Weinreich, David M.

Abstract Background: Cemiplimab is the first treatment approved in the US (as cemiplimab-rwlc) for patients with metastatic basal cell carcinoma (mBCC) or locally advanced disease (laBCC) after hedgehog inhibitor (HHI) treatment or for whom an HHI is not appropriate. Cemiplimab provided substantial clinical benefit and an acceptable safety profile in patients with laBCC who discontinued HHI therapy due to progressive disease (PD), intolerance, or no better than stable disease (SD) after 9 months (NCT03132636). Here, we present the primary analysis of the mBCC cohort. Methods: Patients with mBCC (nodal or distant) post-HHI treatment received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until PD. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Key secondary endpoints included safety and tolerability, ORR per investigator (INV) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and complete response (CR) rate (data cutoff date: May 20, 2021). Results: Fifty-four patients were enrolled (70.4% male; median age 63.5 years [range, 38−90]; Eastern Cooperative Oncology Group performance status 0 [66.7%] and 1 [33.3%]). Median duration of follow-up was 8.4 months (range 1.5-36.2). ORR per ICR was 24.1% (95% confidence interval [CI], 13.5-37.6); with 1 CR and 12 partial responses (PRs). ORR per INV was 25.9% (95% CI, 15.0-39.7), with 2 CRs and 12 PRs. Among responders, median time to response per ICR was 4.0 months (range, 2.0−10.5). Estimated median DOR per ICR was 16.7 months (95% CI, 9.8-not evaluable). Disease control rate was 63.0% (95% CI, 48.7-75.7) per ICR and 70.4% (95% CI, 56.4-82.0) per INV. Median OS was not reached. Median PFS per ICR was 8.3 months (95% CI, 4.2-15.9). The most common treatment-related adverse events were fatigue (37.0%), diarrhea (14.8%), pruritus (13.0%), hyperthyroidism (9.3%), and arthralgia (9.3%) as well as hypothyroidism, asthenia, constipation, and maculo-papular rash (7.4% each). There were no treatment-related deaths. Conclusions: Cemiplimab provided clinically meaningful antitumor activity, including durable responses, and an acceptable safety profile in patients with mBCC who had progressed on or were intolerant to HHI therapy. Citation Format: Karl Lewis, Ketty Peris, Aleksander Sekulic, Alexander J. Stratigos, Lara Dunn, Zeynep Eroglu, Anne Lynn S. Chang, Michael R. Migden, Suk-Young Yoo, Kosalai Mohan, Ebony Coates, Emmanuel Okoye, Timothy Bowler, Jean-François Baurain, Oliver Bechter, Axel Hauschild, Marcus O. Butler, Leonel Hernandez-Aya, Lisa Licitra, Rogerio I. Neves, Emily S. Ruiz, Frank Seebach, David M. Weinreich, George D. Yancopoulos, Israel Lowy, Priscila Goncalves, Matthew G. Fury. Primary analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma who progressed on or were intolerant to hedgehog inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT165.

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based CD3 x CD20 bispecific antibody (bsAb) that has demonstrated encouraging safety, tolerability and preliminary efficacy in a first-in-human study of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). We report updated safety and efficacy data from the dose escalation and early dose expansion phase of the ongoing Phase (P)1 study (NCT02290951). METHODS: Odronextamab was administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing. Dexamethasone premedication was used to mitigate the risk for cytokine release syndrome (CRS). Key primary objectives were to assess safety and dose-limiting toxicities (DLTs), and to establish a maximum tolerated dose (MTD) and recommended P2 dosing regimen (RP2DR). Secondary objectives included a preliminary assessment of anti-tumor activity. RESULTS: As of Jun 25, 2020, 127 pts with R/R B-NHL have been treated at doses ranging from 0.03-320 mg. The study included pts with diffuse large B-cell lymphoma (DLBCL; n=71), follicular lymphoma (FL) Grade (Gr) 1-3a (n=37), mantle cell lymphoma (MCL; n=11), marginal zone lymphoma (n=6), and other B-NHLs (n=2). Pts were highly refractory (80.3%) and had received a median of 3 (range: 1‒11) prior lines of therapy; 29 pts (22.8%) received prior CAR T therapy (FL: 2; DLBCL: 25; MCL: 2) and 85 pts (66.9%) were double refractory to alkylator and anti-CD20 antibody, in any line of therapy. Median follow-up was 3.9 (0.4‒37.6) months (mo). No DLTs were reported during dose escalation and MTD was not reached with odronextamab doses up to 320 mg weekly. The most frequent treatment-related adverse events (AEs) of any grade were pyrexia (76.4%), CRS (62.2%), and chills (48.0%). Gr 3 CRS occurred in 8 pts (6.3%) and a Gr 4 CRS occurred in 1 pt (0.8%). Most of the CRS events occurred during the first 2 weeks of step-up dosing and resolved within a median of 2 days (range 1-41) with supportive care measures. No pts discontinued odronextamab treatment due to CRS. Gr 3 neurologic AEs were noted in 5 pts, of which only 3 (2.3%) were considered treatment-related: somnolence, syncope, and encephalopathy. None of these events required treatment discontinuation. There were no Gr 4 or higher neurologic AEs. Overall, 7 pts (5.5%) discontinued treatment due to treatment-related AEs. In pts with R/R FL Gr 1-3a, odronextamab demonstrated a broad window of therapeutic activity. In pts treated at doses of ≥5 mg (n=28), objective response rate (ORR) was 92.9%, and complete response (CR) rate was 75.0%; median duration of response (DoR) was 7.7 mo (range 0+-20.9+), with 13 of 21 CRs ongoing at last tumor assessment. The median duration of complete response (DoCR) was 8.1 mo (range 0+-19.9+) and follow-up is ongoing (Table). In pts with R/R DLBCL, encouraging activity was observed at higher odronextamab dose levels. In DLBCL pts who had not received prior CAR T therapy, treated at doses ≥80 mg (n=10), ORR and CR rate were 60%; median observed DoR was 10.3 mo (range 2.9-18.6+), with 4 of 6 CRs ongoing at last tumor assessment. The median DoCR was 9.5 mo (range 2.9-18.6+) and follow-up is ongoing. In DLBCL pts who were refractory to prior CAR T therapy, treated at doses ≥80 mg (n=21), ORR was 33.3%, and CR rate was 23.8%; median observed DoR was 2.8 mo (range 0+-18.9+), with 5 of 5 CRs ongoing at last tumor assessment. The median DoCR was 4.4 mo (range 0+-18.9+) and follow-up is ongoing. Based on an evaluation of preliminary antitumor activity and PK, RP2DR was identified for dose expansion cohorts. CONCLUSIONS: Odronextamab has demonstrated encouraging single agent antitumor activity in highly refractory pts with B-NHLs. Durable CRs have been observed in both indolent and aggressive B-NHL pts, including in pts refractory to CAR T therapy. Most CRs are ongoing at time of data cutoff, and updated data will be presented. Odronextamab has an acceptable safety and tolerability profile. Dexamethasone premedication and step-up dosing mitigates the risk for CRS and allows odronextamab administration up to 320 mg weekly without DLTs. A global P2 trial investigating odronextamab in R/R B-NHL is ongoing. Disclosures Bannerji: Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Catapult: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Eli Lilly and Company: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Duell:Morphosys: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Janssen: Consultancy. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Flink:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of odronextamab in a Phase 1 clinical trial of patients with B-NHL