RELATIVITY-123 Unlikely to Reach Primary Endpoints in MSS CRC, To Be Discontinued

Other trials assessing the fixed-dose combination of nivolumab and relatlimab as a treatment for other tumor types will continue.

The phase 3 RELATIVITY-123 trial (NCT05328908), which is assessing the efficacy of the nivolumab (Opdivo) and relatlimab (Opdualag) combination in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) whose disease has progressed following 1 to 4 prior lines of therapy for metastatic disease, will be discontinued due to futility, according to a news release by the drugs’ developer Bristol Myers Squibb.¹

The discontinuation is due to an assessment by an independent data monitoring committee, which determined that the trial was unlikely to meet its coprimary end points of overall survival (OS) in all randomized patients as well as in randomized patients with a PD-L1 combined positive score (CPS) of at least 1 upon completion.

The discontinuation was not based on safety concerns; the safety profile was consistent with previous studies assessing the fixed-dose combination of nivolumab and relatlimab.

“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,” Jeffrey Walch, MD, PhD, vice president and global program lead at Bristol Myers Squibb, said in the news release. “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. We continue to be committed to the development of [immuno]therapies, including nivolumab and ipilimumab [Yervoy], in MSI-H/dMMR colorectal cancers, and we thank the investigators, patients, and their loved ones who participated in this trial.”

This randomized open-label study aimed to assess nivolumab plus relatlimab vs regorafenib (Stivarga) or TAS-102 (trifluridine/tipiracil; Lonsurf) in patients with later lines of non–MSI-H/dMMR mCRC.² Inclusion in the trial was contingent on having recent progression following 1 to 4 prior lines of therapy, an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. Patients were excluded from the study if they had confirmed MSI-H/dMMR disease, prior treatment with an immunotherapy, regorafenib, or TAS-102, and/or a history of significant cardiovascular disease, interstitial lung disease/pneumonitis, or autoimmune disease.

The secondary end points to this trial included overall response rate (ORR), progression-free survival (PFS), duration of response as assessed by blinded independent central review and investigator per RECIST v1.1 criteria, safety, and time until definitive deterioration-physical function and quality of life in all randomized patients, as well as those with a PD-L1 CPS of 1 or over.

Next steps will be determined for the patients currently enrolled in the RELATIVITY-123 trial; data will be shared with other investigators. Other trials assessing the fixed-dose combination of nivolumab and relatlimab as a treatment for other tumor types will continue. Bristol Myers Squibb noted that these results do not impact the approval of nivolumab plus relatlimab as a combination therapy for patients with unresectable or metastatic melanoma.³

References

1. Bristol Myers Squibb Provides Update on RELATIVITY-123 Trial Evaluating the Fixed-Dose Combination of Nivolumab and Relatlimab in Patients with Previously Treated Metastatic Microsatellite Stable (MSS) Colorectal Cancer. News release. Bristol Myers Squibb. December 15, 2023. Accessed December 18, 2023. https://tinyurl.com/yvyv84rj
2. Feeney K, Joubert WL, Bordoni RE, et al. RELATIVITY-123: A phase 3, randomized, open-label study of nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) versus regorafenib or trifluridine + tipiracil (TAS-102) in later-line metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(4_suppl):TPS278-TPS278. doi:10.1200/jco.2023.41.4_suppl.tps278
3. FDA approves Opdualag for unresectable or metastatic melanoma. News release. FDA. March 18, 2022. Accessed December 19, 2023. https://tinyurl.com/cwbnkbkm