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point description

0 Fully active, able to carry on all pre-disease performance without restriction.  
1 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.  
2 Ambulatory and capable of self-care but unable to carry out any work activities; up and about more than 50% of waking hours.  
3 Capable of limited self-care, confined to bed or chair more than 50% of waking hours.  
4 Completely disabled; cannot carry on any self-care; totally confined to bed or chair.
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10.5 time to death

From date of sub-study registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
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10.6 irrc-progression

irRC-progression is defined by progression per RECIST 1.1 except that progression determined by appearance of new lesions or by a 20% increase in the sum of diameters must be confirmed by a second consecutive determination of progression at least 28 days from the date of initial documentation of progression.  
10.7 Investigator-Assessed Progression-Free Survival
From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration (as defined above), or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans)
whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.  
10.8 Progression-Free Survival by Central Review From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration (as defined above), or death due to any cause. Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.  
10.9 Duration of Response (DoR)
From date of first documentation of response (CR or PR) to date of first documentation of progression assessed by local review or symptomatic deterioration (as defined above), or death due to any cause among patients who achieve a response (CR or PR). Patients last known to be alive without report of progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan determines progression, the expected date of the first missing scan (as defined by the disease assessment schedule) will be used as the date of progression.  
10.10 irRC Investigator-Assessed Duration of Response (irRC-IA-DoR)
From date of first documentation of response (CR or PR) to date of first documentation of irRC-progression assessed by local review or symptomatic deterioration, or death due to any cause. Patients last known to be alive without report of irRC-progression are censored at date of last disease assessment. For patients with a missing scan (or consecutive missing scans) whose subsequent scan(s) determine irRC-progression, the date of irRCprogression will be the expected date of the first missing scan (as defined by the disease assessment schedule) or the date of the first scan documenting potential irRC-progression, whichever is earliest.
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11.0 statistical considerations

This study will enroll patients into two parallel and independently evaluated cohorts; patients will be defined as either acquired (Cohort 1) or primary (Cohort 2) resistance. See Section 6.0 for the definition of the cohorts. Both cohorts have separate accrual goals and analysis plans. This study is employing Design \#2 for non-match therapies. A complete description of the statistical design and analysis plan is included this section and in Section 11.2a of **S1400**. This section includes details specific to **S1400F.**
The objectives will be addressed in each cohort separately.
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11.1 primary objective

The primary objective within each cohort is to assess the response rate (confirmed and unconfirmed, complete and partial) among patients treated with MEDI4736 (Durvalumab)
plus tremelimumab.
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11.2 secondary objectives

Secondary objectives include an evaluation of IA-PFS, OS, DoR, and toxicities.  
11.3 Sample Size with Power Justification The accrual goals for this study are to accrue up to 60 eligible patients per cohort and the same design assumptions apply to both cohorts. A design with 82% power and 1-sided 0.05 level type I error would require 60 patients to rule out an ORR of 5% or less if the true ORR is 15% or greater. If the true ORR is 20%, this design has 96% power. The observation of at least 6 responses of the 60 patients (10%) would be considered evidence to rule out an ORR of 5%. Assuming 90% of accrued patients will satisfy eligibility, **the total**
accrual goal is 66 patients/cohort (132 total).  
11.4 Analysis Plan
The evaluation within each cohort will include two interim analyses. The interim analyses within each cohort are as follows: Interim 1: The first interim analysis will take place when 20 patients are evaluable for response. This interim analysis will only evaluate early stopping for futility. If no responses are observed, this will be considered evidence of futility and the recommendation will be to close the cohort for lack of evidence of efficacy of the regimen. In addition to evaluating early stopping for futility, this analysis will evaluate the safety/tolerability of the regimen. All grade 4 hematologic and grade 3 or worse nonhematologic will be evaluated with a particular focus on diarrhea, colitis, transaminitis and lipase levels, and other immune-related adverse events (pneumonitis and other immune events). These toxicities will be evaluated by the **S1400F** Study Chairs, the **S1400** Study Chairs, and the study pharmaceutical collaborator. With 20 patients evaluable for toxicities, any toxicity with at least 10% prevalence has at least an 88% chance of being observed. Interim 2: The second interim analysis will take place when 40 patients are evaluable for response. This interim analysis will also only evaluate early stopping for futility. If 3 or fewer responses are observed, this will be considered evidence of futility and the recommendation will be to close the cohort for lack of evidence of efficacy of the regimen. Final Analysis: If a cohort is not closed to accrual at the first or second interim analysis, the cohort will proceed to full accrual of 60 evaluable patients. If the cohort continues to full accrual, the observation of at least 6 responses will be considered evidence to rule out the null hypothesis of a 5% response rate.  
| Summary of analyses:  Analysis Sample Size   | Futility    | Continue/Positive   |                       |
|----------------------------------------------|-------------|---------------------|-----------------------|
| 1st interim                                  | 20 patients | No responses        | 1+ response ( 5% RR)  |
| 2nd interim                                  | 40 patients | ≤3 responses        | 4+ responses (10% RR) |
| Final                                        | 60 patients | ≤5 responses        | 6+ responses (10% RR) |  
Evaluability for response: Evaluability for response is defined based on RECIST 1.1 and accrual to each cohort is to remain open while patients are being evaluated for response. However, within a cohort, if 20 or more eligible patients for the first interim analysis or 40 or more eligible patients for the second interim analysis, have made it to their second disease assessment and the required number of responses to continue past that interim analysis has not been observed, then the accrual to the cohort will be placed in temporary closure until the response status for all patients in the interim analysis set is known. The following table describes the likelihood of stopping at the interim analyses under a response rate of 5%, 10%, 15%, and 20% and the probability of a rejecting the null.  
| Expected  number of     |                      |             |    |    |       |
|-------------------------|----------------------|-------------|----|----|-------|
| Interim                 | Probability          |             |    |    |       |
| RR                      | responses            |             |    |    |       |
| Interim 1               | 2                    | reject null |    |    |       |
| 5%                      | 36%                  | 51%         | 36 | 2  | 5.6%  |
| 10%                     | 12%                  | 31%         | 49 | 5  | 46.8% |
| 15%                     | 4%                   | 11%         | 56 | 8  | 82.2% |
| 20%                     | 1%                   | 2%          | 59 | 12 | 96.5% |
| Probability of stopping | Average  sample size |             |    |    |       |  
Response rates and associated confidence intervals will be calculated. Survival, IA-PFS,
irRC-IA-PFS, and DoR will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median OS, IA-PFS, and DoR. With 60 patients, ORR and toxicity rates can be estimated within 13%
with 95% confidence. Any toxicity with at least 5% prevalence has at least a 95% chance of being observed.  
With 60 patients, OS and PFS rates at landmark times can be estimated within 13% with 95% confidence. The analysis of PFS and OS will occur approximately 6 months after completion of accrual when at least 41 OS events have been observed (but not prior to 6 months after completion of accrual). It is estimated that the null rate (with docetaxel) in the population would be a median of 5 months (or a 6-month OS of 44%) for OS and of interest would be an improvement to a median of 9 months (a 6-month OS rate of 63%). With 60 patients accrued over 18-22 months and an additional 6 months of follow-up, the expected number of OS events is 41 events (under the alternative). The estimated number of PFS
events at this time is at least 50 (under an alternative median PFS of 5 months). With 41 OS events, this study has 90% power to rule out a median OS of 5 months if the true median OS is 9 months or greater at the 1-sided 5% level. The observation of a 6-month OS rate of 55% or greater would be considered evidence to rule out the null rate.  
The null median OS of 5 months was estimated by simulation under the assumption of exponential survival post progression on nivolumab and based on the data presented on the Checkmate 017 study which had a median PFS of 3.5 months with nivolumab and median OS of 9.2 months with nivolumab.
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11.5 accrual information

The estimated average monthly accrual rate to **S1400F** is 3-4 patients with acquired resistance (Cohort 1) and 4-6 patients with primary resistance (Cohort 2). The estimated duration of accrual for Cohort 1 is 16-23 months and for Cohort 2 is 11-16 months, provided there are no halts in accrual. The accrual duration within a cohort may be different if accrual is temporarily halted for an interim analysis or closed for futility at an interim analysis. See the **S1400** main protocol for a description of the accrual rate assumptions/justification.
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11.6 data and safety monitoring

A Data and Safety Monitoring Committee will oversee the conduct of the study. The Committee consists of four members from outside of SWOG. Group members, 3 nonvoting representatives from the National Cancer Institute (NCI), and the Group Statistician
(non-voting). The members of this Committee will receive confidential reports every 6 months from the SWOG Statistics and Data Management Center, and will meet at the Group's bi-annual meetings as necessary.
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13.0 registration guidelines

See Section 13.0 of S1400 or **LUNGMAP** for registration guidelines. NOTE: At the time of LUNGMAP activation, **S1400** screening will close to accrual. Please see the Lung-MAP protocol training webpage for additional information (https://www.swog.org/required-lung-map-s1400training). 13.1 Registration Timing Patients must plan to begin treatment within 10 calendar days after sub-study registration.
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14.0 data submission schedule 14.1

Data must be submitted according to the protocol requirements for ALL patients registered, whether or not assigned treatment is administered, including patients deemed to be ineligible. Patients for whom documentation is inadequate to determine eligibility will generally be deemed ineligible.
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14.2 master forms 14.3 data

Master forms can be found on the protocol abstract page on the SWOG website
(www.swog.org) and (with the exception of the sample consent form and the Registration Worksheet) must be submitted on-line via the Web; see Section 14.3 for details.  
a. Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. Access to the trial in Rave is granted through the iMedidata application to all persons with the appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site user must have an active CTEP-IAM account (check at < https://eappsctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave CRA, ReadOnly, Site Investigator) on either the LPO or participating organization roster at the enrolling site. To hold the Rave CRA role or CRA Lab Admin role, the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the individual must be registered as an NPIVR or IVR. Associates can hold readonly roles in Rave. If the study has a DTL, individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on the DTL.  
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the appropriate roster ill be sent a study invitation e-mail from iMedidata. To accept the invitation, site users must log into the Select Login
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and password, and click on the "accept" link in the upper right-corner of the iMedidata page. Please note, site users will not be able to access the study in Rave until all required Medidata and study specific trainings are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by clicking on the link in the upper right pane of the iMedidata screen.  
Users that have not previously activated their iMedidata/Rave account at the time of initial site registration approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. Account activation instructions are located on the CTSU website, Rave tab under the Rave resource materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU members' website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1888-823-5923 or by e-mail at ctsucontact@westat.com.  
b. You may also access Rave® via the SWOG CRA Workbench via the SWOG
website (www.swog.org).  
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| Tumor Tissue  prior to Tx (Optional a)                                              | Peripheral Blood  (Optional a)   | Re-biopsy Tumor  Tissue at  Progression  (Optional a, b)  See Sub-Study  Section 15.0.   |
|-------------------------------------------------------------------------------------|----------------------------------|------------------------------------------------------------------------------------------|
| Screening/PreScreening Tumor  Tissue (Required) See S1400 or  LUNGMAP Section 5.1.                                                                                     | See Sub-Study  Section 15.0.     |                                                                                          |
| See Sub-Study  Section 15.0.  Lab 201: SWOG  Biospeciment  Bank - Solid  Tissue     |                                  |                                                                                          |
| Lab #211:  Foundation  Medicine, Inc.  (FMI) Test: Biomarker  Profiling (Required)* | Test: Exploratory Testing        |                                                                                          |
| See S1400 or LUNGMAP Section 15.2                                                   | See S1400F Section 15.0          | Lab #201: SWOG  Biospecimen Bank -  Solid Tissue                                         |
| For Patients  registered to                                                         |                                  |                                                                                          |
| S1400F, SWOG  Biospecimen Bank will forward 2-4  slides to Lab #214: Clarient       | Banking (c)                      |                                                                                          |
| See Sub-Study Section  15.0.                                                        |                                  |                                                                                          |
| Test: PD-L1 IHC  Testing See S1400F Section 15.0.                                   |                                  |                                                                                          |  
15.4 Specimen Flow Diagram
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Expedited reporting is required if the patient has received at least one dose of the investigational agent(s) as part of the trial. Reporting requirements are provided in Table 16.1. The investigational agent(s) used in this study MEDI4736 (Durvalumab) and tremelimumab. [Please note - For this sub-study the post dosage expedited reporting requirement window has been extended to 90 days rather than the normal 30 day requirement or until the initiation of alternative anticancer therapy]. If there is any question about the reportability of an adverse event or if on-line CTEP-AERS cannot be used, please telephone or email the SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, before preparing the report.  
Table 16.1: Late Phase 2 and Phase 3 Studies: Expedited Reporting Requirements for Adverse Events that Occur on Studies under a Non-CTEP IND within 90 **Days of the Last Administration of the**
Investigational Agent/Intervention1 MEDI4736 (Durvalumab) and tremelimumab:
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)
NOTE: Investigators **MUST** immediately report to the sponsor (NCI) **ANY** Serious Adverse Events, whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)
An adverse event is considered serious if it results in ANY of the following outcomes:
1) Death 2) A life-threatening adverse event 3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for
≥ 24 hours 4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5) A congenital anomaly/birth defect. 6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon 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. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).  
ALL **SERIOUS** adverse events that meet the above criteria **MUST** be immediately reported to the NCI via CTEP-AERS within the timeframes detailed in the table below.  
| CTEP-AERS within the timeframes detailed in the table below. Hospitalization Grade 1  Timeframes                 | Grade 3 Timeframes   | Grade 4 & 5      |
|------------------------------------------------------------------------------------------------------------------|----------------------|------------------|
| Grade 2                                                                                                          |                      |                  |
| Timeframes                                                                                                       | Timeframes           |                  |
| Resulting in  Hospitalization                                                                                    | 10 Calendar Days     | 24-Hour 5        |
| ≥ 24 hrs                                                                                                         | Calendar             |                  |
| Not resulting in                                                                                                 | Days                 |                  |
| Hospitalization                                                                                                  | Not required         | 10 Calendar Days |
| ≥ 24 hrs NOTE: Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are |                      |                  |  
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events (if applicable) are  
found in the Section 16.1f.  
Expedited AE reporting timelines are defined as:  
o "24-Hour; 5 Calendar Days" - The AE must initially be reported via CTEP-AERS within 24 hours of  
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report.  
  
  
1Serious adverse events that occur more than 30 days after the last administration of investigational agent/intervention and have an attribution of possible, probable, or definite require reporting as follows: Expedited 24-hour notification followed by complete report within 5 calendar days for:
- All Grade 4, and Grade 5 AEs Expedited 10 calendar day reports for:
- Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization
- Grade 3 adverse events May 5, 2011
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NOTE: When submitting CTEP-AERS reports for "Pregnancy, "Pregnancy loss",
or "Neonatal loss", the Pregnancy Information Form should also be completed and faxed with any additional medical information to 301-897-7404. The potential risk of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s)
should be documented in the "Description of Event" section of the CTEP-AERS report. The Pregnancy Information Form is available at: http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm
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17.0 bibliography

1 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015. [PMID: 26028407].  
2 Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015. [PMID: 26028407].
3 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med, 373:1627-1639, 2015. [PMID: 26412456].  
4 Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PDL1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): randomized controlled trial.  
Lancet Oncol 2015. [PMID: 26712084].  
5 Drake CG. Combination immunotherapy approaches. Annals of Oncology;23 (Supplement 8): 4146, 2012. [PMCID: PMC3845488].  
6. Curran MA, Montalvo W, Yagita H et al. PD-1 and CTLA-4 combination blockade expands infiltrating T-cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA; 107: 4275–4280, 2010. [PMID: 20160101].
7 Larkin et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med; 373:23-34, DOI: 10.1056/NEJMoa1504030, 2015. [PMID: 26398076].  
8 Antonia SJ, Bendell JC, Taylor MH, et al. Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer (SCLC): CA209-032. J Clin Oncol 33, 2015. [(suppl, abstr 7503) http://meetinglibrary.asco.org/content/146138-156].  
9 Antonia S, Goldberg S, Balmanoukian A, et al. A Phase 1 open-label study to evaluate the safety and tolerability of MEDI4736, an anti-programmed cell death-ligand 1 (PD-L1) antibody, in combination with tremelimumab in patients with advanced non-small cell lung cancer (NSCLC).  
Presented at ESMO 2014. Poster 1327P, Abstract 5924.  
http://annonc.oxfordjournals.org/content/25/suppl_4/iv466.3.  
10 Rizvi N, Chaft J, Balmanoukian A, et al. Tumor Response from Durvalumab (MEDI4736) +
Tremelimumab Treatment in Patients with Advanced Non-small Cell Lung Cancer is observed regardless of PD-L1 Status. *Journal for ImmunoTherapy of Cancer*, 3(Suppl 2):P193, 2015.  
Abstract, http://www.immunotherapyofcancer.org/content/3/S2/P193.
11 Antonia Goldberg, balmanoukian et al. Phase Ib study of MEDI4736, a programmed cell death ligand-1 (PD-L1) antibody, in combination with tremelimumab, a cytotoxic T-lymphocyteassociated protein-4 (CTLA-4) antibody, in patients (pts) with advanced NSCLC. 2015 asco annual meeting abstr 3014; J Clin Oncol 33, 2015. [(suppl abstr 3014) http://meetinglibrary.asco.org/content/147703-156].  
12 Rizvi N, Chaft J, Balmanoukian A, et al. Tumor Response from Durvalumab (MEDI4736) +
Tremelimumab Treatment in Patients with Advanced Non-small Cell Lung Cancer is observed regardless of PD-L1 Status. *Journal for ImmunoTherapy of Cancer*, 3(Suppl 2):P193, 2015.  
Abstract, http://www.immunotherapyofcancer.org/content/3/S2/P193.  
13 Herbst RS, Gordon MS, Fine GD, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advance or metastatic tumors. J Clin Oncol., 2013. [(suppl; abstr 3000), http://meetinglibrary.asco.org/content/115865-132].
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18.0 appendix

18.1 Background of Adverse Events of Special Interest (AESIs) 18.4 Instructions for the SWOG Biospecimen Bank  
| 18.2   | Biomarker Analysis of Immunotherapy Resistance   |
|--------|--------------------------------------------------|  
| 18.3   | PD-L1 IHC Testing   |
|--------|---------------------|  
18.1 Background of Adverse Events of Special Interest (AESIs)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of the Investigational Product and may require close monitoring and rapid communication by the investigator to the sponsor. An AESI may be serious or non-serious.  
The rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize and understand them in association with the use of this investigational product. AESIs for MEDI4736 (durvalumab) in combination with tremelimumab include but are not limited to events with a potential inflammatory or immune-mediated mechanism and which may require more frequent monitoring and/or interventions such as steroids, immunosuppressants and/or hormone replacement therapy. These AESIs are being closely monitored in clinical studies with durvalumab monotherapy and combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI that is associated with drug exposure and is consistent with an immune-mediated mechanism of action and where there is no clear alternate etiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE diagnosis.  
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE.  
If the treating Investigator has any questions in regards to an event being an imAE, the Investigator should promptly contact the Study Chair.  
AESIs observed with MEDI4736 (durvalumab) and tremelimumab are listed in Section 16.1f2.  
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different underlying pharmacological etiology are also considered AESIs. Further information on these risks (e.g. presenting symptoms) can be found in the current version of the durvalumab and tremelimumab Investigator's Brochures. More specific guidelines for their evaluation and treatment are described in Section 8.3. These guidelines apply to AEs considered causally related to the study drug/study regimen by the reporting investigator.  
If new or worsening pulmonary symptoms (e.g. dyspnea) or radiological abnormality suggestive of pneumonitis/interstitial lung disease is observed, toxicity management as described in Section 8.3. It is strongly recommended to perform a full diagnostic workup, to exclude alternative causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT
scans where other causes of respiratory symptoms have been excluded, a diagnosis of pneumonitis (ILD) should be considered.  
18.2 Biomarker Analysis of Immunotherapy Resistance
Background: Although immunotherapies have proven efficacy in NSCLC patients, the majority of patients do not respond or relapse after an initial response. Obtaining biopsies prior to the start of the combination of durvalumab and tremelimumab will allow possible mechanisms of resistance to be identified. Such identification could provide rationale for development of novel combinations to overcome resistance to immunotherapies. Objective: To obtain fresh biopsies prior to the start of MEDI4736 (Durvalumab) and tremelimumab in patients that previously received immunotherapies. Laboratory: Specimens will be shipped to the SWOG Biospecimen Bank - Solid Tissue, Myeloma and Lymphoma Division, Lab \#201 and stored until a laboratory has been identified to perform the analysis.
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specimen requirements

A new biopsy is required from patients who consent to have an optional biopsy to collect a sample of tissue prior to starting protocol treatment. The biopsy will be used to identify possible mechanism of resistance to immunotherapies to develop future novel combinations. The new biopsy should be either bronchoscopy/surgical biopsy or CT guided biopsy. The biopsy should be performed prior to the start of protocol treatment and should be processed as FFPE material. The minimum requirement is a 5-10 unstained, charged, and unbaked 4-5 micron sections.  
Specimen collection kits are not being provided for this submission; sites must use institutional supplies.  
18.3 PD-L1 IHC Testing  
PD-L1 expression localization within the tumor microenvironment will be assessed in patients registered to **S1400F**. Tumor specimens will be shipped from the SWOG
Biospecimen Bank at Nationwide Children's Hospital to Clarient about every 3 months. The SWOG Statistics and Data Mangaement Center will provide the SWOG Biospecimen Bank with the list of patient specimens to ship to Clarient. Objective To identify PD-L1 status in tumor samples from patients who have progressed on an antiPD-1/PD-L1 and enrolled onto the **S1400F** sub-study.
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assay description

AstraZeneca has developed a technically validated immunohistochemistry (IHC)-based assay for PD-L1 determination in partnership with Ventana Medical Systems Inc. a CAPaccredited/CLIA-certified laboratory (Tucson, AZ).  
Laboratory Clarient will serve as the central laboratory for testing PD-L1 expression in patients who register to **S1400F**.  
Specimen Requirements For the PD-L1 IHC testing, no on-site processing of specimens will be required prior to shipment to the SWOG Biospecimen Bank. Tissue sample collected for **S1400** or LUNGMAP biomarker profiling will be used. The preferred thickness is 4 micron unstained tissue sections; although 5 micron unstained tissue sections are allowable. For patients with tumor blocks at SWOG Biospecimen Bank, SWOG Biospecimen Bank will prepare 4 micron, unstained slides. At least 100 tumor cells are defined to be sufficient viable tumor tissue for PD-L1 IHC testing. Fine needle aspirates are not acceptable. A minimum of 2
(preferably 4) unstained tissue sections along with a hematoxylin-eosin (H&E)-stained slide or Aperio H&E-stained image will be sent to Clarient for PD-L1 IHC testing from consented patients with sufficient tissue.  
Lab \#214: Clarient  
18.4 Instructions for the SWOG Biospecimen Bank
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frozen plasma and buffy coat

The SWOG Biospecimen Bank will receive frozen plasma and buffy coat at up to 5 time points per patient. Upon receipt, the Bank will accession, barcode, and bank specimens in a -80°C freezer.
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formalin-fixed paraffin-embedded (ffpe) tissue

The SWOG Biospecimen Bank will receive FFPE specimens as either blocks or slides/sections at up to 2 time points per patient. Upon receipt, the Bank will accession, barcode, and bank specimens at ambient temperature. At the end of the study, the Bank will receive notification from the SWOG Statistics and Data Management Center (SDMC) to distribute specimens for testing. The SDMC will create three pull lists for Nationwide informing them which samples are:
- leftover tissue from patients biopsied at screening
- patients who consented to a biopsy prior to treatment
- patients who consented to a biopsy at progression Tumor Tissue for PD-L1 IHC Testing The SWOG Biospecimen Bank will send FFPE slides from consented patients for PD-L1 IHC testing at Clarient. About every 3 months, the Bank will receive notification from the SWOG Statistics and Data Management Center to distribute specimens for testing.  
The Bank will send 2-4 unstained slides. If an FFPE tissue block was received, then the SWOG Biospecimen Bank will process 2-4 unstained slides (4 micron, charged) and an H&E-stained slide. The unstained slides will be shipped to Clarient for testing, and the H&E
slides will be scanned to a 40x digital image.  
Tumor Tissue for Immunotherapy Resistance Analysis The SWOG Biospecimen Bank will send FFPE slides from consented patients for immunotherapy resistance analysis. The Bank will send 5-10 unstained slides. If an FFPE tissue block was received, then the SWOG Biospecimen Bank will process up to 10 unstained slides (4 micron, charged, unbaked) to send for testing.