Reshma Rangwala

Pembrolizumab for the Treatment of Non–Small-Cell Lung Cancer

BACKGROUND We assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non-small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. METHODS We assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. RESULTS Common side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all the patients, the objective response rate was 19.4%, and the median duration of response was 12.5 months. The median duration of progression-free survival was 3.7 months, and the median duration of overall survival was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among patients with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all the patients with a proportion score of at least 50%, median progression-free survival was 6.3 months; median overall survival was not reached. CONCLUSIONS Pembrolizumab had an acceptable side-effect profile and showed antitumor activity in patients with advanced non-small-cell lung cancer. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab. (Funded by Merck; KEYNOTE-001 ClinicalTrials.gov number, NCT01295827.).

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial

Background Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1–Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial

Purpose The KEYNOTE-028 trial ( ClinicalTrials.gov identifier: NCT02054806) was designed to assess the safety and efficacy of pembrolizumab in 20 programmed death ligand 1-positive, advanced solid tumor cohorts. Here, we present the results from the cohort of patients with advanced cervical cancer. Methods Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety was a secondary end point. Results Twenty-four patients were enrolled in the cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22 patients (92%) had received prior radiation therapy, and 15 patients (63%) had received two or more lines of therapy, including bevacizumab (10 of 24 patients), for advanced disease. At the data cutoff, median follow-up duration was 11.0 months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to 37%); four patients (17%) achieved a confirmed partial response, and three patients (13%) had stable disease. Median duration of response for the four patients who achieved a partial response was 5.4 months (4.1 to 7.5 months). Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in ≥ 10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed. Conclusion In patients with programmed death ligand 1-positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.

Health-related quality-of-life results for pembrolizumab versus chemotherapy in advanced, PD-L1-positive NSCLC (KEYNOTE-024): a multicentre, international, randomised, open-label phase 3 trial

BACKGROUND In the phase 3 KEYNOTE-024 trial, treatment with pembrolizumab conferred longer progression-free survival than did platinum-based therapy in patients with treatment-naive, advanced non-small-cell lung cancer (NSCLC) with a programmed cell death-ligand 1 (PD-L1) tumour proportion score of 50% or greater (PD-L1-positive). Here we report the prespecified exploratory endpoint of pembrolizumab versus chemotherapy on patient-reported outcomes (PROs). METHODS In this multicentre, international, randomised, open-label, phase 3 trial, we recruited patients with treatment-naive, stage IV NSCLC in 102 sites in 16 countries. Eligible patients had measurable disease (per RECIST version 1.1) and an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Patients were randomly assigned (1:1) via an interactive voice response system and integrated web response system to receive either pembrolizumab 200 mg every 3 weeks (35 cycles) or investigator-choice platinum-doublet chemotherapy (4-6 cycles or until documented disease progression or unacceptable toxicity). Randomisation was stratified according to geography, ECOG performance status, and histology. PROs were assessed at day 1 of cycles 1-3, every 9 weeks thereafter, at the treatment discontinuation visit, and at the 30-day safety assessment visit using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), the EORTC Quality of Life Questionnaire Lung Cancer 13 items (QLQ-LC13), and the European Quality of Life 5 Dimensions-3 Level (EQ-5D-3L) questionnaire. The key exploratory PRO endpoints (analysed for all patients who received at least one dose of study treatment and completed at least one PRO instrument at at least one timepoint) were baseline-to-week-15 change in the QLQ-C30 global health status (GHS)/quality-of-life (QOL) score and time to deterioration of the composite of cough, chest pain, and dyspnoea in the QLQ-LC13. This study is registered with ClinicalTrials.gov, number NCT02142738, and is ongoing but no longer enrolling patients. FINDINGS Between Sept 19, 2014, and Oct 29, 2015, 305 patients were randomly assigned to pembrolizumab (n=154) or chemotherapy (n=151). Three patients in each group did not complete any PRO instruments at any timepoints, and so 299 patients were included in the full analysis set. Of these patients, one in each group did not complete any PRO instruments before week 15, and so were not included in analyses of change from baseline to week 15. PRO compliance was greater than 90% at baseline and approximately 80% at week 15 for both groups. Least-squares mean baseline-to-week-15 change in QLQ-C30 GHS/QOL score was 6·9 (95% CI 3·3 to 10·6) for pembrolizumab and -0·9 (-4·8 to 3·0) for chemotherapy, for a difference of 7·8 (2·9 to 12·8; two-sided nominal p=0·0020). Fewer pembrolizumab-treated patients had deterioration in the QLQ-LC13 composite endpoint than did chemotherapy-treated patients (46 [31%] of 151 patients vs 58 [39%] of 148 patients). Time to deterioration was longer with pembrolizumab than with chemotherapy (median not reached [95% CI 8·5 to not reached] vs 5·0 months [3·6 to not reached]; hazard ratio 0·66, 95% CI 0·44-0·97; two-sided nominal p=0·029). INTERPRETATION Pembrolizumab improves or maintains health-related QOL compared with that for chemotherapy, and might represent a new first-line standard of care for PD-L1-expressing, advanced NSCLC. FUNDING Merck & Co.

195TiP: Pembrolizumab (MK-3475) versus platinum-based chemotherapy for PD-L1+ NSCLC in a phase 3, randomized, open-label study: KEYNOTE-042.

T. Mok1, Y.-L. Wu2, S. Sadowski3, J. Zhang4, R. Rangwala3, D. Kush3, G. de Lima Lopes5. 1 Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China, 2 Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong, China, 3 Clinical Oncology, Merck & Co., Inc., Kenilworth, NJ, USA, 4 BARDS, Merck & Co., Inc., Kenilworth, NJ, USA, 5 Oncology, Centro Paulista de Oncologia e HCor Onco, members of the Oncoclinicas do Brasil Group, Sao Paulo, Brazil

P2.43: Pembrolizumab vs Platinum-Based Chemotherapy for PD-L1+ NSCLC: Phase 3, Randomized, Open-Label KEYNOTE-042 (NCT02220894): Track: Immunotherapy

Method: We used in vitro assays, as well as xenografts of PC9ER and H1975 NSCLC, which are resistnat to erlotinib. Tumour growth was followed in mice for 3-4 months. Results: Anti-EGFR antibodies recognize mutant EGFRs, hence might overcome resistance to kinase inhibitors. Employing T790M models we showed that an anti-EGFR mAb induces feedback loops that activate MET and increases two EGFR’s family members, namely HER2 and HER3, thereby over-activate ERK. Amixture of threemAbs simultaneously targeting EGFR, HER2 and HER3 abolished feedback and, when tested in animals, completely inhibited erlotinib-resistant tumours. We will report our most recent results performed with AZD9291-resistant NSCLC. In addition, we will present evidence indicating that the mechanism of action of kinase inhibitors differs from the mechanism of action of monoclonal antibodies, hence combining antibodies and kinase inhibitors might elicit synergistic effects on tumours. Conclusion: Our findings propose a previously untested pharmacological strategy to overcome recurring resistance of NSCLC to EGFR inhibitors. This includes resistance due to emergence of the C797S mutation, which prevents binding of third generation inhibitors to EGFR.

Abstract CT104: Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001)

Background: Preliminary KEYNOTE-001 data showed that the PD-1 inhibitor pembro has manageable safety and antitumor activity in previously treated and treatment-naive advanced non-small cell lung cancer (NSCLC). In a training set of 182 pts, 129 of whom had measurable disease and tumor evaluable by an IHC clinical trial assay (CTA) for PD-L1 expression, ORR was higher in pts with membranous PD-L1 expression in ≥50% of tumor cells (proportion score [PS] ≥50%) vs PS Methods: Advanced or metastatic NSCLC pts received pembro 2 mg/kg Q3W, 10 mg/kg Q3W, or 10 mg/kg Q2W. Response was assessed every 9 wk. Treatment decisions were managed per investigator-assessed irRC. Efficacy evaluation was per centrally assessed RECIST v1.1. PD-L1 expression was determined by the CTA. Before analysis, ORR and PD-L1 data from the validation set were merged in pts with measurable disease and CTA-evaluable tumors. Duration of response (DOR), PFS, and OS were assessed in all treated pts from the training and validation sets with CTA-evaluable tumors. Results: In all 495 pts from the training and validation sets, irrespective of PD-L1 expression, ORR was 19.4%, median DOR was 12.4 mo, median PFS was 3.7 mo, and median OS was 12.0 mo. 9% experienced grade 3-5 treatment-related AEs; 4% discontinued due to a treatment-related AE. There was 1 treatment-related death (pneumonitis). Of the 313 pts in the validation set, ORR in the 204 pts evaluable by the CTA was 45.2% in those with PS ≥50% (Table). The relationship between ORR and PD-L1 expression was observed in previously treated and treatment-naive pts (Table). In the 356 pts evaluable by the CTA in the total population, PFS and OS were longer in pts with PS ≥50% (Table). Median OS was not reached in pts with PS ≥50%, regardless of prior treatment. Median (range) DOR was similar in pts with PS ≥50% (12.4 mo [2+ to 22.8+]), 1-49% (10.3 mo [1.4+ to 10.3]), and Conclusion: Pembro provides durable antitumor efficacy and safety in pts with treatment-naive and previously treated NSCLC. These data validate that membranous PD-L1 expression in ≥50% of tumor cells identifies pts with advanced NSCLC who are particularly likely to obtain clinical benefit from pembro. Citation Format: Edward B. Garon, Naiyer Rizvi, Rina Hui, Natasha B. Leighl, Ani S. Balmanoukian, Joseph P. Eder, Amita Patnaik, Charu Aggarwal, Matthew A. Gubens, Leora Horn, Enric Carcereny, Myung-Ju Ahn, Enriqueta Felip, Jong-Seok Lee, Jin Zhang, Reshma A. Rangwala, Gregory M. Lubiniecki, Charlotte M. Roach, Kenneth Emancipator, Leena Gandhi. Efficacy of pembrolizumab (MK-3475) and relationship with PD-L1 expression in patients with non-small cell lung cancer: Findings from KEYNOTE-001). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT104. doi:10.1158/1538-7445.AM2015-CT104