Pembrolizumab for Advanced NSCLC and PS 2-3

Primary Objective To assess the effects of first-line pembrolizumab upon patient quality of life in patients with metastatic non-small cell lung cancer who are ineligible for standard first line treatments due to poor performance status (ECOG PS of 2 or 3).

Secondary Objectives

• To assess the clinical outcomes of first-line pembrolizumab in this patient population.
• To evaluate the toxicity of first-line pembrolizumab in this patient population.
• To assess patient reported QOL in the emotional domain (using HADS).
• To assess baseline patient-reported performance status and correlate with QOL and clinical outcomes.
• To assess baseline geriatric assessment score for patients 70 years of age and older and correlate with QOL and clinical outcomes.
• To correlate QOL and outcomes with demographic and clinical factors including: age, gender, race/ethnicity, zip code, insurance type, presence/absence of CNS metastases, PD-L1 TPS (<1%, 1-49%, ≥50%), geriatric assessment scores, presence or absence of other major organ dysfunction (e.g. CKD), ECOG 2 vs 3, adverse events: G2, G3-4.

Primary Endpoint Change in QOL score after 12 weeks of treatment as measured by EORTC's QLQ-C30

Secondary Endpoints

• Change in QOL score after 6 weeks of treatment as measured by EORTC's QLQ-C30
• Change in QOL score after 6 and 12 weeks of treatment as measured by EORTC's QLQ-LC13.
• Change in QOL score in the emotional domain after 6 and 12 weeks of treatment as measured by HADS
• Overall survival
• Objective response rate, as determined by independent radiology review and assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, at 12 weeks after treatment
• Progression free survival
• Emergency room visits and hospitalizations
• Adverse events, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
• Patient reported ECOG performance status and correlation with QOL and clinical outcomes.
• Treating physician clinical assessment of whether poor PS, as measured by the ECOG Performance Status Scale, is due to disease, other comorbidities, or both and correlation with QOL and clinical outcomes
• Geriatric assessment at baseline for patients 70 years of age and older and correlation with QOL and clinical outcomes, using the Cancer Aging and Research Group (CARG) Chemo-Toxicity Calculator Survey https://www.mycarg.org/?page_id=4480
• Patient Reported Outcome (PRO) completion rate
• Difference in QOL score objective response proportion (CR + PR), and OS at 12 weeks between categories of:

• Age group
• Gender
• Race/ethnicity
• Zip code
• Insurance type
• Presence/absence of CNS metastases
• PD-L1 (TPS <1%, 1-49%, ≥50%)
• Geriatric assessment scores
• Presence or absence of other major organ dysfunction
• ECOG PS 2 vs 3
• Adverse events G2, G3-4

Study Drug, Dose, Route, and Regimen: Pembrolizumab 200 mg IV every 3 weeks for 12 weeks, with the option to transition to pembrolizumab 400 mg IV every 6 weeks thereafter. Pembrolizumab will then be continued until disease progression, unacceptable toxicity, withdrawal of consent, or death.

Statistical Considerations: This is a phase II clinical trial to assess the change in Quality of Life (QoL), measured by EORTC QLQ-C30 scores, for patients with treatment-naïve, advanced or metastatic NSCLC and ECOG 2/3 on Pembrolizumab treatment. The global QoL (QLQ-30) at baseline in 218 lung cancer patients had a mean of 57.6 and standard deviation (SD) of 24.3. The research team will test the difference in the change in QoL score between baseline and 12 weeks after Pembrolizumab treatment. A meaningful change, as documented in the literature, has determined to be a 10 score difference. The SD of the change is 18.9, assuming that the pre-/post- correlation is 0.7. A sample of 31 achieves 81% power to detect a mean of paired differences of 10 with an estimated SD of differences of 18.9 and with a significance level of 0.05 using a two-sided paired t-test. Considering the potential 30% drop-out, this study will enroll 45 patients to ensure at least 31 evaluable patients.

Approximately 20 new patients with metastatic NSCLC are seen per month at the Mount Sinai Hospital and Mount Sinai Chelsea sites; of these, approximately 7-8 have a PS of 2-3 based on past experience. Thus, the study can reasonably expect to accrue 2 patients per month to the study, with approximately 24 months needed to complete accrual.

Total number of participants: 45 Estimated Enrollment Period: 24 Months Estimated Duration of Participation: 24 Months Estimated Study Duration: 40 Months Participating Sites: Mount Sinai Hospital and Mount Sinai Chelsea

Inclusion criteria

• Men and women, aged 18 years and older, with locally advanced NSCLC who are ineligible for definitive surgical resection or concurrent chemoradiation, or metastatic NSCLC
• Patients must not have received any systemic therapy for metastatic cancer
• Patients must not have received any PD-1 or PD-L1 inhibitor
• ECOG performance status of 2 or 3 at the time of consent and on the first day of therapy
• Patients may not have a molecular alteration in ALK, ROS1, EGFR, BRAF, NTRK, RET, MET, or any other gene for which first-line FDA approved targeted therapy exists.
• Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period.
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS directed therapy is not required and is unlikely to be required during the first cycle of therapy.
• Patients with HIV on effective anti-retroviral therapy with an undetectable viral load within 6 months are eligible for this trial.
• Adequate organ and marrow function as defined below:

• Leukocytes ≥ 3,000/mcL
• Absolute neutrophil count ≥ 1,000/mcL
• Platelets ≥ 100,000/mcl
• Total bilirubin ≤ 1.5 x ULN
• AST (SGOT)/ALT (SPGT) ≤ 3 x ULN or ≤5 x ULN if liver metastases present
• GFR (Cockroft-Gault) ≥ 30 mL/min
• Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 3 days prior to C1D1 of pembrolizumab therapy. For the purposes of this trial, WOCBP are defined as women who have had a menstrual period within the last 48 months.
• Provision of signed and dated informed consent form
• Ability to take the study medication, and complete the study questionnaires
• Stated willingness to comply with all study procedures for the duration of the study
• For women of reproductive potential, agreement to use highly effective contraception during study treatment and for at least 4 months after the final dose
• For men of reproductive potential, agreement to use condoms or other methods to ensure effective contraception with female partners of reproductive potential

Exclusion criteria

• Autoimmune conditions requiring >10mg prednisone (or its equivalent) of daily therapy or other systemic immunosuppressive therapy.
• Patients who are receiving other investigational agents
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with known leptomeningeal disease for which CNS therapy is required
• Pregnant or lactating patients