On December 15, 2023 Bristol Myers Squibb (NYSE: BMY) reported that the Phase 3 RELATIVITY-123 trial evaluating the fixed-dose combination of nivolumab and relatlimab for the treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC) patients whose disease has progressed following at least one, but no more than four, prior lines of therapy for metastatic disease will be discontinued due to futility based on a planned analysis conducted by an independent data monitoring committee (Press release, Bristol-Myers Squibb, DEC 15, 2023, View Source [SID1234638613]). It was determined that the trial was unlikely to meet its primary endpoints upon completion.
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The recommendation to stop the study was not based on safety concerns. The safety profile was consistent with previously reported studies of the fixed-dose combination of nivolumab and relatlimab.
Investigation of the fixed-dose combination of nivolumab and relatlimab as a treatment for other tumor types will continue as planned. These results do not impact the currently approved indication for patients with unresectable or metastatic melanoma.
"Metastatic colorectal cancer is a challenging cancer to treat with high unmet needs. Though there have been advances in treating patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) colorectal cancers, patients with microsatellite stable (MSS) tumors continue to have limited treatment options in later lines of therapy. While we know immunotherapies have historically demonstrated limited efficacy in MSS colorectal cancers, we had hoped to demonstrate meaningful clinical benefit in this patient population and are disappointed in this outcome," said Jeffrey Walch, M.D., Ph.D., vice president, global program lead, Bristol Myers Squibb. "We continue to be committed to the development of I-O therapies, including Opdivo (nivolumab) and Yervoy (ipilimumab), in MSI-H/dMMR colorectal cancers, and we thank the investigators, patients, and their loved ones who participated in this trial."
The company will share the data with investigators so they may determine appropriate next steps for patients enrolled in the RELATIVITY-123 trial. The company will complete a full evaluation of the data and work with investigators to share the results with the scientific community.
About RELATIVITY-123
RELATIVITY-123 is a Phase 3 randomized, open label, multi-center trial evaluating the fixed-dose combination of nivolumab and relatlimab compared to regorafenib or trifluridine plus tipiracil (TAS-102) in approximately 700 adult patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) whose disease has progressed following at least one but no more than four prior lines of therapy for metastatic disease. The study did not include patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors. The dual primary endpoints are overall survival (OS) in all randomized patients and in randomized patients with PD-L1 combined positive score (CPS) ≥ 1. Secondary endpoints include objective response rate (ORR), progression-free survival (PFS), and duration of response (DoR) by Blinded Independent Central Review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, safety, and time until definitive deterioration-physical function and quality of life in all randomized patients and in randomized patients with PD-L1 CPS ≥ 1.
About LAG-3
Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. LAG-3 inhibits the function of T cells when it interacts with the cell’s ligands and reduces the activation and growth of the cell on which it is found.
This T cell dysfunction allows tumors to avoid attack from the immune system and grow unchecked. Preclinical studies indicate that inhibition of LAG-3 may promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.
Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types.
About Colorectal Cancer
Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. Globally, CRC is the third most commonly diagnosed cancer in the world. In 2020, it is estimated that there were approximately 1,931,000 new cases of the disease and that it will be the second leading cause of cancer-related deaths among men and women combined.
Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, leading to microsatellite instability-high (MSI-H) tumors. Approximately 5-7% of metastatic CRC patients have dMMR or MSI-H tumors. The remaining 95% of colorectal cancer patients with microsatellite stable (MSS)/proficient mismatch repair (pMMR) tumors have limited treatment options in later-lines of therapy.