Fixed-Dose Favezelimab Combo Fails to Improve OS in Pretreated, PD-L1+, MSS mCRC

The investigational fixed-dose combination of the anti–LAG-3 antibody favezelimab and pembrolizumab (Keytruda) failed to improve overall survival (OS) vs regorafenib (Stivarga) or trifluridine/tipiracil (Lonsurf; TAS-102) in patients with previously treated, PD-L1–positive, microsatellite stable (MSS) metastatic colorectal cancer (mCRC), according to topline data from the final prespecified analysis of the phase 3 KEYFORM-007 trial (NCT05064059).¹

The safety profile of the combination was in line with that reported with the fixed-dose regimen in prior research, with no new onset toxicity. A complete assessment of the trial data is underway, and Merck and investigators are working to make the results available to the medical community.

“mCRC continues to be a challenging disease to treat, especially for the majority of patients who have MSS disease, which has had limited response to immunotherapies,” M. Catherine Pietanza, MD, vice president of global clinical development at Merck Research Laboratories, stated in a news release. “We are grateful to the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate [pembrolizumab]-based combinations and novel candidates for patients with CRC in need of new options.”

Pembrolizumab is currently indicated for use in the United States for the treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) CRC, as determined by an FDA-approved test.²

However, treatment options for patients with refractory MSS mCRC are limited. Prior research has shown that inhibition of both LAG-3 and PD-1 can enhance antitumor activity as evidenced by findings from the first-in-human study (NCT02720068) evaluating the combination of favezelimab and pembrolizumab in patients with MSS, PD-(L)1–naive mCRC.³

Findings from the trial published in ESMO Open in 2022 demonstrated that the combination (n = 89) led to a confirmed objective response rate (ORR) of 6.3%, a median duration of response (DOR) of 10.6 months (range, 5.6-12.7), median OS of 8.3 months (95% CI, 5.5-12.9), and median progression-free survival (PFS) of 2.1 months (95% CI, 1.9-2.2). In an exploratory analysis performed in the subset of patients with a PD-L1 combined positive score of 1 or greater (n = 48), the confirmed ORR was 11.1%, and the median OS and PFS were 12.7 months (95% CI, 4.5-not reached) and 2.2 months (95% CI, 1.8-4.2), respectively.³

KEYFORM-007 is a randomized, open-label, phase 3 trial evaluating the fixed-dose combination of favezelimab and pembrolizumab vs standard-of-care regorafenib or TAS-102 in patients with PD-L1–positive, MSS mCRC following prior treatment with standard therapy.¹

To be eligible for enrollment, patients had to have histologically confirmed, unresectable or metastatic colorectal adenocarcinoma that was previously treated; measurable disease per RECIST 1.1 criteria; and be able to submit a new or archived tumor tissue sample no more than 5 years old. Also required was an ECOG performance status of 0 to 1 within 10 days prior to the first dose of study treatment; a life expectancy of at least 3 months; the ability to swallow and digest oral medication as intended; and adequate organ function.⁴

Patients would be excluded from enrollment if found to have dMMR/MSI-H tumor status, active central nervous system metastases and/or carcinomatous meningitis or leptomeningeal disease, or history of acute or chronic pancreatitis, among other criteria.⁴

A total of 441 patients were randomly assigned to receive 800 mg of favezelimab in combination with 200 mg of intravenous (IV) pembrolizumab on day 1, then every 3 weeks for 35 cycles, or investigator’s choice of oral regorafenib once daily on days 1 through 12 of each 28-day cycle or oral TAS-102 twice daily on days 1 through 5 and 8 through 12 of each 28-day cycle.¹

The primary end point is OS, and key secondary end points include PFS, ORR, DOR, safety, and quality of life.

The combination of favezelimab and pembrolizumab is also under evaluation in the phase 3 KEYFORM-008 trial (NCT05508867), which is comparing the safety and efficacy of the fixed-dose regimen with physician’s choice of chemotherapy in patients with relapsed or refractory classical Hodgkin lymphoma whose disease progressed after prior treatment with anti–PD-1 therapy.

References

1. Merck provides update on phase 3 KEYFORM-007 trial evaluating investigational fixed-dose combination of favezelimab and pembrolizumab for patients with previously treated PD-L1 positive microsatellite stable metastatic colorectal cancer. News release. Merck. September 25, 2024. Accessed September 25, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keyform-007-trial-evaluating-investigational-fixed-dose-combination-of-favezelimab-and-pembrolizumab-for-patients-with-previously-treated-pd-l1-positive-microsatellite/
2. Keytruda. Prescribing information. Merck; 2021. Accessed September 25, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf
3. Garralda E, Sukari A, Lakhani NJ, et al. A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer. ESMO Open. 2022;7(6):100639. doi:10.1016/j.esmoop.2022.100639
4. A study of coformulated favezelimab/pembrolizumab (MK-4280A) versus standard of care in subjects with previously treated metastatic PD-L1 positive colorectal cancer (MK-4280A-007). ClinicalTrials.gov. Updated August 23, 2024. Accessed September 25, 2024. https://clinicaltrials.gov/study/NCT05064059