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11.1 correlative studies

11.2 Tumor Correlative Studies Pre-therapy tumor that has been fixed with 10% buffered formalin solution and processed into paraffin embedded (FFPE) tissue blocks will be collected. The Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 following infiltrating cells will be quantified (0 to 3+) using standing immunofluorescence techniques: CD4+, CD8+, CD68+ , PD 1+CD4+, PD 1+CD8+, PD-1+CD68+, PD-1L+, and CD4+Foxp3+. See Appendix M. Methods: Immunohistochemical staining will be carried out on 4μm-thick sections utilizing an Autostainer Plus (Dako - Agilent Technologies) with appropriate positive and negative controls. Sections are baked for 60 minutes at 60 °C in a dehydration oven and heat-induced epitope retrieved in the PT link (Dako - Agilent technologies) using EnVision FLEX target retrieval solution for 20 minutes at 97 °C then cooled to room temperature in TBST Wash buffer for 5 minutes.  
Slides are incubated with the following antibodies at the following dilutions:  
| Dilution   | Source   |                    |
|------------|----------|--------------------|
| PD-1       | 1:100    | Cell Marque NAT105 |
| PD-L1      | 1:1000   | R&D Systems        |
| CD4        | 1:100    | Cell Marque SP35   |
| CD8        | 1:200    | Cell Marque SP16   |
| FOXP3      | 1:200    | Abcam AB22510      |
| CD68       | 1:1000   | Cell Marque KP-1   |  
Antibody detection will utilize the Envision FLEX kit (K8023) with a DAB
chromagen for visualization according to the manufacturer's instructions (Dako -
Agilent technologies). Slides are then counterstained with hematoxylin. The percentage of tumor which have an infiltrate of lymphocytes or macrophages will be estimated and the average number of positive immune cells per high power field (HPF) in a minimum of 4 representative HPF areas will be determined utilizing a semi-quantitative four tiered scale used for scoring lymphocytes (0= no lymphocytes, 1= 1-10/HPF, 2= 11-50/HPF and 3= >50/HPF) and macrophages (0= no macrophages, 1= 1-50/HPF, 2= 50-100/HPF and 3=>100/HPF). Lymphocyte and macrophage infiltrate scores are obtained by multiplying these scores to attain a score from 0-300.
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11.3 blood correlative studies

Blood will be drawn prior to initiating treatment (C1D1), day 1 of cycle 2 (C2D1), day 1 of cycle 3 (C3D1), and End of Treatment (EOT). All blood samples are collected from the clinic and transported at room temperature within 3 hours after being drawn from each individual. Whole blood is collected in Vacutainer tubes containing EDTA (BD Vacutainer). Peripheral blood mononuclear cells (PBMC)
are isolated from whole blood by density gradient centrifugation using Lymphocyte Separation Medium (Mediatech) and Leucosep tubes (Greiner Bioone). Whole blood is centrifuged at 410 × g for 10 minutes and the plasma layer is collected, centrifuged for 10 minutes at 885 × g, and the supernatant frozen at
−80°C for subsequent experiments. The whole blood is diluted 1:1 with RPMI
(Mediatech) and the PMBCs isolated per manufacturer's guidelines. Cells at the Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 interface are harvested and washed once with RPMI, and red blood cells are lysed with ammonium chloride lysis buffer. Cells are washed, counted, and immediately used fresh for staining and flow cytometry analysis, or 10 million PBMCs are frozen per milliliter of freezing solution (10% DMSO 10% FBSsupplemented RPMI) per NUNC cryovial. PBMCs are frozen in a Nalgene Cryo 1°C freezing container per manufacturer's instructions and stored in liquid nitrogen thereafter.  
See Appendix N. The following will be assessed:
- Frequency (flow cytometry) of Lin−CD14+HLA-DRlow/− MDSC; CD4+,
CD8+, ICOS+CD4+, ICOS+CD8+ effector and CD4+FoxP3+ regulatory T
cells
Method: Antibodies that will be used for flow cytometry analysis include CD4- BV421 (eBiosciences), CD8-PE (BD Pharmingen), CD14-APC (eBiosciences), HLA-DR-FITC (BD Pharmingen), lineage
(CD3/CD16/CD19/CD20/CD56) cocktail FITC (BD Pharmingen), ICOSefluro660 (eBiosciences), and FoxP3-Alexa480 (eBioscience). Isotype controls include the appropriate fluorochrome-conjugated mouse IgG1, IgG 1k, IgG2a, or IgG2b k (BD Pharmingen; Beckman Coulter; R&D Systems).  
Triplicate samples will be analyzed using the FACSCanto II (Becton Dickinson). Data will be analyzed using the BD FACSDiva software. Gates are set according to appropriate isotype controls. Absolute lymphocyte counts will also be determined. Frequency (%) of the following phenotypes will be determined.  
Effector CD4+  
CD8+  
ICOS+CD4+  
ICOS+CD8+  
T regulatory CD4+FoxP3+  
Myeloid derived suppressor Lin-CD14+HLA-DRlow/−  
- Peripheral blood mononuclear cell Th1/Th2/Th17 cytokine production in vitro (BD Cytometric Bead Array) in response to WT-1, p53, Mage-A3, Her2/neu, telomerase, and survivin peptide mixtures (Proimmune Promix), tumor-associated determinants implicated in NSCLC, and to anti-CD3 plus anti-CD28 antibody (BD)
Methods: PBMC that have been separated by gradient centrifugation and cryopreserved are thawed at 37 ºC, diluted in 5 ml RPMI, and incubated at 37 ºC for 1 hour. Cells are then pelleted at 200g, resuspended in complete medium, counted with trypan blue, and suspended at 4x106/ml and plated in 100 µl in 96 well conical wells. PBMC are then cultured with 20 μg/ml of WT1, p53, Her2/neu, Mage-A3, telomerase, and survivin peptide mixtures ProMix Peptide Pools (Proimmune Inc.). As a control PBMC are also stimulated with anti-CD3 plus anti-CD28 antibody (BD Pharmingen). After 3 Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 days, culture supernatants are collected and assayed using BD Cytometric Bead Array Human Th1/Th2/Th17 Cytokine Kit according to the manufacturer's instructions. Positivity criteria include a ≥3.0-fold increase over unstimulated background control, expressed as a stimulation index (SI), as well as a minimum concentration (pg/ml) over background as follows: IL-2, 40; IL-4, 15; IL-6, 20; IL-10, 50; IFN-γ, 75; tumor necrosis factor-α, 30; and IL17A, 20.  
- Plasma levels (ELISA) of TGF-β, VEGF, IL-6, IL-8, PGE2 (metabolite),
and sPD-1L.
Methods: Commercially available ELISA kits will be used according to the recommendation of the manufacturer. Results are expressed as a concentration.  
| Manufacturer      |             |
|-------------------|-------------|
| TGF-β             | R&D Systems |
| VEGF              | R&D Systems |
| IL-6              | R&D Systems |
| IL-8              | R&D Systems |
| PGE2 (metabolite) | Abcam       |
| sPD-1L            | MyBiosource |
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11.4 quality of life correlative

EORTC QLQ-30 and EORTC QLQ-LC13 will be completed by the patient at baseline and then every 12 weeks (Appendices I - L).  
21 The EORTC QLQ-C30 is reportedly the most frequently used QOL instrument in lung cancer clinical trials.22 The QLQ-30 is a 30-item multi-dimensional questionnaire designed for use in cancer populations.21 It contains ninemultiitem scales: five functional scales (physical, role, cognitive, emotional, and social); three symptom scales (fatigue, pain, and nausea and vomiting); and a global health and quality-of-life scale, requested by 4-point Likert or visual analogue scales. Several single-item symptom measures are also included. The QLQ-LC13 is a lung cancer-specific module to be used in conjunction with the QLQ-30 and is 13 additional items. These questionnaires have been shown to be reliable and valid in over 60 languages, can be self or interviewer-administered and take approximately 11 minutes to complete.  
21,22 Both the QLQ-C30and QLQ-LC13 will be available in Spanish for Spanish-speaking participants.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
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12.0 data management

| Informed consent document    | WISER   |
|------------------------------|---------|
| Protocol registration form   | WISER   |
| Tumor measurement form       | REDCap  |
| Screening form               | REDCap  |
| Study data collection form   | REDCap  |
| Follow-up form               | REDCap  |
| EORTC QLQ-C30 & QLQ-LC13     | REDCap  |
| Tumor correlative study form | REDCap  |
| Blood correlative study form | REDCap  |
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13.1 statistical considerations 13.2 power

This is a pilot study and will accumulate useful preliminary data to compare whether a combination of immunotherapy and chemotherapy shows more promising efficacy data than immunotherapy alone. To achieve this goal a total of 40 patients will be randomized, 20 patients will be randomized to single agent and 20 to the combination.  
For the primary outcome of objective response rate, (ORR) patients will be dichotomized to being a success/failure based on whether they have a partial or complete response.  
Exact Clopper-Pearson 95% confidence intervals will be calculated for each group separately. With a sample size of 20 patients in a group, a two-sided 95% confidence interval (Exact Clopper-Pearson interval) will have a total width of 0.324 if the estimated proportion of successes is 50% (most conservative assumption for the confidence interval calculation). This level of precision will provide information (estimate and 95%
confidence interval) as to whether this therapeutic approach is promising and worthy of future studies. Furthermore, a comparison between groups will be made using a Fisher's Exact Test. If we observe a very large difference in ORR (greater than 43% in absolute percent if the ORR was 10%in the Control arm) we will have sufficient power to declare that difference statistically significant. However, since this is a pilot study it is not anticipated that a statistically significant difference will necessarily beobserved. Based on current projects, approximately 30 eligible patients will be enrolled in one year, so overall it is anticipated that the trial will take approximately 18 months to accrue 40 patients followed by a 12-month follow-up period for the patients.
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13.3 analysis of primary objective

13.3.1 The effects of the treatments on immune markers will be analyzed using paired t-tests (possibly after transformation) or the non-parametric Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 counterpart within each group separately. In addition, the two groups will be compared on these measures using two-sample t-tests for outcomes measured only post-randomization or analysis of covariance for measures that have an assessment made prior to randomization. If a measure is assessed a multiple post-randomization times then a longitudinal mixed model will be fit to examine the differences between groups over time accounting for the repeated measurements.  
13.3.2 This study will enroll patients with recurrent or metastatic NSCLC and PS
of 2. In this group of patients, the ORR's is approximately 10% with OS of about 2 to 4 months. With this pilot study, we would be able to conduct two hypothesis tests (one for each arm of the study) to determine whether there is evidence that the observed response rate, using RECIST criteria, is better than 10%. To do this, two one-sided binomial tests will be performed. For each test the null hypothesis is that the response rate is 10% and the alternative hypothesis is that the response rate is higher than 10%. With 20 patients in each analysis there is 80% power to detect a difference of 0.2133 with alpha=0.05 (one sided).  
13.3.3 Duration of response will also be assessed in each group and compared using survival analysis methods. Furthermore, progression free and overall survival rates will be estimated in each group and compared using Kaplan-Meier curves. These comparisons will be for descriptive purposes since it is not anticipated that statistically significant differences will be observed with the small sample sizes.
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13.4 analysis of secondary objectives

13.4.1 Adverse events will be categorized by organ system and severity and summarized as frequency counts and percentages. A treatment will be considered too toxic if ≥6 of 20 patients in a cohort are removed from study because of toxicity.  
13.4.2 Two instruments the EORTC QLQ-30 and EORTC QLQ0LC13 will be administered to patients at baseline and every 12 weeks during the study, thus it is anticipated that patients will have up to 5 assessments made during the trial. Summary scores from each instrument will be assessed at each time point and longitudinal comparisons will be made between groups using a repeated measure mixed model approach.  
13.4.3 The association of immune response with clinical response will also be explored. Treatment response will be grouped into 4 categories as defined earlier in the protocol (irCR, irPR, irSD, irPD). The immune responses for patients within each of these 4 groups will be examined to determine whether there is evidence of an association. This comparison will be primarily descriptive, however we will be examining whether there is evidence that immune response improves as patients go from PD to CR (i.e. it is expected that patients with irPD will have worse immune Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 response than patients with irCR). For continuous measures of immune response the mean value within each response category will be compared. If we dichotomize the immune response assessment into responder yes/no then we will compare the proportion of responders in each category. As stated above, with a small sample size (n=20 per group) this examination will be exploratory since some categories may have less than 4 patients in them.
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13.5 interim analysis plan

There is no planned interim analysis for this study, however the DSMC will monitor this study and if there were to be an unexpected safety concern from unexpected Grade 4 or 5 events occurring on one or both arms of the study then the trial could be suspended or amended if necessary. However, this is not expected.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
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references

1. Azzoli CG, Baker S, Jr., Temin S, et al. [American Society of Clinical OncologyClinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer].  
Zhongguo fei ai za zhi = Chinese journal of lung cancer. Mar 2010;13(3):171-189.  
2. Sculier JP, Chansky K, Crowley JJ, Van Meerbeeck J, Goldstraw P. The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th Edition of the TNM Classification of Malignant Tumors and the proposals for the 7th Edition. *Journal of thoracic oncology : official publication* of the International Association for the Study of Lung Cancer. May 2008;3(5):457-466.  
3. Bunn PA, Jr. Chemotherapy for advanced non-small-cell lung cancer: who, what, when, why? Journal of clinical oncology : official journal of the American Society of *Clinical* Oncology. Sep 15 2002;20(18 Suppl):23s-33s.  
4. Lilenbaum RC, Cashy J, Hensing TA, Young S, Cella D. Prevalence of poor performance status in lung cancer patients: implications for research. Journal of thoracic oncology : official publication of the International Association for the Study of *Lung* Cancer. Feb 2008;3(2):125-129.  
5. Tartarone A, Aieta M. Treatment of performance status 2 patients with advanced nonsmall-cell lung cancer: what we know and what we don't know. *Future Oncol.* Aug 2009;5(6):837-841.  
6. Des Guetz G, Landre T, Westeel V, et al. Similar survival rates with first-line gefitinib, gemcitabine, or docetaxel in a randomized phase II trial in elderly patients with advanced non-small cell lung cancer and a poor performance status (IFCT-0301). Journal of geriatric oncology. Feb 16 2015.  
7. Jouveshomme S, Canoui-Poitrine F, Le Thuaut A, Bastuji-Garin S. Results of platinumbased chemotherapy in unselected performance status (PS) 2 patients with advanced non-small cell lung cancer: a cohort study. Medical oncology (Northwood, London, England). Jun 2013;30(2):544.  
8. Califano R, Griffiths R, Lorigan P, et al. Randomised phase II trial of 4 dose levels of single agent docetaxel in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC): DOC PS2 trial. Manchester lung cancer group. Lung *cancer*
(Amsterdam, Netherlands). Sep 2011;73(3):338-344.  
9. *American Cancer Society. Cancer Facts & Figures 2012.* Atlanta: American Cancer Society;2012.  
10. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews. Cancer. Apr 2012;12(4):252-264.  
11. Spranger S, Spaapen RM, Zha Y, et al. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Science translational medicine. Aug 28 2013;5(200):200ra116.  
12. Grosso J HC, Inzunza D, Cardona DM, Simon JS, Gupta AK, Sankar V, Park J, Kollia G,
Taube JM, Anders R, Jure-Kunkel M, Novotny J Jr., Taylor CR, Zhang X, Phillips T, Simmons P, Cogswell J. Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). Journal of Clinical *Oncology.*
2013;31(suppl):abstract 3016.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 13. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of antiPD-1 antibody in cancer. *The New England journal of medicine.* Jun 28 2012;366(26):2443-2454.  
14. Johnson DB, Rioth MJ, Horn L. Immune checkpoint inhibitors in NSCLC. *Current* treatment options in oncology. Dec 2014;15(4):658-669.  
15. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis.  
Nature medicine. Nov 2013;19(11):1423-1437.  
16. Ralph P, Nakoinz I. Augmentation of macrophage antibody-dependent killing of tumor targets by microtubule inhibitors. *Cellular immunology.* Jul 1 1982;70(2):321-329.  
17. Chang CL, Hsu YT, Wu CC, et al. Dose-dense chemotherapy improves mechanismsof antitumor immune response. *Cancer Res.* Jan 1 2013;73(1):119-127.  
18. He Q, Li J, Yin W, et al. Low-dose paclitaxel enhances the anti-tumor efficacy of GMCSF surface-modified whole-tumor-cell vaccine in mouse model of prostate cancer.  
Cancer immunology, immunotherapy : CII. May 2011;60(5):715-730.  
19. Lu L, Xu X, Zhang B, Zhang R, Ji H, Wang X. Combined PD-1 blockade and GITR
triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. *Journal of translational medicine.* 2014;12:36.  
20. Barbon CM, Yang M, Wands GD, et al. Consecutive low doses of cyclophosphamide preferentially target Tregs and potentiate T cell responses induced by DNA PLG
microparticle immunization. *Cellular immunology.* 2010;262(2):150-161.  
21. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. *J Natl Cancer Inst.* Mar 3 1993;85(5):365-376.  
22. Damm K, Roeske N, Jacob C. Health-related quality of life questionnaires in lung cancer trials: a systematic literature review. *Health economics review.* 2013;3(1):15.  
23. Garon BG, Rizvi NA, HuiR, et al. Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer. N Engl J Med 2015;372:2018-28 Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
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appendix a - protocol registration

DEMOGRAPHICS
Patient: Last Name: First Name:
MRN:
DOB (mm/dd/yy): / /  
  
ZIPCODE:  
| SEX:                                                |  Male                            |  Female   | Ethnicity (choose one):   |  Hispanic Non-Hispanic   |               |
|-----------------------------------------------------|-----------------------------------|------------|---------------------------|----------------------------|---------------|
| Race (choose all that apply):                       |  WHITE                           | BLACK     |  ASIAN                   |                            |               |
|  PACIFIC ISLANDER                                  |  NATIVE AMERICAN                 |            |                           |                            |               |
| Height:                                             | _.                                | inches     | Weight:                   | _.___lbs.(actual)          |               |
| Surface Area:                                       | _._                               | m2         |                           |                            |               |
| Primary Diagnosis:  Date of Diagnosis:              | /                                 | _/         |                           |                            |               |
| ECOG Performance Status:  Prior Chemotherapy?  Yes |  No                              |            |                           |                            |               |
| Prior Therapies/                                    | Start / End Date of Best Response | Date of    | Date of                   | Duration of                |               |
| Protocol # if applicable                            | Prior Therapy                     | (CR, PR,   | Best Response             | Relapse                    | Best Response |
| Treatment Failure)                                  | (in Months)                       |            |                           |                            |               |
| #1                                                  |                                   | /          |                           |                            |               |
| #2                                                  |                                   | /          |                           |                            |               |
| #3                                                  | /                                 |            |                           |                            |               |
| #4                                                  | /                                 |            |                           |                            |               |
| COMMENT:                                            |                                   |            |                           |                            |               |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 PROTOCOL INFORMATION
MD Name (last) : Informed written consent:
PID \# (to be assigned by ORIS):  
  
(consent must be signed prior to registration)
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, *Monday –* Friday.  
Completed Eligibility Checklist and Protocol Registration Form must be hand delivered, faxed or e-mailed to the registrar at 336-7136772 orregistra@wakehealth.edu.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
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appendix b - subject eligibility
irb protocol no. irb00034830 cccwfu

Study Title: Immune response in patients with recurrent or metastatic non-small cell lung cancer and performancestatus of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Principal Investigator: W. Jeff Petty, MD  
| Inclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Criteri   | Criteria is   | Source Used to Confirm *                |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------|---------------|-----------------------------------------|
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | a is      | NOT met       | (Please document dates and lab results) |
| Patients must have histologically or cytologically confirmed NSCLC that is advanced/metastatic (stage IIIB/IV) or recurrent (progression after surgery or radiation or chemo-radiation treatment for loco-regional disease). Patients with epidermal growth factor (EGFR) mutation, anaplastic lymphoma kinase (ALK) gene rearrangement or ROS1 translocation must have received an approved EGFR, ALK, or ROS1-directed therapy and have signs of disease progression prior to receiving pembrolizumab. | □         | □             |                                         |
| Patients must be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 12 weeks (84 days) prior to date of signing consent. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen (up to 3 years) only upon agreement from the Sponsor. At least 4 mm of tumor tissue will be needed for PD-L1 staining.               | □         | □             |                                         |
| Patients who have received zero (0) to two (2) previous lines of systemic chemotherapy and are                                                                                                                                                                                                                                                                                                                                                                                                           | □         | □             |                                         |
| not currently receiving chemotherapy treatment (within 2 weeks of randomization). At least one measurable lesion as defined by RECIST v1.1 on screening CT or MRI                                                                                                                                                                                                                                                                                                                                        | □         | □             |                                         |
| Age >18 years.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | □         | □             |                                         |
| ECOG performance status of 2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | □         | □             |                                         |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
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| CCCWFU # 62415                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                         |                          |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------|--------------------------|
| Patients must have normal organ and marrow functions as described below: -white blood cell count > 2,500 cells/mcL -absolute neutrophil count >1,500/mcL -platelets >100,000/mcL -hemoglobin ≥ 9 g/dL -total bilirubin ≤ 2.0 x upper limit of normal (ULN) -AST(SGOT)/ALT(SGPT) < 2.5 x ULN OR ≤ 5 x ULN in presence of liver metastases -creatinine within normal institutional limits OR creatinine clearance > 50 mL/min for patients with creatinine levels above institutional normal - potassium ≥ lower limit of normal                             | □                                       | □                        |
| Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation and for 4 weeks after the final administration of study drugs. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.                                                                                                                                                      | □                                       | □                        |
| Ability to understand and the willingness to sign an IRB-approved informed consent document.                                                                                                                                                                                                                                                                                                                                                                                                                                                               | □                                       | □                        |
| Criteria NOT present                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                         |                          |
| Exclusion Criteria                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                         |                          |
| (as outlined in study protocol)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Criteria is                             | Source Used to Confirm * |
| present                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | (Please document dates and lab results) |                          |
| Known active (untreated) central nervous system (CNS) metastases that require steroids. Subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 2 weeks before study entry, defined as: - No evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases. - Asymptomatic and receiving either no or stable doses of anticonvulsants and total doses of corticosteroids equivalent to 10 mg of prednisone or less. | □                                       | □                        |
| Current or previous other malignancy within 2 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.                                                                                                                                                                                                                                                                 | □                                       | □                        |
| History of previous exposure to an anti PD1/PDL1 agent                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | □                                       | □                        |
| Patients receiving any other investigational agents and or more than two different                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | □                                       | □                        |
| chemotherapy regimens for treatment of metastatic disease.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                         |                          |
| Protocol Version Date 03/12/2021                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Page 52 of 83                           |                          |  
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| CCCWFU # 62415                                                                                                                                                                                                                                                                                                                                         |    |    |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|
| Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. | □  | □  |
| Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. History of allergic reactions attributed to compounds of similar chemical or biologic                                                                                             | □  | □  |
| composition to pembrolizumab, paclitaxel or carboplatin. Current uncontrolled cardiac disease such as angina or myocardial infarction, congestive heart failure including New York Heart Association functional classification of 3, or arrhythmia requiring treatment.                                                                                | □  | □  |
| History of pneumonitis or active lung infection.                                                                                                                                                                                                                                                                                                       | □  | □  |
| Chronic or current active infectious disease                                                                                                                                                                                                                                                                                                           | □  | □  |
| requiring systemic antibiotics, antifungals, or antivirals. Patients receiving chronic steroids and or immunosuppression                                                                                                                                                                                                                               | □  | □  |
| Known HIV infection, Hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation. HBV DNA and testing for HCV RNA must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti-hepatitis B core antibody positive                                                      | □  | □  |
| History of autoimmune disease(s).                                                                                                                                                                                                                                                                                                                      | □  | □  |
| Psychiatric illness/social situations that would limit compliance with study requirements                                                                                                                                                                                                                                                              | □  | □  |
| Any other condition or circumstance that could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives such as history of, or any evidence of active, non-infectious pneumonitis                                                                                                            | □  | □  |
| Has an active infection requiring systemic therapy.                                                                                                                                                                                                                                                                                                    | □  | □  |
| Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued prior to study entry.                                                                                        | □  | □  |  
Protocol Version Date 03/12/2021 Page 53 of 83  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 This subject is eligible / ineligible for participation in this study.  
ORIS Assigned PID:
Signature of research professional confirming eligibility: Date: Signature of Treating Physician**: Date:  
  
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, specifically state which document in the medical record was used to assess eligibility. Also include the date on the document. Example: "Pathology report, 01/01/14" or "Clinic note, 01/01/14"
**Principal Investigator signature can be obtained following registration if needed Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
appendix b - subject eligibility
appendix c - race &

Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our *information.* As a brief reminder, the information you provide today will be kept *confidential.*
1. Are you:
Hispanic or Latino/a Not Hispanic or Latino/a 2. What is your race? One or more categories may be selected.  
White or Caucasian Black or African American American Indian or Alaskan Native Asian Native Hawaiian or Other Pacific Islander Other, Please Specify:
appendix b - subject eligibility
internal use only

Was the self-reported race and ethnicity of the participant verified at the time ofconsent?  
Yes No Was a discrepancy *found?* Yes No If yes, please provide what is currently indicated in theEMR:
Ethnicity: Race:
Additional comments:
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415
appendix b - subject eligibility
mandatory dsmc sae reporting requirements

This document describes reporting requirements of adverse events from WFBCCC
Investigator Initiated interventional trials to the Data and Safety Monitoring Committee
(DSMC). A trial is considered a **WFBCCC Investigator Initiated interventional trial** if the following criteria are met:
1) The Principal Investigator (PI) of the trial is a member of a department at the Wake Forest University Baptist Medical Center.  
2) WFBCCC is considered as the primary contributor to the design, implementation and/or monitoring of the trial.  
3) The trial is designated as "Interventional" using the Clinical Research Categories definitions provided by the NCI in the Data Table 4 documentation. (https://cancercenters.cancer.gov/GrantsFunding/DataGuide\#dt4)
There are two distinct types of WFBCCC Investigator Initiated interventional trials based on where patient enrollment occurs. These include:
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all patients are enrolled from one of the WFBCCC sites. These include the main outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons, Lexington, High Point, or Wilkesboro.  
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials where patients are enrolled from other sites in addition to WFBCCC sites. There are three types of trials that are included in this category:
a. Trials sponsored by the NCI Community Oncology Research Program
(NCORP) that are conducted at multiple sites where the PI is a member of a department at the Wake Forest University Baptist Medical Center.  
b. Trials sponsored by Industry that are conducted at multiple sites and the PI is a member of a department at the Wake Forest University Baptist MedicalCenter.  
c. Trials sponsored by WFBCCC that are conducted at multiple sites and the PI is a member of a department at the Wake Forest University Baptist MedicalCenter.  
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415 enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the WISERsystem. The only exception to this requirement is for patients enrolled on NCORP
trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, certain actions must be taken regarding the reporting of specific Adverse Events to the DSMC. All Adverse Events that occur during protocol intervention (defined below) and are coded as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours
(regardless of grade), or **grade 5 (death)** must be reported to the DSMC using the using the SAE console in WISER. A research nurse or clinical research coordinator when made aware that an adverse event meets one of the above criteria has occurred on a WFBCCC Investigator Initiated interventional trial, is responsible for informing a clinical member of the DSMC by phone (or in-person) about the adverse event. The nurse/coordinator should contact the treating physician prior to calling the DSMC clinical member to obtain all details of the SAE, as well as all associated toxicities to be recorded along with the SAE. In addition, this nurse or coordinator is responsible for entering theadverse event information into the SAE console in WISER. Once the adverse event has been entered into the SAE console an email informing the entire DSMC will be generated. THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC Institutional Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE identification, documentation, grading and assignment of attribution to the investigational agent/intervention. However, when an AE event as described above is observed, it is the responsibility of the person who observed the event to be sure that it is reported to the **DSMC.**
appendix b - subject eligibility
what is considered during protocol

During protocol intervention is considered to be the time period while a patient is on study treatment or during the time period within 30 days of last study treatment (even if patient begins a new (non-study) treatment during the 30 days). This window of 30 days should be the standard window to be used in all protocols unless a specific scientific rationale is presentedto suggest that a shorter window can be used to identify events. If it is a trial sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, then the longer window of time specified by the sponsor should be followed.  
What is considered as an Unexpected Grade 4 **event?**
Any grade 4 event that was not specifically listed as an expected adverse event in the Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415 protocol should be considered as unexpected. A grade 4 adverse event can be considered to be unexpected if it is an event that would not be expected based on the treatment being received or if it is unexpected based on the health of the patient. In either case, if there is any uncertainty about whether a grade 4 adverse event is expected or unexpected it should be reported to DSMC.
appendix b - subject eligibility
dsmc notification responsibilities of the

DSMC according to the schedule as listed below (page if necessary).  
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in WISER WITHIN 24 HOURS of first knowledge of the event. Information can be entered and saved, but the DSMC members will not be notified until a date is entered into the DSMC Notification Date Field. This will ensure that all persons that need to be made aware of the event (i.e., PI, study team members and DSMC members) will be notified; remember to file a copy of the confirmation.  
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate the name of the DSMC clinician that was contacted and the date and time contacted in the Event Narrative field in the SAE console of the particular subject.  
4. Document whether or not the protocol should be suspended based on the discussion with the DSMC clinician. This is the major function of the email notification. Enter whether the protocol should be suspended in the Event Narrative Field.  
5. Follow up/update the clinical member(s) of DSMC regarding any new developments or information obtained during the course of the SAE investigation and reporting process.
appendix b - subject eligibility
elements needed to complete the

2. Reported Date 3. Reported by 4. If Grade 5, enter Death Date 5. If Grade 5, enter Death occurred: within 30 days 6. Event Narrative: Brief description (include brief clinical history relevant to this event, including therapies believed related to event). Begin narrative with the DSMC clinician who was notified and Date/Time notified. In addition, state attribution by DSMC clinician as either "Unrelated", "Unlikely", "Possibly", "Probably", or "Definitely". Always include the following here:
i. DSMC clinician name, date/time contacted and comments ii. Date of last dose before the event iii. Is suspension of the protocol needed? Y/N
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415 7. Treating Physician comments 8. PI comments, if available 9. Protocol Attribution after discussion with DSMC clinician 10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, NotRecovered/Not Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae, Recovering and Resolving)
11. Consent form Change Required? Y/N
12. SAE Classification *This is required in order for the email notification to be **sent***
13. Adverse Event Details - Enter all details for each AE associated with the SAE.  
a. Course start date b. Category c. AE Detail d. Comments e. Grade/Severity f. Unexpected Y/N g. DLT Y/N h. Attributions i. Action j. Therapy k. Click ADD to attach the AE Detail to the SAE.  
14. Enter Date Notified DSMC -- *This is required for the email notification to be **sent***
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes.  
If you do not receive an email within 5 minutes, check that you have entered the "Date Notified DSMC" and the "SAE Classification". If these have been entered and the email still has not been received, take a screen shot of the SAE in WISER and immediately email it out to all of the DSMC members listed in this SOP. In the subject line, indicate that this is a manual transmission of the SAE in lieu of the autogenerated email. It is required that a notification goes to the DSMC members immediately so that their assessment can be obtained within the 24 hour period requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an issue with the auto-generated email.  
| Monday    | Tuesday   | Wednesday   | Thursday   | Friday    | Saturday Sunday   |           |
|-----------|-----------|-------------|------------|-----------|-------------------|-----------|
| Lesser    | Hughes    | Goodman     | Reed       | Porosnicu | Seegars           | Lesser    |
| Hughes    | Goodman   | Reed        | Porosnicu  | Seegars   | Lesser            | Hughes    |
| Goodman   | Reed      | Porosnicu   | Seegars    | Lesser    | Hughes            | Goodman   |
| Reed      | Porosnicu | Seegars     | Lesser     | Hughes    | Goodman           | Reed      |
| Porosnicu | Seegars   | Lesser      | Hughes     | Goodman   | Reed              | Porosnicu |
| Seegars   | Lesser    | Hughes      | Goodman    | Reed      | Porosnicu Seegars |           |
appendix b - subject eligibility
the clinical members of dsmc

Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance  
  
status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415 Glenn Lesser, MD - Hematology Oncology Mercedes Porosnicu, MD-- Hematology Oncology Ryan Hughes, MD - Radiation Oncology Michael Goodman, MD -- Hematology Oncology Daniel Reed, MD -- Hematology Oncology Mary Beth Seegars, MD -- Hematology Oncology
appendix b - subject eligibility
definition of unavailable

As a general guideline if the first clinician that is contacted does not respond to the phone call or page within 30 minutes, then initiate contact with the next DSMC clinician listed in the table above on the particular day the SAE is being reported. Allow up to30 minutes for the new DSMC clinician to respond to a phone call or page before contacting the next member in the table. These times (30 minutes) are a general guideline. Best judgment as aclinical research professional should be used giving considerations of the time of day, severity ofthe SAE, and other circumstances as to when it is appropriate to contact backup clinicians. Ifthe event occurs near the end of day, then leave messages (voice or email) as appropriate and proceed with submitting the DSMC notification form. It is important to take reasonable steps and to document that some type of contact has been initiated to one or more of the clinical members of DSMC.
appendix b - subject eligibility
dsmc clinican responsibility

It is the responsibility of the DSMC clinician to review all reported events, evaluate the events as they are reported; and communicate a response to the Investigator, event reporter and the members of DSMC. The review will include but not be limited to the information reported;there may be times when additional information is needed in order for an assessment to be made and further communication directly with the investigator may be warranted. DSMC reserves the right to disagree with the Investigator's assessment. If DSMC does not agree with the Investigator, DSMC reserves the right to suspend the trial pending further investigation. If there is any immediate danger or harm that could be present for a future patient based on the information provided in the DSMC report then an immediate suspension of enrollment shouldbe considered.
appendix b - subject eligibility
amendments to previousreports

If all pertinent information is unavailable with the initial submission, once the additional information is available **do not submit a new report**. Rather, go to the original email that was sent to the DSMC and using that email "reply to all". Entitle this new email
"**Amendment**for (list date of event and patient ID)" this will avoid duplications of the same event. List the additional information being reported. This information needs to be entered into WISER as well. To do this, go to the Subject console and click SAEs on the left column. Click on the appropriate SAE number that needs updating. Then click Update. This will allow additional information to be added.  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU) CCCWFU \# 62415
appendix b - subject eligibility
acronyms

AE - Adverse Event DSMC-Data and Safety Monitoring Committee SAE-Serious Adverse Event WFBCCC - Wake Forest Baptist Comprehensive Cancer Center NCI-National Cancer Institute WISER –Wake Integrated Solution for EnterpriseResearch Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
appendix b - subject eligibility
screen shots the following screen

Screen Shot 2:  
  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
   
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
screen shots the following screen

Immune-Related Response Criteria (irRC) Measurement Form  
Patient Name: MRN: Study:  
| Patient Name:                                   | MRN:                             | Study:                  |                |                  |                  |
|-------------------------------------------------|----------------------------------|-------------------------|----------------|------------------|------------------|
| Measurable Sites                                |                                  |                         |                |                  |                  |
| Lesion                                          | Site                             | Imaging  (ie, CT,  MRI) | Baseline Date: | Evaluation Date: | Evaluation Date: |
| (Se,Im)                                         | (Se,Im)                          | (Se,Im) Size of Lesion  | Product of     |                  |                  |
| (mm x mm)                                       | Measurement s (mm2 )             |                         |                |                  |                  |
| 1.                                              | Size of  Lesion                  |                         |                |                  |                  |
| (mm x mm)                                       | Product of  Measurement s (mm2 ) | Size of Lesion          | Product of     |                  |                  |
| (mm x mm)                                       | Measurement s (mm2 )             |                         |                |                  |                  |
| 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. |                                  |                         |                |                  |                  |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| CCCWFU # 62415                                         |         |                          |                |                  |                  |
|--------------------------------------------------------|---------|--------------------------|----------------|------------------|------------------|
| Sum of Product Measurements (mm2) Non-Measurable Sites |         |                          |                |                  |                  |
| Lesion                                                 | Site    | Imagin  g (ie, CT,  MRI) | Baseline Date: | Evaluation Date: | Evaluation Date: |
| (Se,Im)                                                | (Se,Im) | (Se,Im)                  |                |                  |                  |
| 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.     |         |                          |                |                  |                  |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| CCCWFU # 62415 New Sites                        |                                                                                                                                                                                |                        |                |                  |                  |
|-------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|----------------|------------------|------------------|
| Lesion                                          | Site                                                                                                                                                                           | Imaging (ie, CT,  MRI) | Baseline Date: | Evaluation Date: | Evaluation Date: |
| (Se,Im)                                         | (Se,Im)                                                                                                                                                                        | (Se,Im) Size of Lesion | Product of     |                  |                  |
| (mm x mm)                                       | Measurements (mm2 )                                                                                                                                                            |                        |                |                  |                  |
| 1.                                              | Size of  Lesion                                                                                                                                                                |                        |                |                  |                  |
| (mm x mm)                                       | Product of                                                                                                                                                                     |                        |                |                  |                  |
| Measurements (mm2 )                             | Size of Lesion                                                                                                                                                                 | Product of             |                |                  |                  |
| (mm x mm)                                       | Measurements (mm2 )                                                                                                                                                            |                        |                |                  |                  |
| 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. | Sum of Product Measurements (mm2) % Change (difference/nadir) Response (irCR, irPR, irSD, irPD) Radiologist Signature/Date Treating Physician Signature/Date PI Signature/Date |                        |                |                  |                  |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415 Appendix F - Screening **form**
1. Medical history:
Myocardial infarction Congestive heart failure Peripheral vascular disease Cerebrovascular disease Dementia Chronic pulmonary disease Connective tissue disease Peptic ulcer disease Liver disease - mild moderate severe  
  
 Diabetes - end organ damage? Yes No  
 Hemiplegia Other cancer - specify  
  
Prior anticancer interventions? Yes No If yes, specify Date: / /
AIDs
Other medical condition - specify 2. Concurrent medications:
3. Physical exam:  
| Derm -   | WNL     | Abnormal, specify   |
|----------|---------|---------------------|
| HEENT -  | WNL     | Abnormal, specify   |
| CV -     | WNL     | Abnormal, specify   |
| Pulm -   | WNL     | Abnormal, specify   |
| GI -     | WNL     | Abnormal, specify   |
| Other -  | Specify |                     |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415  
  
b. RR f. Height (cm)
appendix e - tumor response
5. performance status

| GRADE   | ECOG                                                                                                                                                       |
|---------|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Fully active, able to carry on all pre-disease performance withoutrestriction                                                                              |
| 1       | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or  sedentary nature, e.g., light house work, office work |
| 2       | Ambulatory and capable of all self care, but unable to carry out any work activities. Up and about more  than 50% of waking hours                          |
| 3       | Capable of only 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                                                                       |
| 5       | Dead                                                                                                                                                       |
| 6.      | Documentation of negative pregnancy test for women of child-bearing potential?  Yes No N/A If N/A, specify:                                                |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix g - study data

To be completed prior to each treatment and at the End of Treatment *visit*  
Study Visit: Cycle 1 Cycle 8  
  
  
  
Cycle 2 Cycle 9 Cycle 3 Cycle 10 Cycle 4 Cycle 11 Cycle 5 Cycle 12 Cycle 6 Cycle 13 Cycle 7 End of Treatment Other (specify below):
1. Concurrent medications:  
  
  
Other - Specify  
  
Derm - WNL Abnormal, specify  
  
  
  
HEENT - WNL Abnormal, specify  
CV - WNL Abnormal, specify Pulm - WNL Abnormal, specify  
GI - WNL Abnormal, specify  
3. Vital signs:  
  
  
  
  
| 0   | Fully active, able to carry on all pre-disease performance withoutrestriction                                                                              |
|-----|------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 1   | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or  sedentary nature, e.g., light house work, office work |
| 2   | Ambulatory and capable of all self care, but unable to carry out any work activities. Up and about more  than 50% of waking hours                          |
| 3   | Capable of only 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                                                                       |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix h - follow-up form

To be completed for long-term follow-up after treatment has *finished* 1. Vital status: Alive Dead If deceased, date of death: / /
2. Disease state (last known, if deceased):  
3. Initiation of any new anticancer interventions since last contact?  
  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix i - eortc qlq-c30

We are interested in some things about you and your health. Please answer all of the questions yourself by circling the number that best applies to you. There are no "right" or "wrong" answers. The information that you provide will remain strictly confidential.  
| Not at  All                                       | A                                                                             |            |       |      |    |
|---------------------------------------------------|-------------------------------------------------------------------------------|------------|-------|------|----|
| Little                                            | Quite a Bit                                                                   | Very  Much |       |      |    |
| 1.                                                | Do you have any trouble doing strenuous activities,                           | 1          | 2     | 3    | 4  |
| like carrying a heavy shopping bag or a suitcase? |                                                                               |            |       |      |    |
| 2.                                                | Do you have any trouble taking a long walk?                                   | 1          | 2     | 3    | 4  |
| 3.                                                | Do you have any trouble taking a short walk outside of the house?             | 1          | 2     | 3    | 4  |
| 4.                                                | Do you need to stay in bed or a chair during the day?                         | 1          | 2     | 3    | 4  |
| 5.                                                | Do you need help with eating, dressing, washing yourself or using the toilet? | 1          | 2     | 3    | 4  |
| During the past week:                             | Not at                                                                        | A          | Quite | Very |    |
| All                                               | Little                                                                        | a Bit      | Much  |      |    |
| 6.                                                | Were you limited in doing either your work or other daily activities?         | 1          | 2     | 3    | 4  |
| 7.                                                | Were you limited in pursuing your hobbies or other leisure time activities?   | 1          | 2     | 3    | 4  |
| 8.                                                | Were you short of breath?                                                     | 1          | 2     | 3    | 4  |
| 9.                                                | Have you had pain?                                                            | 1          | 2     | 3    | 4  |
| 10.                                               | Did you need to rest?                                                         | 1          | 2     | 3    | 4  |
| 11.                                               | Have you had trouble sleeping?                                                | 1          | 2     | 3    | 4  |
| 12.                                               | Have you felt weak?                                                           | 1          | 2     | 3    | 4  |
| 13.                                               | Have you lacked appetite?                                                     | 1          | 2     | 3    | 4  |
| 14.                                               | Have you felt nauseated?                                                      | 1          | 2     | 3    | 4  |
| 15.                                               | Have you vomited?                                                             | 1          | 2     | 3    | 4  |
| 16.                                               | Have you been constipated?                                                    | 1          | 2     | 3    | 4  |
| 17.                                               | Have you had diarrhea?                                                        | 1          | 2     | 3    | 4  |
| 18.                                               | Were you tired?                                                               | 1          | 2     | 3    | 4  |
| 19.                                               | Did pain interfere with your daily activities?                                | 1          | 2     | 3    | 4  |
| Protocol Version Date 03/12/2021                  | Page 70 of 83                                                                 |            |       |      |    |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415  
  
All Little a Bit Very Much
appendix e - tumor response
during the past week for

29. How would you rate your overall health during the past week?  
1 2 3 4 5 6 7 30. How would you rate your overall quality of life during the past week?  
1 2 3 4 5 6 7 Very poor Excellent  
| 20.   | Have you had difficulty in concentrating on things,  like reading a newspaper or watching television?   | 1   | 2   | 3   | 4   |
|-------|---------------------------------------------------------------------------------------------------------|-----|-----|-----|-----|
| 21.   | Did you feel tense?                                                                                     | 1   | 2   | 3   | 4   |
| 22.   | Did you worry?                                                                                          | 1   | 2   | 3   | 4   |
| 23.   | Did you feel irritable?                                                                                 | 1   | 2   | 3   | 4   |
| 24.   | Did you feel depressed?                                                                                 | 1   | 2   | 3   | 4   |
| 25.   | Have you had difficulty remembering things?                                                             | 1   | 2   | 3   | 4   |
| 26.   | Has your physical condition or medical treatment interfered with you family life?                       | 1   | 2   | 3   | 4   |
| 27.   | Has your physical condition or medical treatment interfered with your social activities?                | 1   | 2   | 3   | 4   |
| 28.   | Has your physical condition or medical treatment                                                        |     |     |     |     |  
caused you financial difficulties? 1 2 3 4  
Very poor Excellent Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix j - eortc qlq-lc13

Patients sometimes report that they have the following symptoms or problems. Please indicate the extent to which you have experienced these symptoms or problems during the past week.  
Please answer by circling the number that best applies to you.  
43. Did you take any medicine for pain?
1 No **2 Yes**
If yes, how much did it help? 1 2 3 4  
| Not at                | A                                                 | Quite   | Very   |    |    |
|-----------------------|---------------------------------------------------|---------|--------|----|----|
| All                   | Little                                            | a Bit   | Much   |    |    |
| During the past week: |                                                   |         |        |    |    |
| 31.                   | How much did you cough?                           | 1       | 2      | 3  | 4  |
| 32.                   | Did you cough up blood?                           | 1       | 2      | 3  | 4  |
| 33.                   | Were you short of breath when you rested?         | 1       | 2      | 3  | 4  |
| 34.                   | Were you short of breath when you walked?         | 1       | 2      | 3  | 4  |
| 35.                   | Were you short of breath when you climbed stairs? | 1       | 2      | 3  | 4  |
| 36.                   | Have you had a sore mouth or tongue?              | 1       | 2      | 3  | 4  |
| 37.                   | Have you had trouble swallowing?                  | 1       | 2      | 3  | 4  |
| 38.                   | Have you had tingling hands or feet?              | 1       | 2      | 3  | 4  |
| 39.                   | Have you had hair loss?                           | 1       | 2      | 3  | 4  |
| 40.                   | Have you had pain in your chest?                  | 1       | 2      | 3  | 4  |
| 41.                   | Have you had pain in your arm or shoulder?        | 1       | 2      | 3  | 4  |
| 42.                   | Have you had pain in other parts of your body?    | 1       | 2      | 3  | 4  |
| If yes, where         |                                                   |         |        |    |    |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix k - eortc qlq-c30

Estamos interesados en conocer algunas cosas sobre usted y su salud. Por favor, responda a todas las preguntas personalmente, rodeando con un círculo el número que mejor se aplique a su caso. No hay contestaciones "acertadas" o "desacertadas". La información que nos proporcione será estrictamente confidencial.  
En  
  
absoluto Un 1. ¿Tiene alguna dificultad para hacer actividades
appendix e - tumor response
pocobastante mucho

que requieran un esfuerzo importante, como llevar una bolsa de compra pesada o una 1 2 3 4 maleta?  
2. ¿Tiene alguna dificultad para dar un paseo Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
| Comprehensive Cancer Center of Wake Forest University (CCCWFU)  CCCWFU # 62415   |                                                                                            |          |          |       |    |
|----------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------|----------|----------|-------|----|
| largo?                                                                           | 1                                                                                          | 2        | 3        | 4     |    |
| 3.                                                                               | ¿Tiene alguna dificultad para dar un paseo corto fuera de casa?                            | 1        | 2        | 3     | 4  |
| 4.                                                                               | ¿Tiene que permanecer en la cama o sentado/a en una silla durante el día?                  | 1        | 2        | 3     | 4  |
| 5.                                                                               | ¿Necesita ayuda para comer, vestirse, asearse o ir                                         | 1        | 2        | 3     | 4  |
| al servicio?                                                                     | En                                                                                         |          |          |       |    |
| absoluto                                                                         | Un                                                                                         | Much     |          |       |    |
| Durante la semana pasada:                                                        | poco                                                                                       | Bastante |          |       |    |
| 6.                                                                               | ¿Ha tenido algún impedimento para hacer su                                                 | 1        | 2        | 3     | 4  |
| trabajo u otras actividades cotidianas?                                          |                                                                                            |          |          |       |    |
| 7.                                                                               | ¿Ha tenido algún impedimento para realizar sus                                             | 1        | 2        | 3     | 4  |
| aficiones u otras actividades de ocio?                                           |                                                                                            |          |          |       |    |
| 8.                                                                               | ¿Tuvo sensación de "falta de aire" o dificultad                                            | 1        | 2        | 3     | 4  |
| para respirar?                                                                   |                                                                                            |          |          |       |    |
| 9.                                                                               | ¿Ha tenido dolor?                                                                          | 1        | 2        | 3     | 4  |
| 10.                                                                              | ¿Necesitó parar para descansar?                                                            | 1        | 2        | 3     | 4  |
| 11.                                                                              | ¿Ha tenido dificultades para dormir?                                                       | 1        | 2        | 3     | 4  |
| 12.                                                                              | ¿Se ha sentido débil?                                                                      | 1        | 2        | 3     | 4  |
| 13.                                                                              | ¿Le ha faltado el apetito?                                                                 | 1        | 2        | 3     | 4  |
| 14.                                                                              | ¿Ha tenido náuseas?                                                                        | 1        | 2        | 3     | 4  |
| En                                                                               | Un                                                                                         |          |          |       |    |
| Durante la semana pasada:                                                        | absoluto                                                                                   | poco     | Bastante | Mucho |    |
| 15.                                                                              | ¿Ha vomitado?                                                                              | 1        | 2        | 3     | 4  |
| 16.                                                                              | ¿Ha estado estreñido/a?                                                                    | 1        | 2        | 3     | 4  |
| 17.                                                                              | ¿Ha tenido diarrea?                                                                        | 1        | 2        | 3     | 4  |
| 18.                                                                              | ¿Estuvo cansado/a?                                                                         | 1        | 2        | 3     | 4  |
| 19.                                                                              | ¿Interfirió algún dolor en sus actividades diarias?                                        | 1        | 2        | 3     | 4  |
| 20.                                                                              | ¿Ha tenido dificultad en concentrarse en cosas como leer el periódico o ver la televisión? | 1        | 2        | 3     | 4  |  
Protocol Version Date 03/12/2021 Page 74 of 83  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415  
21. ¿Se sintió nervioso/a? 1 2 3 4  
22. ¿Se sintió preocupado/a? 1 2 3 4  
23. ¿Se sintió irritable? 1 2 3 4 24. ¿Se sintió deprimido/a? 1 2 3 4 25. ¿Ha tenido dificultades para recordar cosas? 1 2 3 4  
26. ¿Ha interferido su estado físico o el tratamiento  
| 26.   | ¿Ha interferido su estado físico o el tratamiento médico en su vida familiar?   | 1   | 2   | 3   | 4   |
|-------|---------------------------------------------------------------------------------|-----|-----|-----|-----|  
27. ¿Ha interferido su estado físico o el tratamiento médico en sus actividades sociales? 1 2 3 4 28. ¿Le han causado problemas económicos su estado físico o el tratamiento médico? 1 2 3 4
appendix e - tumor response
por favor en las siguientes

29. ¿Cómo valoraría su salud general durante la semana pasada?  
1 2 3 4 5 6 7 Pésima Excelente 30. ¿Cómo valoraría su calidad de vida en general durante la semana pasada?  
1 2 3 4 5 6 7 Pésima Excelente Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix e - tumor response
appendix l - eortc qlq-lc13

Los pacientes a veces dicen que tienen los siguientes síntomas o problemas. Por favor Indique hasta qué punto ha experimentado usted estos síntomas o problemas durante la semana pasada. Por favor responda rodeando con un círculo el número que mejor se aplique a su caso.  
| pasada. Por favor responda rodeando con un círculo el número que mejor se aplique a su caso. Durante la semana pasada: En Un absoluto poco Bastante Mucho 31. ¿Cuánto tosió? 1 2 3 4 32. ¿Escupió sangre al toser? 1 2 3 4 33. ¿Le faltó la respiración cuando descansaba? 1 2 3 4 34. ¿Le faltó la respiración al caminar? 1 2 3 4 35. ¿Le faltó la respiración al subir las escaleras? 1 2 3 4 36. ¿Ha tenido algún dolor en la boca o en la  1 2 3 4 lengua? 37. ¿Ha tenido problemas para tragar? 1 2 3 4 38. ¿Ha tenido hormigueos en las manos o en los  1 2 3 4 pies? 39. ¿Ha perdido cabello? 1 2 3 4 40. ¿Ha tenido dolor en el pecho? 1 2 3 4 41. ¿Ha tenido dolor en el brazo o en el hombro? 1 2 3 4 42. ¿Ha tenido dolor en otras partes de su cuerpo? 1 2 3 4En caso afirmativo, ¿dónde?   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
43. ¿Tomó alguna medicina para el dolor?  
1 No **2 Si**
En caso afirmativo, ¿cuánto le alivió? 1 2 3 4 Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix m - tumor correlative
appendix l - eortc qlq-lc13

1. Percentage of tumor with an infiltrate of lymphocytes: 2. Percentage of tumor with an infiltrate of macrophages:
3. Average number of positive immune cells per high power field (HPF) in a minimum of 4  
  
  
representative HPF areas:
a. Lymphocytes 0 = no lymphocytes 1 = 1-10/HPF 2 = 11-50/HPF
3 = >50/HPF
b. Macrophages 0 = no macrophages 1 = 1-50/HPF
2 = 50-100/HPF
3 = >100/HPF
4. Lymphocyte infiltrate score:  
  
5. Macrophage infiltrate score:
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
appendix m - tumor correlative
cellular regulators

1. Absolute lymphocyte count:  
2. Frequency (%) of the following phenotypes:  
| Frequency (%)              |                               |
|----------------------------|-------------------------------|
| Effector                   | CD4+ CD8+ ICOS+CD4+ ICOS+CD8+ |
| T regulatory               | CD4+FoxP3+                    |
| Myeloid derived suppressor | Lin-CD14+HLA-DRlow/−          |
appendix m - tumor correlative
soluble regulators

| [Concentration]                               |
|-----------------------------------------------|
| TGF-β VEGF IL-6 IL-8 PGE2 (metabolite) sPD-1L |
appendix m - tumor correlative
antigen specific response

| PBMC response:                                                      | Positivity criteria     |
|---------------------------------------------------------------------|-------------------------|
| Stimulation index                                                   | [concentration] (pg/mL) |
| IL-2, 40 IL-4, 15 IL-6, 20 IL-10, 50 IFN-γ, 75 TNF-α, 30 IL-17A, 20 |                         |  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University (CCCWFU)
CCCWFU \# 62415
appendix o - adverse event
wfbccc adverse event (ae) log

PI: Subject **PID: MRN:**
Cycle \#: Cycle Start Date: Cycle Start Time: Cycle End Date: Cycle End Time:  
| *Serious Adverse  Event Detail: NO= No LT= Life Threatening DTH= Death DIS= Disability HOS= Hospitalization CA= Caused congenital anomaly  RI= Required intervention to prevent impairment                                                                    | Action Taken NO= None DR= Dose Reduced RI= Regimen Interrupted TD= Therapy discontinued INTR= Interrupted then reduced Therapy  Given NO= None   | Reportable?   |          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|---------------|----------|
| SYM=                                                                                                                                                                                                                                                          | IRB= IRB                                                                                                                                         |               |          |
| Symptomatic DSMC= DSMC SUP= FDA= FDA Supportive SPON= Sponsor VSUP= (Mark all that Vigorous apply) Supportive Advers e Event  Report  (AER) filed? N= No Y= Yes Outcome  R= Recovered TX= Still under treatment or observation A= Alive with Sequalae D= Died |                                                                                                                                                  |               |          |
| Attribution  DEF= Definite PROB= Probable POSS= Possible UNLK= Unlikely UNRL= Unrelated                                                                                                                                                                       | Dose  Limiting  Toxicity  (DLT)  N= No Y= Yes                                                                                                    |               |          |
| Lab                                                                                                                                                                                                                                                           | Grade                                                                                                                                            |               |          |
| Value                                                                                                                                                                                                                                                         | (2-5) per CTC                                                                                                                                    | Treating MD   | Expected |
| Initials +                                                                                                                                                                                                                                                    | End Date N= No                                                                                                                                   |               |          |
| Date                                                                                                                                                                                                                                                          | Y= Yes                                                                                                                                           |               |          |
| Adverse Event CTC  Term                                                                                                                                                                                                                                       | Start  Date                                                                                                                                      |               |          |  
*Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening;Death.  
CTCAE Version 4 - http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf DSMC = Data and Safety Monitoring CommitteeVersion 10/30/17 Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix o - adverse event
appendix p - pembrolizumab guidance

Please refer to the package insert PDF for Pembrolizumab, available from www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf Last updated December 2018 Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix q - ecog performance
ecog performance status

GRADE 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 house work, office work 2 Ambulatory and capable of all self care, but unable to carry out any work activities.  
Up and about more than 50% of waking hours 3 Capable of only 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 5 Dead Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix q - ecog performance
appendix r response criteria

Study Visit: Pre-Study Week 8 ( ± 3 days) Week 20 ( ± 7 days) Week 32 ( ± 7 days)
End of Treatment Visit Other visit: (please specify)
appendix q - ecog performance
evaluation of target lesions

Complete Response (irCR): Complete disappearance of all target and new, measurable lesions, with the exceptions of lymph nodes which must decrease to < 10 mm in short axis.  
Partial Response (irPR): Decrease in total measured tumor burden (TMTB*) >30%
relative to baseline.  
Stable Disease (irSD): Not meeting criteria for irCR or irPR, in absence of irPD. Progressive Disease (irPD): Increase in TMTB >20% relative to nadir.
appendix q - ecog performance
evaluation of non-target lesions

Complete Response (irCR): Complete disappearance of all non-target lesions. Non-irCR/Non-irPD: Non-target lesions do not meet the criteria for irCR orirPD.
Progressive Disease (irPD): Unequivocal increase in the number or size of nontarget lesions. To achieve unequivocal progression of non-target lesions, there must be a substantial worsening of non-target disease of a magnitude that, according to the treating physician, warrants a change in anticancer therapy. NOTE: Equivocal findings of progression of non-target lesions (e.g., small and uncertain new lesions; cystic changes or necrosis in existing lesions) should be considered irSD and treatment may continue until the next scheduled assessment. *TMTB=sum of the longest diameters (SOD) + SOD new, measureable lesions. When no imaging/measurement is done at all at a particular time point, the patient is not evaluable (NE) at that time point.  
Treating Physician Signature: Date: / /  
  
Immune response in patients with recurrent or metastatic non-small cell lung cancer and performance status of 2 treated with a combination of pembrolizumab and low dose weekly carboplatin/paclitaxel Comprehensive Cancer Center of Wake Forest University
(CCCWFU)
CCCWFU \# 62415
appendix q - ecog performance
evaluation of best overall response

The overall response according to irRECIST is derived from the responses in TMTB as well as the presence of any non-target lesions as follows:
Complete Response (irCR): Complete disappearance of all lesions (whether measureable or not); lymph nodes must decrease to < 10 mm in shortest dimension.  
Partial Response (irPR): Decrease in TMTB >30% relative to baseline. Disease (irSD): Not meeting criteria for irCR or irPR, in absence of irPD. Progressive Disease (irPD): Increase in TMTB >20% relative to nadir.
appendix q - ecog performance
confirmatory measurement

Confirmation: If there is suspicion of tumor progression at eight weeks, a second CT/MRI study 4 weeks after will need to be done as a confirmatory test. Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for irCR or irPR (if irCR is never met) until the first date that irPD is confirmed by independent radiology review or death, whichever comes first. Duration of disease control: The duration of time from the date measurement criteria are first met for irCR, irPR, or irSD, until the first date that irPD is confirmed by independent radiology review or death, whichever comes first.  
Treating Physician Signature: Date: / /  
  
 PI Signature: Date: / /