On April 8, 2025, the Food and Drug Administration approved nivolumab (Opdivo, Bristol Myers Squibb Company) and ipilimumab (Yervoy, Bristol Myers Squibb Company) for adults and children 12 years and older with colorectal cancer (CRC) that cannot be surgically removed or has spread, and is either microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).
The FDA has switched nivolumab’s fast-track approval for use alone to regular approval for adults and kids aged 12 and older with MSI-H or dMMR metastatic CRC that has gotten worse after treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
Effectiveness and Safety
The effectiveness of nivolumab with ipilimumab was evaluated in CHECKMATE-8HW (NCT04008030), a study where patients with advanced colorectal cancer who had not received immunotherapy before and had known MSI-H or dMMR status were randomly assigned to one of three treatment groups. We randomly assigned patients to receive one of the following treatments:
Nivolumab 240 mg is administered every 3 weeks, and ipilimumab 1 mg/kg every 3 weeks for a maximum of 4 doses, followed by nivolumab 480 mg every 4 weeks, or nivolumab 240 mg every 2 weeks for 6 doses; thereafter, nivolumab 480 mg every 4 weeks, or chemotherapy at the investigator’s discretion.
The main goal of the study was to measure how long patients with confirmed MSI-H/dMMR status lived without their disease getting worse, as assessed by an independent review team using RECIST v1.1.
First treatment: nivolumab with ipilimumab compared to chemotherapy; later treatments: nivolumab with ipilimumab versus nivolumab alone.
The study compared nivolumab + ipilimumab to chemotherapy in the first treatment line using 255 patients who had their MSI-H/dMMR status confirmed, out of a total of 303 patients assessed locally. The median progression-free survival (PFS) was not reached (NR) (95% CI: 38.4, not estimable [NE]) in the nivolumab + ipilimumab cohort, while it was 5.8 months (95% CI: 4.4, 7.8) in the chemotherapy cohort (Hazard ratio 0.21 [95% CI: 0.14, 0.32], p-value <0.0001). Comparative data on the overall response rate (ORR) and overall survival (OS) between the arms were unavailable during the interim progression-free survival (PFS) analysis due to the statistical testing approach employed.
The study compared nivolumab with ipilimumab to nivolumab by itself in 582 people who had their MSI-H/dMMR status confirmed, out of 707 patients tested locally. The average time without the disease getting worse (PFS) was not reached (NR) in the nivolumab + ipilimumab group and was 39.3 months in the nivolumab group, with a hazard ratio of 0.62 and a p-value of 0.0003.
The overall response rate (ORR) was 71% (95% CI: 65, 76) for the nivolumab + ipilimumab group and 58% (95% CI: 52, 63) for the nivolumab group (p-value 0.0011). The overall survival results between the groups could not be accessed during the early analysis of progression-free survival because of the way the statistical tests were done.
The predominant adverse events observed in ≥20% of individuals receiving nivolumab in conjunction with ipilimumab included fatigue, diarrhea, pruritus, stomach discomfort, musculoskeletal pain, and nausea. The predominant adverse responses observed in ≥20% of individuals administered nivolumab as a monotherapy included fatigue, diarrhea, abdominal pain, pruritus, and musculoskeletal pain.
- advanced colorectal cancer drugs, checkpoint inhibitors for CRC, combination therapy for MSI-H tumors, dMMR colorectal cancer therapy, immunotherapy for metastatic CRC, microsatellite instability-high cancer, mismatch repair deficient treatment, MSI-H CRC treatment, nivolumab ipilimumab colorectal cancer, Opdivo Yervoy FDA approval
Dr. Nishant Mittal is a highly accomplished researcher with over 13 years of experience in the fields of cardiovascular biology and cancer research. His career is marked by significant contributions to stem cell biology, developmental biology, and innovative research techniques.
Research Highlights
Dr. Mittal's research has focused on several key areas:
1) Cardiovascular Development and Regeneration: He studied coronary vessel development and regeneration using zebrafish models1.
2) Cancer Biology: At Dartmouth College, he developed zebrafish models for studying tumor heterogeneity and clonal evolution in pancreatic cancer.
3) Developmental Biology: His doctoral work at Keio University involved identifying and characterizing medaka fish mutants with cardiovascular defects.
4) Stem Cell Research: He investigated the effects of folic acid on mouse embryonic stem cells and worked on cryopreservation techniques for hematopoietic stem cells.
Publications and Presentations
Dr. Mittal has authored several peer-reviewed publications in reputable journals such as Scientific Reports, Cardiovascular Research, and Disease Models & Mechanisms1. He has also presented his research at numerous international conferences, including the Stanford-Weill Cornell Cardiovascular Research Symposium and the Weinstein Cardiovascular Development Conference.
In summary, Dr. Nishant Mittal is a dedicated and accomplished researcher with a strong track record in cardiovascular and cancer biology, demonstrating expertise in various model systems and a commitment to advancing scientific knowledge through innovative research approaches.
