Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142

Background In the phase 2 multicohort CheckMate 142 study (NCT02060188), nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at a median follow-up of 13.4 months (Overman M et al. J Clin Oncol 2018;36:773–779). At 25.4 months of follow-up, nivolumab plus low-dose ipilimumab continued to provide robust and durable clinical benefit with deepening of response, and no new safety signals were identified (Overman M et al. J Clin Oncol 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Methods Patients received nivolumab (3 mg/kg) + low-dose (1 mg/kg) ipilimumab Q3W (4 doses) followed by nivolumab (3 mg/kg) Q2W until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; per RECIST v1.1). Other key endpoints reported here include disease control rate (DCR, per investigator), duration of response (DOR, per investigator), progression-free survival (PFS, per investigator), overall survival (OS), and safety. Results For the 119 treated patients, median age was 58 years, 59% were male, 76% had ≥ 2 prior lines of therapy, 55% had ECOG performance status (PS) 1, 25% had BRAF mutation, 37% had KRAS mutation, and 26% were BRAF/KRAS wild type. Median follow-up was 50.9 months (range, 46.9–62.7 months). Investigator-assessed ORR (95% CI) increased from 55% (45–64) at 13.4 months to 65% (55–73) at 50.9 months; DCR (95% CI) at 50.9 months was 81% (72–87). Complete response (CR) rate increased with longer follow-up from 3% at 13.4 months to 13% at 50.9 months. Partial responses (PR) were observed in 52% of patients; 21% had stable disease (SD), and 12% had progressive disease (PD) as best response. Median time to response was 2.8 months (range, 1.1–37.1 months) and median DOR was not reached (range, 1.4+ to 58.0+ months). At data cutoff, 37 (48%) patients had ongoing responses. Median PFS was not reached (95% CI, 38.4 to not estimable [NE]) and median OS was not reached (95% CI, NE). The 48-month rates of PFS (95% CI) and OS (95% CI) were 53% (43–62) and 70.5% (61.4–77.9), respectively. ORR benefit was observed across evaluated subgroups by BRAF/KRAS mutation status, ECOG PS, age, and sex, and each was consistent with that in the overall population. Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 10% (grade 3-4) and 13% (any grade) of patients had TRAEs leading to discontinuation. Conclusions Nivolumab plus low-dose ipilimumab provided durable clinical benefit (ORR, PFS, and OS) over 13.4, 25.4, and 50.9 months of follow-up. Extended follow-up showed increasing ORR and deepening of response. The safety profile was manageable with no new safety signals. These results demonstrate long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC. Clinical trial identification NCT02060188. Editorial acknowledgement All authors contributed to and approved the abstract; writing and editorial assistance was provided by Puneet Dang, PhD, of Parexel International, funded by Bristol Myers Squibb. Legal entity responsible for the study Bristol Myers Squibb. Funding The study was supported by Bristol Myers Squibb. Disclosure T. André: Honoraria (self): BMS, MSD Oncology, GSK; Advisory / Consultancy: BMS, MSD Oncology, GSK; Research grant / Funding (institution): BMS, MSD Oncology, GSK; Travel / Accommodation / Expenses: BMS, MSD Oncology. H. Lenz: Honoraria (self): Bayer, Merck KG, Roche; Advisory / Consultancy: Bayer, Merck KG, Roche. M. Morse: Research grant / Funding (institution): BMS. E. Van Cutsem: Advisory / Consultancy: Array, Astellas, Astrazeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho; Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. M. Sawyer: Honoraria (self): BMS, Merck; Advisory / Consultancy: BMS, Merck; Research grant / Funding (institution): BMS. S. Abdullaev: Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Full / Part-time employment: Bristol Myers Squibb. A. Memaj: Full / Part-time employment: Bristol Myers Squibb, Bristol Myers Squibb, Bristol Myers Squibb. M. Lei: Full / Part-time employment: Bristol Myers Squibb. S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx. M. Overman: Advisory / Consultancy: AbbVie and Takeda Pharamceuticals (Japan), AgilVax and Merck Sharp & Dohme Corp, Acrotech Biopharma and Novartis Pharmaceuticals corp. All other authors have declared no conflicts of interest.