (initial and follow-up) will be either electronically or by fax and 
within the timelines specified below: 
 
Type of Report  
Timelines 
(for 
Approved 
Product/s) 
Timelines 
(For 
Unapproved product/s) 
Serious 
Adverse 
Events  
(related and not related to the 
Product) 
 
 
30 calendar days from 
awareness date 
 
 
 
1 calendar days from 
awareness date 
 
Special Situation Reports ( With 
or without AE  and pregnancy) 
 
Product Complaints (With or 
without AE) 
 
AESI 
 
 
Case Transmission Verification of Single Case Reports 
If Single Case Reports are exchanged via Genentech approved reporting forms, use the 
following: 
• PI/UPMC will verify that all single case reports have been adequately received by 
Genentech via PI/UPMC emailing Genentech a Quarterly line-listing documenting single 
case reports sent to Genentech in the preceding time period.  
 
• The periodic line-listing will be exchanged within seven (7) calendar days of the end of 
the agreed time period. Confirmation of receipt should be received within the time period 
mutually agreed upon. 
 
• If discrepancies are identified, PI and Genentech will cooperate in resolving the 
discrepancies. The responsible individuals for each party shall handle the matter on a 
case-by-case basis until satisfactory resolution. The sponsor will receive reconciliation 

59 
 
guidance documents within the ‘Activation Package’. 
 
• Following Case Transmission Verification, single case reports that have not been 
received by Genentech will be forwarded by PI to Genentech within five (5) calendar 
days from request by Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech 
 
Monthly or quarterly line-listings, Non-serious line listings and cumulative/final CTV should be 
sent to ctvistsa@gene.com 
 
 
10.4 Review of Safety Information: Sponsor-Investigator Responsibilities 
 
The sponsor must promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from foreign or domestic sources, including information 
derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in 
the scientific literature, and unpublished scientific papers, as well as reports from foreign 
regulatory authorities and reports of foreign commercial marketing experience for drugs that are 
not marketed in the United States. 
 
10.5 IND safety reports 
 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom 
the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety 
report of potential serious risks, from clinical trials or any other source, as soon as possible, but 
in no case later than 15 calendar days after the sponsor determines that the information qualifies 
for reporting under Sections 10.5.1 to 10.5.4 below. In each IND safety report, the sponsor must 
identify all IND safety reports previously submitted to FDA concerning a similar suspected 
adverse reaction and must analyze the significance of the suspected adverse reaction in light of 
previous, similar reports or any other relevant information. 
 
10.5.1 Serious and unexpected suspected adverse reaction 
 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
• 
A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known 

60 
 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
 
10.5.2 Findings from other studies 
 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under section 10.5.1), whether or not 
conducted under an IND, and whether or not conducted by the sponsor, that suggest a significant 
risk in humans exposed to the drug. Ordinarily, such a finding would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates of 
these documents), or other aspects of the overall conduct of the clinical investigation. 
 
10.5.3 Findings from animal or in vitro testing 
 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted 
by the sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near 
the expected human exposure. Ordinarily, any such findings would result in a safety-related 
change in the protocol, informed consent, investigator brochure (excluding routine updates of 
these documents), or other aspects of the overall conduct of the clinical investigation. 
 
10.5.4 Increased rate of occurrence of serious suspected adverse reactions 
 
The sponsor must report any clinically important increase in the rate of a serious suspected 
adverse reaction over that listed in the protocol or investigator brochure. 
 
10.6 Submission of IND safety reports 
 
The sponsor must submit each IND safety report in a narrative format or on Form FDA 3500A or 
in an electronic format that FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of transmission, media, file 
formats, preparation and organization of files). The sponsor may submit foreign suspected 
adverse reactions on a Council for International Organizations of Medical Sciences (CIOMS) I 
Form instead of a Form FDA 3500A. Reports of overall findings or pooled analyses from 
published and unpublished in vitro, animal, epidemiological, or clinical studies must be 
submitted in a narrative format. Each notification to FDA must bear prominent identification of 
its contents, i.e., "IND Safety Report," and must be transmitted to the review division in the 
Center for Drug Evaluation and Research or in the Center for Biologics Evaluation and Research 
that has responsibility for review of the IND. Upon request from FDA, the sponsor must submit 
to FDA any additional data or information that the agency deems necessary, as soon as possible, 
but in no case later than 15 calendar days after receiving the request. 

61 
 
 
10.6.1 Unexpected fatal or life-threatening suspected adverse reaction reports 
 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial 
receipt of the information. 
 
10.6.2 Reporting format or frequency 
 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different 
than that required under this paragraph. The sponsor may also propose and adopt a different 
reporting format or frequency if the change is agreed to in advance by the director of the FDA 
review division that has responsibility for review of the IND. 
 
10.6.3 Investigations of marketed drugs 
 
A sponsor of a clinical study of a drug marketed or approved in the United States that is 
conducted under an IND is required to submit IND safety reports for suspected adverse reactions 
that are observed in the clinical study, at domestic or foreign study sites. The sponsor must also 
submit safety information from the clinical study as prescribed by the post marketing safety 
reporting requirements. 
 
10.6.4 Reporting study endpoints 
 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 10.7 third bullet of 
this section. However, if a serious and unexpected adverse event occurs for which there is 
evidence suggesting a causal relationship between the drug and the event (e.g., death from 
anaphylaxis), the event must be reported under Serious and unexpected suspected adverse 
reaction as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (e.g., all-cause mortality). 
 
10.7 Follow-up 
 
• 
The sponsor must promptly investigate all safety information it receives. 
• 
Relevant follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., "Follow-up IND Safety 
Report." 
• 
If the results of a sponsor's investigation show that an adverse event not initially 
determined to be reportable under section 10.5 IND safety reports is so reportable, the 
sponsor must report such suspected adverse reaction in an IND safety report as soon as 
possible, but in no case later than 15 calendar days after the determination is made. 

62 
 
 
10.8 Disclaimer 
 
A safety report or other information submitted by a sponsor under this part (and any release by 
FDA of that report or information) does not necessarily reflect a conclusion by the sponsor or 
FDA that the report or information constitutes an admission that the drug caused or contributed 
to an adverse event. A sponsor need not admit, and may deny, that the report or information 
submitted by the sponsor constitutes an admission that the drug caused or contributed to an 
adverse event. 
The principal investigator must promptly review all information relevant to the safety of the drug 
obtained or otherwise received from foreign or domestic sources, including information derived 
from any clinical or epidemiological investigations, animal or in vitro studies, reports in the 
scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not 
marketed in the United States.  The study sponsor must notify all participating investigators of 
potential serious risks, from clinical trials or any other source, as soon as possible. 
 
10.9 Reporting adverse events to the responsible IRB  
  
In accordance with applicable policies of the University of Pittsburgh Human Research 
Protection Office (HRPO), the Principal Investigator will report, to the IRB, any observed or 
volunteered adverse event that is determined to be 1) associated with the investigational drug or 
study treatment(s); 2) serious; and 3) unexpected. Adverse event reports will be submitted to the 
IRB in accordance with the respective IRB procedures.  
  
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later 
than 10 calendar days following the principal investigator’s knowledge of the respective 
information. Adverse events which are 1) associated with the investigational drug or study 
treatment(s); 2) fatal or life-threatening; and 3) unexpected will be reported to the IRB within 24 
hours of the Principal Investigator’s knowledge of the respective information.  
  
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the Principal Investigator’s follow-up 
investigation show that an adverse event that was initially determined to not require reporting to 
the IRB does, in fact, meet the requirements for reporting; the Principal Investigator will report 
the adverse event to the IRB as soon as possible, but in no event later than 10 calendar days, after 
the determination was made.  
  
  
AGGREGATE REPORTS 
 
IND ANNUAL REPORTS 
 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. 
 

63 
 
Copies of such reports should be emailed to Genentech at:  Genentech Drug Safety CTV mail 
box: ctvistsa@gene.com. 
 
OTHER REPORTS  
 
UPMC /PI will forward a copy of the Publication and/or Final Study Report to Genentech upon 
completion of the Study.  
 
 
STUDY CLOSE-OUT 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 
Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
tiragolumab-gsur-d@gene.com 
 
And to Genentech Drug Safety CTV oversight mail box at ctvistsa@gene.com  
 
QUERIES 
 
Queries related to the Study will be answered by UPMC /PI . However, responses to all safety  
queries  from  regulatory  authorities, Ethics Committees and Institutional Review Board  or  for 
publications will be discussed and coordinated between the Parties. The Parties agree that 
Genentech shall have the final say and control over safety queries relating to the Product. UPMC 
/PI  agrees that it shall not answer such queries from regulatory authorities and other sources 
relating to the Product independently but shall redirect such queries to Genentech. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests  from Regulatory Authorities and/or IRB/IEC for information or review of data are met. 
The Parties will clearly indicate on the request the reason for urgency and the date by which a 
response is required. 
 
SIGNAL MANAGEMENT AND RISK MANAGEMENT  
 
Genentech is responsible for safety signal management (signal detection and/or evaluation) for 
their own Product. However, it is agreed that UPMC /PI, as Sponsor of the Study, will be 
primarily responsible for assessment of the benefit-risk balance of the Study. 
 
If UPMC /PI  issues a safety communication relevant for Genentech (i.e., a safety issue that 
notably impacts the benefit-risk balance of the Study and / or triggers any changes to the Study) 
this will be sent to Roche within five (5) business days of its internal approval. 
 
As needed, Genentech will reasonably assist UPMC /PI with signal and risk management 
activities related to the Product within the Study. 

64 
 
 
Genentech will also provide UPMC /PI with any new relevant information that may modify or 
supplement known data regarding the Product (e.g., relevant Dear Investigator Letter). 
 
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party regarding AE 
report timeliness in accordance with its own procedures. The Parties agree to provide written 
responses in a timely manner to inquiries from the other Party regarding AE reports received 
outside the agreed upon Agreement timelines. If there is any detection of trends of increasing or 
persistent non-compliance to transmission timelines stipulated in this Agreement, both Parties 
agree to conduct ad hoc or institute a regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange timelines, with 
this Agreement, the Parties will jointly discuss and collaborate on clarifying and resolving the 
issues causing non-compliance. Every effort will be made by the non-compliant Party to solve 
the non-compliance issues and inform the other Party of the corrective and preventative actions 
taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an audit 
under the provisions of this Agreement can be requested by either Party. The Parties will then 
discuss and agree in good faith upon the audit scope, agenda and execution of the audit. The 
requesting Party will bear the cost of the audit. 
 
 
 

65 
 
 
11. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to start of protocol therapy. In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy.  
 
 
Pre- 
Study 
Cycle 1  
Cycle 2 
Subsequent 
Cycles 
Off 
Treatmentk 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
1 
Wk 
2 
Wk 
3 
Tiragolumab 
 
X 
 
 
X 
 
 
X 
 
 
 
Atezolizumab 
 
X 
 
 
X 
 
 
X 
 
 
 
Carboplatinm 
 
X 
 
 
X 
 
 
X 
 
 
 
Pemetrexedm 
 
X 
 
 
X 
 
 
X 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X------------------------------------------------------X X 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signsa 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Performance statusb 
X 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, pltsc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Serum chemistryd 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Serum β-HCGf 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysisg 
X 
Xe 
 
 
Xe 
 
 
Xe 
 
 
Xe 
Thyroid function 
testingh 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Amylase and Lipase 
X 
X 
 
 
X 
 
 
X 
 
 
X 
Viral Serologiesi 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
X 
X------------------------------------------------------X X 
Radiologic evaluationj X 
X------------------------------------------------------X  
Additional MRI brain 
 
 
 
 
X 
 
 
 
 
 
 
PD-L1 TPSl l 
X 
 
 
 
 
 
 
 
 
 
 

66 
 
a Heart rate, respiratory rate, systolic and diastolic blood pressure while the patient is in a seated position, 
and temperature. For additional guidelines for measurement of vital signs with atezolizumab infusions, 
please reference Section 6.1.1. 
b Appendix A.  
c Hemoglobin, hematocrit, platelet count, WBC count, percent and absolute differential count 
(neutrophils, bands, eosinophils, lymphocytes, monocytes, basophils, other cells).  
d Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, phosphorus, magnesium, 
total, total protein, albumin, ALT, AST, and alkaline phosphatase.  
e As clinically indicated 
f For women of childbearing potential and who are premenopausal. To be performed at screening and 
otherwise, if clinically indicated.  
g Specific gravity, pH, glucose, protein, ketones, and blood.  
h TSH, free T4  
i Hepatitis B virus (HBV) serology (HBsAg, antibodies against HBsAg, hepatitis B core antigen), and 
HCV serology (anti-HCV)  
j Radiographic evaluation include a CT scans of the chest and all other known sites of metastatic disease, 
as well as an MRI of the brain. Radiographic evaluations must be performed every 9 weeks ± 1 week. 
Confirmatory scans will also be obtained ≥4 weeks following initial documentation of an objective 
response or progressive disease. In patients with baseline CNS lesions less than 1 cm, MRI imaging 
with 1.5 mm slice thickness is required. Please note an additional MRI brain will be performed prior to 
C2D1 of treatment for safety purposes. For patients treated past radiographic progression, 
establishment of new baseline tumor measurements is required for assessment of PFS2.  
k Patients who discontinue from treatment will be asked to return to the clinic no more than 30 days after 
the last treatment for a treatment discontinuation visit. The visit at which a response assessment shows 
progressive disease may be used as the treatment discontinuation visit. Patients who have an ongoing 
study treatment-related AE upon study completion or at discontinuation from treatment will be followed 
until the event has resolved to baseline grade, the event is assessed by the investigator as stable, new 
anticancer treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or until it 
has been determined that study treatment or participation is not the cause of the AE.  
l PD-L1 Tumor Proportion Score required. This can come from an existing pathology report or can be 
requested to be performed on archival tissue. 
MCohort 1 only. 
 
Note: There is a window of ± 1 week available for rescheduling treatment and/or procedures at the 
discretion of the treating investigator.  
 
12. MEASUREMENT OF EFFECT 
 
12.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 9 (+/- 1) weeks. 
In addition to a baseline scan, confirmatory scans should also be obtained not less than 4 weeks 
following initial documentation of objective response. 
 
Response and progression in the CNS will be evaluated in this study using the new international 
criteria proposed by the Response Assessment in Neuro-Oncology Brain Metastases (RANO-
BM) working group revised [Lancet Oncology 2015;16: e270–78].  
 
Non-CNS disease will be evaluated using the Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1) [Eur J Ca 45:228-247, 2009]. Changes in the largest diameter 

67 
 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
If progression occurs in both CNS and non-CNS sites of disease, progression events in both 
compartments should be scored. In cases of discordant response between CNS and non-CNS 
disease, local therapy to site(s) of progression in either or both compartments is permitted while 
on study, as is treatment past progression, provided the criteria in Section 6.3 are met.   
 
12.1.1 Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with tiragolumab and atezolizumab. 
 
Evaluable for objective response. Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response. These patients will have their response classified 
according to the definitions stated below. (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease. The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
12.1.2 RECIST v1.1 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) by chest x-ray or as 
≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm [0.5 cm]). At baseline and in follow-up, only the short 
axis will be measured and followed. 
 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 to <1.5 cm] 
short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, 
ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 

68 
 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
12.1.3 RANO-BM Disease Parameters 
 
Measurable disease is defined as a contrast-enhancing lesion that can be accurately measured in 
at least one dimension, with a minimum size of 5 mm, and is visible on two or more axial slices. 
For targets lesions ≥ 10 mm, axial slices are preferably 5 mm or less apart with 0 mm skip (and 
ideally ≤1.5 mm apart with 0 mm skip). In patients with baseline CNS lesions less than 1 cm, 
MRI imaging with 1.5 mm slice thickness is required.  
 
12.1.4 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as assessed using 

69 
 
calipers (e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
Conventional CT and MRI  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans have slice 
thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans).  
 
Use of MRI for the evaluation of disease outside the CNS is a complex issue. MRI has excellent 
contrast, spatial, and temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. 
Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, 
the technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-
up should be the same as was used at baseline and the lesions should be measured/assessed on 
the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific 
MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
PET-CT  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.  
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
 

70 
 
Tumor markers  Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008]. In addition, the Gynecologic 
Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with 
objective tumor assessment for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 
2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT  scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. 
The use of FDG-PET in this circumstance should be prospectively described in the protocol 
and supported by disease-specific medical literature for the indication. However, it must be 
acknowledged that both approaches may lead to false positive CR due to limitations of FDG-
PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.1.5 Response Criteria 
 
12.1.5.1 Disease Evaluation by RECIST v1.1 
 

71 
 
Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (0.5 cm). (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment will 
depend on the achievement of both measurement and confirmation criteria. 
 
 
 
 
 

72 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
≥4 wks. Confirmation 
CR 
Non-CR/Non-
PD 
No 
PR 
≥4 wks. Confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once ≥4 
wks. from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
∗ 
See RECIST 1.1 manuscript for further details  
**  In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
∗ 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
 
 
12.1.5.2 Disease Evaluation by RANO-BM 
 

73 
 
 
 
For target lesions 5 mm to 10 mm, complete response and unequivocal progressive disease can 
probably be interpreted on their merits. However, measurement of small changes, such as the 
minimum 20% increase in longest diameter to determine progressive disease or the minimum 
30% decrease in longest diameter to determine partial response, might not be robust or 
reproducible. For this reason, target lesions less than 10 mm in longest diameter should be 
regarded as unchanged from baseline unless there is a minimum 3 mm change in the 
measured longest diameter. 
 

74 
 
12.1.5.3 Evaluation and recording of bi-compartmental response 
 
 
 
12.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first. PFS should be recorded in a bi-compartmental manor: 
 
 
 
12.1.7 Intracranial Progression-Free Survival (PFS) 
 
Intracranial PFS is defined as the duration of time from start of treatment to time of progression 
in the CNS or death. 
 
12.1.8 Progression-Free Survival 2 (PFS2) 
PFS2 is defined as months from initiation of salvage radiotherapy to CNS and or non-CNS 
lesions to time of progression, death or last radiographic assessment without PD, whichever 
occurs first. 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
 
13.1 
Data Safety Monitoring Plan 
 
Principal Investigator, Sub-investigators, regulatory, CRS management, clinical research 
coordinators, research coordinators, clinical research associates, data managers, and clinic staff 
meet regularly in disease center Data Safety Monitoring Boards (DSMB) to review and discuss 
study data to include, but not limited to, the following: 
 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 

75 
 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
 
Minutes from the DSMB meetings are available to those who are unable to participate during the 
scheduled meeting time. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to 
the NCI Common Toxicity Criteria version 5.0. All study treatment associated adverse events 
that are serious, at least possibly related and unexpected will be reported to the IRB and FDA. 
Any modifications necessary to ensure subject safety and decisions to continue, or close the trial 
to accrual are also discussed during these meetings. If any literature becomes available which 
changes the risk/benefit ratio or suggests that conducting the trial is no longer ethical, the IRB 
will be notified in the form of an Unanticipated Problem submission and the study may be 
terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any 
breach in subject confidentiality will be reported to the IRB in the form of an Unanticipated 
Problem submission. The summaries of these meetings are forwarded to the UPMC Hillman 
Cancer Center DSMC which also meets regularly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for 
reporting unanticipated problems involving risk to subjects or others (including adverse events). 
DSMC progress reports, to include a summary of all serious adverse events and modifications, 
and approval will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will 
be reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCM Hillman Cancer Center DSMC as well as the individual disease center DSMB 
have the authority to suspend accrual or further investigate treatment on any trial based on 
information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the 
researchers affiliated with the research study and their staff will have access to the research 
records. 
 
13.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical 
Practice compliance will be conducted periodically (i.e., at a minimum of annually) by qualified 
staff of the Education and Compliance Office – Human Subject Research, Research Conduct and 
Compliance Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh Medical Center will permit direct access of the study monitors and 

76 
 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
13.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance 
with Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not 
submitted or approved for the investigational drug, until 2 years after investigations under the 
IND have been discontinued and the FDA so notified. 
 
13.4 
Institutional Review Board (IRB) Approval 
 
The investigator (i.e., the study site principal investigator) will obtain, from the University of 
Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and 
corresponding informed consent forms, and advertisements (i.e., directed at potential research 
subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
investigator will promptly notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice. 
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event 
of an sponsor’s decision to modify the previously accepted clinical protocol, the sponsor will 
submit (i.e., in advance of implementing the change) a Protocol Amendment to the IND 
describing any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of protocol changes requiring the 
submission of a Protocol Amendment include: 
 
• Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
• Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
• The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 

77 
 
 
13.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, 
requirements, and regulations of the University of Pittsburgh IRB, University of Pittsburgh and 
University of Pittsburgh Medical Center, Commonwealth of Pennsylvania, and applicable federal 
agencies. 
 
13.6 
Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the 
potential risks and benefits of study participation, and their rights as research subjects. The 
investigator, or a sub-investigator(s) designated by the sponsor, will obtain the written, signed 
informed consent of each subject, or the subject’s authorized representative, prior to performing 
any study-specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the issues discussed 
during the informed consent process will be documented in the subject’s case history. The 
investigator or sub-investigator will retain the original copy of the signed informed consent form, 
and a copy will be provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study. In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigator will obtain the informed consent of 
enrolled subjects for continued participation in the clinical study. 
 
 
 
 
 
 
 
 
 

78 
 
 
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83 
 
15. APPENDICES 
 
15.1 APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time. 
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time. Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 

84 
 
16.2 APPENDIX B: Anaphylaxis Precautions 
 
Equipment Needed 
• 
Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation monitor, and 
thermometer 
• 
Oxygen 
• 
Epinephrine for intravenous, intramuscular, and endotracheal administration in accordance 
with institutional guidelines 
• 
Antihistamines 
• 
Corticosteroids 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
In the event of a suspected anaphylactic reaction during study treatment infusion, the following 
procedures should be performed: 
1. Stop the study treatment infusion. 
2. Call for additional medical assistance. 
3. Ensure that appropriate monitoring is in place, with continuous ECG and pulse oximetry 
monitoring, if possible. 
4. Administer antihistamines, epinephrine, or other medications as required by participant 
status and as directed by the physician in charge. 
5. Continue to observe the participant and document observations. 
6. Draw serum/plasma samples for immunogenicity testing. 
7. Ask participant to return for washout immunogenicity sample if appropriate 
 
 
 

85 
 
15.3 APPENDIX C: Safety Reporting Fax Cover Sheet 
 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
 
SAE or Safety Reporting questions, contact Genentech Drug Safety: (888) 835-2555 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
APPENDIX NUMBER: 
FDA MedWatch 3500 Form 
 
APPENDIX NUMBER# 

86 
 
Current National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE) 
Please use the following link to the NCI CTCAE website (CTCAE v5.0 will be utilized for this 
study): 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
15.4 APPENDIX D: Administration of Atezolizumab and Tiragolumab infusions 
 
Administration of First and Subsequent Infusions of Atezolizumab and Tiragolumab 
Study drug 
First Infusion 
Subsequent Infusions 
Atezolizumab 
infusion 
• No premedication is permitted prior 
to the atezolizumab infusion. 
• Vital signs (pulse rate, respiratory 
rate, blood pressure, and temperature) 
should be recorded within 60 minutes 
prior to the infusion. 
• Atezolizumab should be infused over 
60 (± 15) minutes. 
• If clinically indicated, vital signs 
should be recorded every 
15 (± 5) minutes during the infusion. 
• If the patient experienced an IRR with any 
previous infusion of atezolizumab, premedication 
with an antihistamine and/or antipyretic 
medication may be administered for subsequent 
doses at the discretion of the investigator. 
• Vital signs should be recorded prior to the 
infusion. 
• Atezolizumab should be infused over 30 (± 10) 
minutes if the previous infusion was tolerated 
without an IRR or 60 (± 15) minutes if the patient 
experienced an IRR with the previous infusion.  
• If clinically indicated, vital signs should be 
recorded during the infusion. 
Observation 
period after 
infusion of 
atezolizumab 
• After the infusion of atezolizumab, the 
patient begins a 60-minute 
observation period. 
• Vital signs should be recorded at 
30 (± 10) minutes after the infusion of 
atezolizumab. 
• Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact 
their study physician if they develop 
such symptoms. 
• If the patient experienced infusion-associated 
adverse events in the previous infusion, the 
observation period should be 60 minutes. 
• If clinically indicated, vital signs should be 
recorded at 30 (± 10) minutes after the infusion of 
atezolizumab. 
IRR= infusion-related reaction. 
 

87 
 
Table 2 
Administration of First and Subsequent Infusions of Atezolizumab and 
Tiragolumab (cont.) 
 
First Infusion 
Subsequent Infusions 
Infusion of 
tiragolumab 
• No premedication is permitted prior 
to the tiragolumab infusion. 
• Vital signs (pulse rate, respiratory 
rate, blood pressure, and temperature) 
should be recorded within 60 minutes 
prior to the infusion. 
• Tiragolumab should be infused over 
60 (± 15) minutes. 
• Vital signs should be recorded every 
15 (± 5) minutes during the infusion. 
• If the patient experienced an IRR during any 
previous infusion of tiragolumab, premedication 
with an antihistamine and/or antipyretic may be 
administered for subsequent doses, at the 
discretion of the investigator. 
• Vital signs should be recorded within 60 minutes 
prior to the tiragolumab infusion. 
• Tiragolumab should be infused over 
30 (± 10) minutes if the previous infusion was 
tolerated without an infusion-related reaction, or 
60 (± 15) minutes if the patient experienced an 
infusion-related reaction with the previous 
infusion. 
• Vital signs should be recorded during the 
infusion if clinically indicated. 
Observation 
period after 
infusion of 
tiragolumab 
• After the infusion of tiragolumab, the 
patient begins a 60-minute 
observation period. 
• Vital signs should be recorded at 
30 (± 10) minutes after the infusion of 
tiragolumab. 
• Patients will be informed about the 
possibility of delayed post-infusion 
symptoms and will be instructed to 
contact their study physician if they 
develop such symptoms. 
• If the patient tolerated the previous infusion of 
tiragolumab well without infusion-associated 
adverse events, the observation period may be 
reduced to 30 minutes. 
• If the patient experienced an infusion-associated 
adverse event in the previous infusion, the 
observation period should be 60 minutes. 
• If clinically indicated, vital signs should be 
recorded at 30 (± 10) minutes after the infusion 
of tiragolumab. 
• Patients will be informed about the possibility of 
delayed post-infusion symptoms and will be 
instructed to contact their study physician if they 
develop such symptoms. 
IRR = infusion-related reaction.