A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

Abstract

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

Clinical management of metastatic colorectal cancer in the era of precision medicine

“…Several clinical studies are investigating the potential role of immune checkpoint inhibitors in combination with chemotherapy, including combinations with antiangiogenic drugs (monoclonal antibodies and multikinase inhibitors); anti-EGFR monoclonal antibodies; inhibitors of intracellular signal-transduction pathways, including KRAS G12C, BRAF V600E, or MEK inhibitors; or radiotherapy. 129,[171][172][173][174][180][181][182][183][184][185][186][187][188][189][190] Although promising signs of therapeutic activity have been observed in some of these studies, further translational and clinical investigation is needed to identify the most effective combination strategies as well to appropriately select the patients who could obtain a clinical benefit from this approach.…”

Exploring immunotherapy in colorectal cancer

“…An increase in reliable clinical data on the double blocking of LAG-3 and PD-1 has prompted people to focus on this combination immunotherapy. A clinical trial (NCT02720068) [ 221 ] demonstrated that the combination of LAG-3 inhibitor (Favezelimab) and Pembrolizumab exhibits good antitumor activity, especially in patients with PD-L1 CPS ≥ 1.…”

Combined Treatment with Immunotherapy-Based Strategies for MSS Metastatic Colorectal Cancer

“…Exploratory analyses showed that patients presenting plasma TMB of 28 variants per megabase or more (21% of MSS tumors) had the greatest OS benefit (hazard ratio [HR]: 0.34, p = 0.004). Results from the phase I first-in-human clinical trial testing the anti-LAG-3 antiboy favezelimab and the anti-PD-1 pembrolizumab in previously treated patients with advanced MSS CRC were recently reported [ 12 ]. Of 89 patients receiving the combined blockade, four patients presented partial response and one patient achieved complete response.…”