favezelimab (MK-4280)

Currently, with the approval of relatlimab, a LAG-3 blocking antibody, a third player, has been used in the fight against cancer...However, the complex biology of LAG-3 may hinder its full development as a therapeutic alternative. In this review, we provide in-depth insight into the biology of LAG-3 and its current and future development in cancer treatment.

P1/2, N=174, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Apr 2028 --> Oct 2028 | Trial primary completion date: Apr 2028 --> Oct 2028

P1/2, N=174, Recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2027 --> Apr 2028 | Trial primary completion date: Oct 2027 --> Apr 2028

P1, N=482, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT02625961.

With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti–PD-1–naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

Accordingly, we engineered a bivalent version of Fab favezelimab that doubled the size of the Fab-LAG3 complex and conferred a highly identifiable shape to the complex that facilitated particle selection and orientation for image processing. This study establishes bivalent Fabs as new fiducial markers for cryoEM analysis of small proteins.

1 Recent results from MK4280–001 phase I clinical study (NCT02720068) have demonstrated clinical activity of a combined therapy regimen of the anti-LAG3 antibody favezelimab plus pembrolizumab in patients with microsatellite stable metastatic CRC whose tumors express PD-L1 with a Combined Positive Score (CPS) ≥ 1. 4% OA for both endpoints. Conclusions This study demonstrates high external lab reproducibility of PD-L1 IHC 22C3 pharmDx with respect to PD-L1 expression in CRC at the CPS ≥ 1 cutoff.

Patients were categorized by T-cell-inflamed gene expression profile (TcellGEP) and tumor mutational burden (TMB) status and randomly assigned 1:1:1 to receive pembrolizumab + lenvatinib, pembrolizumab + quavonlimab or pembrolizumab + favezelimab. These data demonstrate the feasibility of prospective TcellGEP and TMB assessment to study the clinical activity of first-line pembrolizumab-based combination therapies in advanced NSCLC. ClinicalTrials.gov registration: NCT03516981 .

The combination of favezelimab plus pembrolizumab continued to demonstrate antitumor activity and manageable safety in pts with R/R cHL whose disease progressed following anti–PD-1 therapy. Clinical trial, Immunotherapy, Hodgkin's lymphoma

Favezelimab + pembrolizumab continued to demonstrate sustained antitumor activity and acceptable safety in anti–PD-1–naive patients with R/R cHL. Further studies comparing this combination with pembrolizumab alone would be beneficial. Clinical trial, Hodgkin's lymphoma, Immunotherapy

In this post hoc analysis, the combination of favezelimab + pembrolizumab was associated with a higher ORR and deeper responses than pembrolizumab monotherapy in patients with PD-1–refractory R/R cHL. Although limited by its retrospective nature, the results support the hypothesis that favezelimab contributed substantially to the efficacy observed in the MK-4280-003 study. Clinical trial, Hodgkin's lymphoma, Immunotherapy

Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in anti–PD-1–naive patients with R/R cHL. Further studies comparing the activity of this combination to that of single-agent pembrolizumab would be of clinical benefit.

After additional follow-up, favezelimab plus pembrolizumab combination therapy continued to demonstrate sustained antitumor activity and acceptable safety in pts with R/R cHL whose disease progressed following anti–PD-1 therapy. A phase 3 study is planned to further investigate the promising results found in this patient population.

Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in pts with R/R cHL and PD following anti–PD-1 therapy. This combination shows potential to reinduce a response in this pt population.

The multicohort phase 1/2 MK-4280–003 study (NCT03598608) evaluated the safety and efficacy of a LAG-3 inhibitor favezelimab (MK-4280) + pembrolizumab (pembro) in pts with R/R hematologic malignancies. Favezelimab 800 mg + pembro 200 mg Q3W demonstrated acceptable safety and effective antitumor activity in anti–PD-1–naive pts with R/R cHL. Comparative studies on its activity to that of single-agent pembro would be of clinical benefit.

Conclusion Favezelimab 800 mg + pembrolizumab 200 mg Q3W demonstrated an acceptable safety profile and effective antitumor activity in anti–PD-1–naïve patients with R/R cHL. Further studies are merited to compare the activity of this combination to that of pembrolizumab alone.

No treatment-related deaths occurred. Conclusion Favezelimab 800 mg + pembrolizumab 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated patients with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these patients.

P2, N=318, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Oct 2025 --> Jun 2025 | Trial primary completion date: Oct 2025 --> Jun 2025

This ongoing, open-label, multicenter, multiarm, randomized, phase 2 trial (NCT04895722) will evaluate efficacy and safety of coformulated pembro and anti–CTLA-4 quavonlimab compared with pembro monotherapy in chemotherapy-refractory stage IV dMMR/MSI-H CRC in cohort A; the study will also evaluate the efficacy and safety of 4 pembro-based combinations (coformulation of pembro with either quavonlimab, anti–LAG-3 favezelimab, or anti-TIGIT vibostolimab; anti-ILT4 MK-4830 given sequentially with pembro) compared with pembro monotherapy in previously untreated stage IV dMMR/MSI-H CRC in cohort B. Pts aged ≥18 y with histologically confirmed stage IV dMMR/MSI-H CRC who have measurable disease per RECIST v1.1 by investigator and confirmed by blinded independent central review (BICR), will be enrolled. Pts in cohort A must have experienced PD after fluoropyrimidine, irinotecan, and oxaliplatin, with or without anti-VEGF antibody, and anti-EGFR antibody for pts with left-sided tumors that are RAS WT...For both cohorts, primary end point is ORR by BICR per RECIST v1.1; secondary end points are ORR assessed by investigator, DOR and PFS assessed by BICR and by investigator per RECIST v1.1, OS, and safety and tolerability graded per NCI CTCAE v5.0. Enrollment in this trial is ongoing.

P2, N=318, Active, not recruiting, Merck Sharp & Dohme Corp. | Recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Oct 2025 | Trial primary completion date: Feb 2025 --> Oct 2025

P2, N=318, Recruiting, Merck Sharp & Dohme Corp. | Trial completion date: Jan 2023 --> Feb 2025 | Trial primary completion date: Jan 2023 --> Feb 2025