untitled h1
11.7 publications

This trial is intended for publication, even if terminated prematurely. Publication may include any or all of the following: posting of a synopsis online, abstract and/or presentation at a scientific conference, or publication of a full manuscript. The Sponsor will work with the authors to submit a manuscript describing trial results within 12 months after the last data become available, which may take up to several months after the last subject visit in some cases such as vaccine trials. However, manuscript submission timelines may be extended on OTC trials. For trials intended for pediatric-related regulatory filings, the investigator agrees to delay publication of the trial results until the Sponsor notifies the investigator that all relevant regulatory authority decisions on the trial drug have been made with regard to pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the primary outcome, 12 months after the decision to discontinue development, or product marketing (dispensed, administered, delivered or promoted), whichever is later.  
These timelines may be extended for products that are not yet marketed, if additional time is needed for analysis, to protect intellectual property, or to comply with confidentiality agreements with other parties. Authors of the primary results manuscript will be provided the complete results from the Clinical Study Report, subject to the confidentiality agreement. When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include the protocol and statistical analysis plan to facilitate the peer and editorial review of the manuscript. If the manuscript is subsequently accepted for publication, the Sponsor will allow the journal, if it so desires, to post on its website the key sections of the protocol that are relevant to evaluating the trial, specifically those sections describing the trial objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, the efficacy and safety measures, the statistical analysis plan, and any amendments relating to those sections. The Sponsor reserves the right to redact proprietary information.  
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an investigator and his/her colleagues may publish their data independently. In most cases, publication of individual trial site data does not add value to complete multicenter results, due to statistical concerns. In rare cases, publication of single trial site data prior to the main paper may be of value. Limitations of single trial site observations in a multicenter trial should always be described in such a manuscript. Authorship credit should be based on 1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published. Authors must meet conditions 1, 2 and 3. Significant contributions to trial execution may also be taken into account to determine authorship, provided that contributions have also been made to all three of the preceding authorship criteria. Although publication planning may begin before conducting the trial, final decisions on authorship and the order of authors' names will be made based on participation and actual contributions to the trial and writing, as discussed above. The first author is responsible for defending the integrity of the data, method(s) of data analysis and the scientific content of the manuscript. The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.
untitled h1
12.0 literature cited

1. Howlader NA, Krapcho M, Neyman N, et al. Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). 2012.  
2. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169–81.  
3. Garon EB, Leighl NB, Rizvi NA, et al. Safety and clinical activity of MK-3475 in previously treated patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol 2014; 32:5s (suppl; abstr 8020).  
4. Kris MG, Johnson BE, Berry LD et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014 May 21; 311(19):1998-2006.  
5. Shi Y, Au JS, Thongprasert S, Srinivasan S, Tsai CM, et al. A Prospective, Molecular Epidemiology Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer of Adenocarcinoma Histology (PIONEER). J Thorac Oncol 2014; 9: 154–162.  
6. Barlesi F, Blons H, Beau-Faller M, et al. Biomarkers (BM) France: results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). J Clin Oncol 2013; 31(suppl);abstr8000.  
7. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19; 6550-6565 8. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefinitib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361:947–57.  
9. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013 Sep 20;31(27):3327-34.  
10. Jänne PA, Boss DS, Camidge DR, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res. 2011; 17(5):11319.  
11. Miller VA, Hirsh V, Cadranel J, et al. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial. Lancet Oncol 2012; 13:528– 538.  
12. Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M
mutation. Clin Cancer Res. 2011; 13:1616–1622.  
13. Zhou W, Ercan D, Chen L et al. Novel mutant-selective EGFR kinase inhibitors against EGFR
T790M. Nature 2009; 462:1070–1074.  
14. Cross DA, Ashton SE, Ghiorghiu S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Jun 3. pii:
CD-14-0337.  
15. Sakuma Y, Yamazaki Y, Nakamura Y, et al. WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors. Lab Invest. 2012; 92:371–83.  
16. Soria JC, Sequist LV, Gadgeel S, et al. First-in-human evaluation of CO-1686, an irreversible, highly selective tyrosine kinase inhibitor of mutations of EGFR (activating and T790M). In Proceedings of the 15th World Conference on Lung Cancer; Sydney, Australia; 2013.  
17. Ranson M, Pao W, Kim DW, et al. Preliminary results from a Phase I study with AZD9291: An irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small-cell lung cancer (NSCLC). European Cancer Congress 2013 Abstract.  
18. Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain containing tyrosine phosphatase 2 to phosphotyrosine. PNAS 2001; 98(24).  
19. Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009; 229:114-25.  
20. Sheppard K-A, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3 signalosome and downstream signaling to PKCO. FEBS Lett 2004; 574:37-41.  
21. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 2010; 37(Suppl 1): 48-53 22. Keir, M.E., Butte, M.J., Freeman, G.J., et al. PD-1 and its ligands in tolerance and immunity. Annu.  
Rev. Immunol 2008; 26, 677–704.  
23. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discovery 2013.  
24. Kudo-Saito C, Shirako H, Takeuchi T,et al. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell 2009; 15: 195–206.  
25. Akalay I, Janji B, Hasmim M, et al. Epithelial-to-mesenchymal transition and autophagy induction in breast carcinoma promote escape from T-cell-mediated lysis. Cancer Res 2013; 73:2418–2710.  
26. Cao Y, Zhang L, Kamimura Y, et al. B7–H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Res. 2011;71(4):1235–1243.  
27. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer.  
2012; 12:252–64.  
28. Garon EB, Rizvi N, Hui R, et al. Pembrolizumab in Non-Small Cell Lung Cancer. NEJM. 2015.  
29. Motz GT, Coukos G. Deciphering and reversing tumor immune suppression. Immunity. 2013 Jul 25; 39(1):61-73.  
30. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (Anti-PD-1)
in melanoma. N Engl J Med 2013; 369:134–44.  
31. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012; 366:2443–54.  
32. Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer. 2014 Jun 1;120(11):1695701.  
33. Tang Y, Fang W, Zhang Y, et al. The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFRTKIs. Oncotarget. 2015;6(16):14209-19.  
34. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer.  
N Engl J Med. 2015;372(21):2018-28.  
35. Zatloukal P, Heo DS, Park K, Kang J, Butts C, Bradford D, Graziano S, Huang B, Healey D.  
Randomized phase II clinical trial comparing tremelimumab (CP-675,206) with best supportive  
care (BSC)following first-line platinum-based therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27(suppl; abstr 8071).  
36. Hellmann MD, Garon EB, Gandhi L, Hui R, Zhang J, Rangwala R, Lubiniecki GM,
Rizvi NA. Efficacy of pembrolizumab in key subgroups of patients with advanced nonsmall cell lung cancer (aNSCLC). World Conference on Lung Cancer. 2015 September 6-9. Denver, Colorado. Abstract nr.3057.  
37. Reck M, Rodriguez-Abreu D, Robinson A, et al. KEYNOTE-024: Pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) as first-line therapy for advanced NSCLC with PD-L1 tumour proportion score (TPS) .50%. ESMO. 2016, October 9. Copenhagen, Denmark. Abstract nr. LBA8_PR.
untitled h1
13.0 appendices 13.1 ecog performance

| Grade                                                                                                                                                                                                                                                                                                                       | Description                                                                                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                                                                                                                                                                                           | Normal activity. Fully active, able to carry on all pre-disease performance  without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity, but             |
| 1                                                                                                                                                                                                                                                                                                                           | ambulatory and able to carry out work of a light or sedentary nature (e.g.,  light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but unable |
| 2                                                                                                                                                                                                                                                                                                                           | to carry out any work activities. Up and about more than 50% of waking  hours.                                                                                                           |
| 3                                                                                                                                                                                                                                                                                                                           | In bed >50% of the time. Capable of only limited self-care, confined to bed  or chair more than 50% of waking hours.                                                                     |
| 4                                                                                                                                                                                                                                                                                                                           | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                   |
| 5                                                                                                                                                                                                                                                                                                                           | Dead.                                                                                                                                                                                    |
| *As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J.,  Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern  Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative  Oncology Group, Robert Comis M.D., Group Chair. |                                                                                                                                                                                          |
untitled h1
13.2 common terminology criteria for

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html)
13.3 **Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating**
Response in Solid Tumors
untitled h1
recist v1.1 tumor assessment worksheet

1. Refer to the protocol for specific tumor assessment requirements noting:
a. any protocol specific modifications to RECIST v1.1 criteria - be sure to incorporate these into your assessment (i.e., imaging modality)
b. screening window for tumor assessment c. time-points/windows/frequency of tumor assessments during treatment and follow-up when applicable determine time-point that first assessment is to be done, i.e.,: 6 weeks from randomization date or 6 weeks from C1D1 (+/- 7days)
2. Standard method of assessment for RECIST v1.1 remains grounded in the anatomical assessment of disease by contrast CT of Chest, Abdomen, and Pelvis, and CT or MRI of brain when clinically indicated. If contrast CT is contraindicated, then a non-contrast CT of Chest and MRI of Abdomen and Pelvis should be done. Functional imaging or FDG-PET is not an acceptable method of tumor assessment per RECIST v1.1 criteria; rather it is used as an adjunct to determination of disease progression. Bone scan or plain films are not considered adequate imaging techniques to measure bone lesions; however these techniques can be used to confirm the presence or disappearance of bone lesions. Imaging based evaluation should always be done rather than clinical exam unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam.  
3. Radiologist should provide a thorough baseline assessment of all sites of disease, non-nodal and nodal, along with the longest diameter in mm of non-nodal disease and the short axis measurement in mm of nodal disease. Non-disease findings should also be documented in the radiology report and noted in the investigator's note (i.e.: simple cyst, fatty tissue).  
4. Using the radiologist's assessment, the investigator should select a total of ten (10) target lesions (TL) with a maximum of five (5) lesions per organ on the basis of their size, be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. All other sites of disease should be identified as nontarget lesions (NTL). The investigator should document his/her choice and rationale for selection of lesions for baseline assessment of overall tumor burden to be assessed for response.  
Note: You may record multiple non-target lesions involving the same organ as a single NTL on the form, i.e.: multiple bone mets, multiple liver mets; multiple enlarged pelvic lymph nodes.  
a. **Target Lesions (TLs)** are defined as non-nodal lesions with a minimum longest diameter (LD) of≥10mm by CT/MRI; 10mm caliper measurement by clinical exam
(documented with photo and ruler); ≥20mm by chest X-ray (For the purpose of this study, CT is preferred); and lymph nodes >15mm in the *short axis (SA)*. **Note:** Measure the longest diameter of the node first. Then determine the longest dimension perpendicular to the longest diameter and report that measurement as the short axis.  
(For example: a cervical lymph node is reported as being 17mm x 22mm. The SA measurement would be 17mm). *Note:* Lytic or mixed lytic-blastic bone lesions with identifiable soft tissue components that can be evaluated by CT/MRI and meet the definition of measurability can be considered as measurable lesions b. **Non-Target Lesions (NTLs)** are defined as non-measurable and include: any measurable lesions that were not selected as target lesions; non-nodal lesions <10mm in *longest diameter*; lymph nodes that have a *short axis* >10mm and <15mm *Note:* SA nodal non-target lesion must have a reduction in SA to <10mm to be considered a CR; therefore, documenting nodal non-target lesions SA is recommended. ; blastic bone lesions, lytic or mixed lytic-blastic lesions without an identifiable soft tissue component that meets the definition of measurable, and lesions considered truly nonmeasurable which include: leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitic involvement of skin/lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques. *Note*: lesions situated in a previously irradiated area are considered non-measurable lesions (non-target) unless there has been demonstrated progression in the lesion and then it may be considered a target lesion.  
c. **Non-Pathological Lesions** include nodes that have a short axis of <10mm and simple cysts. These should not be recorded as target or non-target lesions.  
5. List each selected baseline target lesion under the column "Lesion Description" and record the LD/SA (Largest Diameter(non-nodal)/Short Axis(nodal)) for each lesion in the corresponding Baseline LD/SA mm column. Baseline assessment of overall tumor burden is calculated by adding the longest diameter measurement of non-nodal target lesions and the short axis measurement for target nodal lesions in mm and reporting this as the baseline Sum of the Diameters (SOD). Add the baseline measurements and record the SOD in the corresponding space.  
6. List all non-target sites of disease under the column "Lesion Description" and record as present in the corresponding Baseline Present/Absent column. Measurements are not required and should be followed as "present", "absent", or in rare cases "unequivocal progression" (write this in space when applicable). Note: There are not a maximum number of non-target lesions; therefore, you may need to use an additional assessment form to document all non-target lesions. However, keep in mind that multiple non-target lesions involving the same organ may be recorded as a single item, i.e., multiple liver mets 7. Document the time-point response of Target Lesions in the row labeled "**TL Response"** that corresponds to the specific assessment time-point. Target lesion response is determined by the SOD of subsequent tumor assessments. **Note**: All Target Lesions (nodal and non-nodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small. If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as "0"mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5mm should be recorded.  
a. **Complete Response (CR)**: Disappearance of all target lesions (each pathological lymph nodes must have a reduction in short axis to <10mm)
b. **Partial Response (PR**): >30% decrease in the **baseline SOD**. To find the PR
threshold, at baseline, multiple the baseline SOD x 0.7 and record this in the corresponding spaces for each tumor assessment time-point. Note: This calculation only needs to be calculated at baseline. For example: Baseline SOD = 32mm x 0.7 =
22.4mm; therefore, on subsequent assessments, the SOD would have to be <22.4mm to be documented and recorded as a PR.  
c. **Progressive Disease (PD):** >20% increase in the **Nadir SOD** (this includes the Baseline SD if it is the smallest on study) + an absolute increase of 5mm over the nadir SOD. The appearance of one or more new lesions representing disease is also considered PD. To find the PD threshold, determine the smallest SD recorded and multiple it by 1.20 and record this calculation in the corresponding space for each tumor assessment time-point. *Note: This calculation must be done at each assessment*.  
Example: Baseline SOD = 43mm PD threshold = 43 x 1.20 = 51.6mm. Assessment \#2 SOD = 35mm, = 1.2 x 35 = new PD threshold = 42mm Assessment \#3 SOD =
37mm. PD threshold = 42mm (Nadir SOD of 35mm). Assessment \#4 SOD = 43mm = >20% ↑ over nadir SOD (Assessment \#2) and the SOD of 43mm is an absolute increase of 8mm over the nadir SOD of 35mm.  
d. **Stable Disease (SD):** There is neither sufficient shrinkage (compared to baseline) to qualify for PR nor sufficient increase (taking as reference the smallest SOD while on study) to qualify for PD.  
e. **Not All Evaluated (NE)**: When no imaging/measurement is done at all at a particular assessment time point or only a subset of lesion measurements are made at an assessment (unless documentation is made that the contribution of the individual missing lesion(s) measurements would not change the assigned time point response. This would most likely happen in the case of PD). *Note:* Make all attempts at obtaining/clarifying measurements for all baseline sites of disease at each subsequent assessment time-point.  
8. Document the time-point response of Non-Target Lesions in the row labeled **"NTL Response"**
that corresponds to the specific assessment time-point. Non Target Lesion response is defined as:
a. **Complete Response (CR)**: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis)
b. **Non CR/Non PD**: Persistence of one or more non-target lesions and/or maintenance of tumor marker level above normal limits c. **Progressive Disease (PD):** Unequivocal progression of existing non-target lesions.  
The appearance of one or more new lesions is also considered progression. *Note:* When there is measurable disease, to achieve unequivocal progression, there must be an overall level of substantial worsening in non-target disease, such that even in presence of SD or PR of target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. When there is only non-measurable disease, there needs to be an increase in tumor burden representing an additional 73% increase in volume (example: increase in pleural effusion from trace to large)
d. **Not All Evaluated (NE)**: When none or only some imaging is done at a particular assessment time point.  
9. Document the presence or absence of any new lesion (Target or Non-Target) in the row labeled
"NEW LESION" at each assessment time point after baseline. This represents disease progression; however, this finding should be unequivocal and not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor (Example: a new bone lesion may represent healing or flare of pre-existing lesions).  
a. A lesion identified on a follow-up study in an anatomical location that **was not**
scanned at baseline is considered a new lesion and will indicate disease progression b. If a new lesion is equivocal (i.e. because of small size), continued therapy and follow up evaluation may clarify if it truly represents new disease. Discuss and obtain approval from medical monitor to continue treatment and re-evaluate. If re-eval confirms it as a new lesion, then PD should be recorded as the date of initial scan.  
10. Document the overall response in the row labeled **"OVERALL RESPONSE"** at each assessment time point after baseline. Refer to Table 1 (for subjects with Target +/- Non Target Disease) and Table 2 (for subjects with Non Target Disease only).  
11. Document the review and confirmation date of the Clinical Investigator in the row labeled
"Investigator Signature/Date" at baseline and each subsequent assessment time point.  
Important: This is source documentation that disease burden and response have been confirmed by the investigator prior to continued study treatment after each assessment time point. In addition, the investigator's documentation should reflect any clarifications related to imaging/treatment discussed with radiologist and/or study monitor.
untitled h1
additional recist v1.1 guidance 1.

When nodal disease is included in the Sum of Largest Diameter of target lesions and the nodes decrease to "normal" size (<10mm), measurements may still be reported on scans. The measurements should be recorded even though the nodes are normal to prevent the overstatement of progression should progression be based on increase in the size of the nodes. This means that responses with CR may not have a total sum of "zero".  
When it is difficult to distinguish residual disease from normal tissue and the evaluation of CR depends upon this determination, it is recommended that the residual lesion be investigated (FNA/Biopsy) before assigning a status of CR. FDG-PET may be used to upgrade a response to CR in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. *Note: both approaches may lead to false* positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.  
Progression:
For equivocal findings of progression (i.e., very small and uncertain new lesions, cystic changes or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression is confirmed, the date of progression should be the earlier date when progression was suspected.  
Note: The investigator's documentation should reflect the equivocal findings with decision to continue to treat until the next scheduled assessment.  
Patients with 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 objective progression even after discontinuation of treatment. Symptomatic deterioration is a reason for discontinuing study therapy, not an objective response which is determined by evaluation of target and non-target disease.  
Target Lesions that Split or Coalesce:
When non-nodal lesions split, the longest diameters of the split portions should be added together to calculate the target lesion sum When a non-nodal lesion has coalesced (no longer separable), the vector of the longest diameter should be the maximal longest diameter for the coalesced lesion Target Lesions that become "too small to measure":
o Actual measurements of all baseline nodal and non-nodal lesions should be recorded at each subsequent assessment, even when very small (i.e., 2mm). If the radiologist is not comfortable with assigning an exact measurement and the radiologist feels o that the lesion has likely disappeared, the measurement should be recorded as
"0"mm o that the lesion is believed to be present and is faintly seen but too small to measure, a default value of "5"mm should be recorded
untitled h1
2. confirmatory measurement of response

a. In non-randomized trials where response is the primary endpoint, confirmation of CR
and PR is required to ensure responses identified are not due to measurement error.  
b. In randomized (phase II or III) trials where SD or PD are the primary endpoints, confirmation of response is not required c. Stable Disease measurements must have met the SD criteria at least once after study entry at a minimum interval (in general > 6-8 weeks) that is defined in the study protocol.
untitled h1
modified recist definitions

Definition for SD, PR, and CR are the same as RECIST 1.1. PD by modified RECIST: Although the same rules for progression apply for modified RECIST, if the subject is clinically stable, at the discretion of the PI, they may continue treatment until the next imaging time points ≥4 weeks later. If PD is confirmed, the date of PD is the same as the initial date of PD by RECIST. If PD is not confirmed, the date of PD is based on the second event for PD by imaging.  
o The following scenarios defined confirmation of PD or lack thereof at the repeat imaging time point. Note that if PD is not confirmed, imaging should resume the regular interval per the schedule. Also, if a second PD event occurs, no further confirmation of PD is required. Note; if PD is confirmed and the subject is achieving a clinically meaningful benefit, the site should speak with DSMB to discuss the potential to continue on treatment.
untitled h1
pd is confirmed

1. If initial PD is due to increase in tumor burden ≥ 20% compared to nadir, PD is Confirmed if ANY of the following are met:
o At follow-up scan tumor burden remains ≥ 20% compared to nadir + 5mm absolute increase if tumor burden is small o New unequivocal PD of non-target lesion (NTL) qualitative)
o One or more new lesion(s)
o Clinical instability 2. If initial PD is due to unequivocal PD of NTL, PD is CONFIRMED at follow up if ANY of the following conditions are met:
o NT disease resulting in initial PD is worse (qualitative) o New additional unequivocal PD of NTL
o ( qualitatively assessed)
o Additional new lesion (s) o New PD due to tumor burden (SOD) ≥ 20% compared to nadir+ 5 mm absolute increase if tumor burden is small 3. If PD is due to New Lesion, PD is CONFIRMED at follow up time point if ANY of the following conditions are met:
o New lesion resulting in initial PD is worse (qualitative) o Additional new lesion (s ) o New unequivocal PD of non target (qualitative)
o New PD due to tumor burden (SOD) ≥ 20% compared to nadir + 5 mm absolute increase if tumor burden is small
untitled h1
pd is not confirmed at

4. If PD is due to increase in tumor burden by 20% compared to nadir, PD is NOT CONFIRMED
at follow up if ALL of the following conditions are met o Tumor burden is <20% compared to nadir o No unequivocal PD of non target lesion (qualitative) o No new lesion(s)
o Continued clinical stability 5. If PD is due to New Lesion(s), PD is NOT CONFIRMED at follow up time point if ALL of the following conditions are met:
o Previous new lesion (that was initially called PD) is not worse (qualitative) o No additional new lesion(s) o No unequivocal PD of non target (qualitative) o No new PD due to tumor burden (SOD) ≥ 20% compared to nadir o Continued clinical stability 6. If PD is due to unequivocal PD of non target, PD is NOT CONFIRMED at follow up if ALL
of the following conditions are met:
o Initial PD of non target disease is not worse (qualitative) o No additional new unequivocal PD of non target qualitative)
o No new lesion(s )
o No new PD due to tumor burden (SOD) ≥ 20% compared to nadir o Continued clinical stability  
Time point response of Measurable Disease (Target Lesions) with or without Non-Measurable Disease (Non Target Lesions)  
| Disease (Non Target Lesions) Target Lesion Response   | Non Target Lesion    | New Lesions                       | Overall Response   |
|-------------------------------------------------------|----------------------|-----------------------------------|--------------------|
| CR                                                    | CR                   | No                                | CR                 |
| Response                                              |                      |                                   |                    |
| CR                                                    | Non-CR/Non-PD        | No                                | PR                 |
| CR                                                    | NE                   | No                                | PR                 |
| PR                                                    | Non-PD or NE         | No                                | PR                 |
| SD                                                    | Non-PD or NE         | No                                | SD                 |
| NE                                                    | Non-PD               | No                                | NE                 |
| PD                                                    | Any                  | Yes or No                         | PD                 |
| Any                                                   | PD                   | Yes or No                         | PD                 |
| Any                                                   | Any                  | Yes                               | PD                 |
| CR=Complete Response,                                 | PR=Partial Response, | SD=Stable Disease, PD=Progressive |                    |
| Disease, and NE=Not All Evaluated                     |                      |                                   |                    |  
Time point response of Non-Measurable Disease Only (Non Target Lesions)  
| Non Target Lesion Response   | New Lesions   | Overall Response   |
|------------------------------|---------------|--------------------|
| CR                           | No            | CR                 |
| Non-CR/Non-PD                | No            | Non-CR/Con-PD      |
| NE                           | No            | NE                 |  
| Unequivocal Progression                                                                                                                                                                                                                                                                                        | Yes or No   | PD   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|------|
| Any                                                                                                                                                                                                                                                                                                            | Yes         | PD   |
| CR=Complete Response, PD=Progressive Disease, and NE=Not All Evaluated Non-CR/Non-PD is preferred over "Stable Disease" for non-target disease since SD is  increasingly used as endpoint for assessment of efficacy in some trials so to assign this  category when no lesions can be measured is not advised |             |      |  
Note: If a CR is truly met at a time point, then any disease seen at a subsequent time point, even disease meeting PR criteria relative to baseline, makes the disease PD at that time point since disease must have reappeared after CR.