Phase II Study of Lenvatinib Plus Pembrolizumab for Disease Progression after PD-1/PD-L1 Immune Checkpoint Inhibitor in Metastatic Clear Cell Renal Cell Carcinoma (mccrcc): Results of an Interim Analysis

Abstract Background Lenvatinib (LEN) is a multikinase VEGFR inhibitor approved for use in combination with everolimus to treat advanced RCC after prior VEGF-targeted therapy. Pembrolizumab (PEMBRO) is an anti-PD-1 antibody. Here, we report results of an interim analysis of the RCC cohort of a phase II trial of LEN + PEMBRO, specifically in patients (pts) who progressed with prior immune checkpoint inhibitor (ICI) therapy. Methods This is a per-protocol interim analysis of a multicenter, open-label study for pts with mccRCC, ≥1 prior therapy, RECIST disease progression on or following an ICI regimen (confirmed ≥ 4 weeks later), measurable disease, and Eastern Cooperative Oncology Group performance status ≤ 1. Pts received LEN 20 mg/d PO plus PEMBRO 200 mg intravenously Q3W until disease progression or toxicity occurred. Tumor assessments were performed every 6 weeks (until week 24), then every 9 weeks. Results At data cutoff (March 29, 2019), the first 33 pts enrolled were followed for ≥12 weeks for response evaluation, and 24 (73%) pts were still on study treatment. The objective response rate was 52%, the disease control rate was 94%, and most pts had tumor shrinkage. Median follow-up time for progression-free survival was 4.2 months. Pt characteristics and efficacy outcomes are summarized in the table. The most common treatment-related adverse events were fatigue (49%), dysphonia (36%), diarrhea (33%), stomatitis (30%), hypertension (24%), dry mouth, nausea, proteinuria, and hand-foot syndrome (21% each). Three (9%) pts discontinued treatment due to adverse events. Conclusions For the subset of mccRCC pts with disease progression during or following ICI therapy, LEN + PEMBRO demonstrated promising antitumor activity. No new safety signals were detected. The study will continue to full cohort expansion. Table . 1187PD Summary of patient characteristics and efficacy outcomes Patient Characteristics, n (%) LEN + PEMBRO (n = 33) ECOG performance status 0 18 (54.5) 1 15 (45.5) Prior anticancer regimens 1 prior regimen 14 (42%) >1 prior regimen 19 (58%) Prior VEGF-targeted therapy 26 (78.8%) Prior ICI therapy 33 (100%) PD-1/PD-L1 monotherapy 14 (42.4%) with VEGF agents 9 (27.7%) nivolumab + ipilimumab 7 (21.2%) with other agents 2 (6.1%) PD-L1 positive 12 (36.4) * Investigator assessment of efficacy outcomes by irRECIST LEN + PEMBRO (n = 33) ORR, n (%) 95% CI 17 (51.5) 33.5–69.2 Median PFS (95% CI), months PFS rate, % (95% CI) at: 3 months 6 months 9 months NR (5.6–NR) 93.4 (76.1–98.3) 73.8 (45.7–88.9) 64.6 (34.5–83.5) Median DOR, (95% CI) months NR (4.2–NR) Median follow-up time for DOR, months 6.0 (1.4–7.0) Response duration > = 6 months, n (%) ** 80.8 (42.3–94.9) * 30.3% were negative and 33.3% were not available ** Response duration is based on Kaplan-Meier estimation with 95% CI based on the Greenwood formula using log-log transformation DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; irRECIST, immune-related Response Evaluation Criteria In Solid Tumors; NR, not reached; ORR, objective response rate; PD-L1, programmed death-ligand-1; PFS, progression-free survival; VEGF, vascular endothelial growth factor. Clinical trial identification NCT02501096; Release date: July 17, 2015. Editorial acknowledgement Tarah M. Connolly, PhD of Oxford PharmaGenesis, Newtown, PA, funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure C. Lee: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Calithera; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Amgen. A.Y. Shah: Honoraria (self), Non-remunerated activity/ies, research: Eisai Inc.; Honoraria (self): Oncology Information Group; Non-remunerated activity/ies, research: EMD Serono; Non-remunerated activity/ies, research: Bristol-Myers Squibb. V. Makker: Non-remunerated activity/ies: AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Eisai; Honoraria (self), Non-remunerated activity/ies: Merck; Non-remunerated activity/ies: Lilly; Honoraria (self), Non-remunerated activity/ies: Karyopharm; Non-remunerated activity/ies: Takeda; Non-remunerated activity/ies: Genentech. M.H. Taylor: Research grant / Funding (institution): BioAlta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Array Biopharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: LOXO; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy: Arquele; Honoraria (self), Advisory / Consultancy: Novartis. J.J. Hsieh: Honoraria (self): Eisai Inc. A. Pinto Marin: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis; Honoraria (self): Aveo. D.W. Rasco: Research grant / Funding (self): Eisai Inc.; Research grant / Funding (self): Merck. D.E. Stepan: Full / Part-time employment: Formerly of Eisai Inc. C.E. Dutcus: Leadership role, Full / Part-time employment: Eisai Inc. J. Wu: Full / Part-time employment: Eisai Inc. E.V. Schmidt: Full / Part-time employment: Merck & Co Inc. R.F. Perini: Full / Part-time employment: Merck & Co Inc. R.J. Motzer: Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Exelixis; Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Incyte. All other authors have declared no conflicts of interest.