Phase 3 KEYFORM-007 Misses Primary End Point in MSS mCRC

The fixed-dose combination did not show an improvement in OS compared with the standard of care, regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf), at the final prespecified analysis.

The phase 3 KEYFORM-007 trial (NCT05064059) assessing the anti-LAG-3 antibody favezelimab plus pembrolizumab (Keytruda) did not meet its primary end point of overall survival (OS) in patients with previously treated PD-L1-positive microsatellite stable metastatic colorectal cancer (mCRC), according to a press release from Merck.¹

The fixed-dose combination did not show an improvement in OS compared with the standard of care, regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf), at the final prespecified analysis. The safety profile remained consistent with findings in previously reported studies.

“Metastatic colorectal cancer continues to be a challenging disease to treat, especially for the majority of patients who have microsatellite stable disease, which has had limited response to immunotherapies,” M. Catherine Pietanza, MD, vice president of global clinical development at Merck Research Laboratories, stated in the press release.¹ “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 colorectal cancer in need of new options.”

Secondary end points in KEYFORM-007 included progression-free survival, objective response rate, duration of response, safety, and quality of life.² A total of 441 patients were enrolled and randomly assigned 1:1 to receive favezelimab 800 mg and pembrolizumab 200 mg intravenously on day 1 followed by every 3 weeks for 35 cycles vs investigator’s choice of regorafenib orally once daily on days 1 to 12 of each 28-day cycle or TAS-102 orally twice daily on days 1 to 5 and days 8 to 12 of each 28-day cycle.

To be eligible for the study, patients were required to have histologically confirmed metastatic and unresectable colorectal adenocarcinoma, with measurable disease per RECIST 1.1, and an ECOG performance status of 0 or 1. Inclusion criteria included prior treatment for the disease and radiographic progression during or after treatment or intolerance to standard treatment.

Of note, patients with deficient mismatch repair (dMMR) or microsatellite instability (MSI)-high status were not eligible for the study. Active central nervous system (CNS) metastases or carcinomatous meningitis or leptomeningeal disease were also some excluding factors.

Pembrolizumab is indicated for the treatment of patients with unresectable or metastatic MSI-high or dMMR CRC in the United States. The fixed-dose combination of favezelimab and pembrolizumab is currently being evaluated in hematologic malignancies and multiple solid tumor types, including in in phase 3 KEYFORM-008 (NCT05508867).³

KEYFORM-008 is a phase 3 study of the combination in patients with relapsed/refractory classical Hodgkin lymphoma who have progressed following prior anti-PD-1 therapy. The study is currently recruiting patients across 99 treatment centers. Patients are required to have a histologically confirmed diagnosis of classical Hodgkin lymphoma (cHL) which is 2-fluorodeoxyglucose-avid (FDG-avid). The study is limited to patients who have exhausted all available treatment options with clinical benefit and patients who have progressed on an anti-PD-1 monoclonal antibody as monotherapy or in combination with other therapies or checkpoint inhibitors.

Excluding factors include CNS metastases or active CNS involvement, an active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy, active infections requiring treatment, and active cardiovascular disease.

Patients will receive co-formulated favezelimab/pembrolizumab (800 mg/200 mg) by intravenous infusion or intravenous chemotherapy (bendamustine or gemcitabine). The primary end point is PFS per Lugano Response Criteria as assessed by a blinded independent central review. Secondary end points include OS, objective response rate, duration of response, number of participants who experienced at least 1 adverse effect (AE), and number of participants who discontinued study treatment due to an AE.

Reference

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-L1positive microsatellite stable metastatic colorectal cancer. News Release. Merck. September 25, 2024. Accessed September 25, 2024. https://tinyurl.com/3d82mvr8
2. 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://tinyurl.com/3rdbpjm4
3. A study of coformulated favezelimab/​pembrolizumab (MK-4280A) versus physician's choice chemotherapy in PD-(L)1-refractory, relapsed or refractory classical Hodgkin lymphoma (MK-4280A-008). ClinicalTrials.gov. Updated September 23, 2024. Accessed September 25, 2024. https://tinyurl.com/m7xyzfs2