FDA approves Opdivo (nivolumab) plus Yervoy (ipilimumab) as a treatment for patients with previously untreated microsatellite instability-high or mismatch repair deficient unresectable or metastatic colorectal cancer - BMS

Bristol Myers Squibb announced that the FDA approved Opdivo (nivolumab) plus Yervoy (ipilimumab) as a first-line treatment of adult and pediatric patients (12 years and older) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC). This approval is based on the CheckMate-8HW trial, which is the largest Phase III trial (n=839) of immunotherapy in patients with MSI-H/dMMR mCRC, evaluating Opdivo plus Yervoy (n=354) vs. Opdivo monotherapy (n=353) in the all-lines setting and Opdivo plus Yervoy (n=202) vs. investigator’s choice chemotherapy (n=101) (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in the first-line setting. Opdivo plus Yervoy met the dual primary endpoints of progression free survival (PFS) when compared to Opdivo monotherapy across all lines of therapy and when compared to chemotherapy in the first-line setting, as assessed by Blinded Independent Central Review (BICR). This approval, granted more than two months ahead of the June 23, 2025 Prescription Drug User Fee Act goal date, follows the FDA’s prior decision to grant the application Breakthrough Therapy Designation and Priority Review status.

“There is an unmet need for additional treatment options such as a dual immunotherapy approach for patients with previously untreated MSI-H/dMMR unresectable or metastatic CRC, which is an aggressive form of cancer and can be particularly difficult to treat,” said Heinz-Josef Lenz, MD, CheckMate-8HW investigator and Deputy Director for Research Programs and Head of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center. “The meaningful outcomes in CheckMate-8HW underscore how initiating treatment with the dual immunotherapy combination of nivolumab plus ipilimumab may result in a notable survival benefit. This approval has the potential to redefine traditional approaches of care for patients with this form of CRC.”

In the CheckMate-8HW trial, Opdivo plus Yervoy demonstrated a 38% reduction in the risk of disease progression or death vs. Opdivo monotherapy in immunotherapy-naïve patients across all lines of therapy (Hazard Ratio [HR] 0.62; 95% Confidence Interval [CI] 0.48–0.81; P=0.0003). Assessing the dual primary endpoint of PFS, the trial demonstrated that median PFS was not reached with Opdivo plus Yervoy (95% CI: 53.8-Not Estimable [NE]) and was 39.3 months with Opdivo monotherapy (95% CI: 22.1-NE). PFS rates at 12-, 24-, and 36-months were also numerically higher compared to Opdivo monotherapy (76% vs. 63%, 71% vs. 56%, and 68% vs. 51%, respectively). In Kaplan-Meier (KM) curves showing PFS rates with Opdivo plus Yervoy compared to Opdivo monotherapy, an early separation was observed at two months and sustained at three years. Opdivo plus Yervoy also met a key secondary endpoint, demonstrating superior overall response rate (ORR) by BICR compared to Opdivo monotherapy (n=296, 71% vs. n=286, 58%; P=0.0011). Of the most common all-cause adverse reactions (ARs) occurring in ≥10% of patients, similar rates of grade 3-4 ARs were observed between Opdivo plus Yervoy and Opdivo monotherapy. The safety profile for the dual immunotherapy combination remained consistent with previously reported data and the ARs observed were manageable with established protocols, with no new safety signals identified. Additional safety information can be found in the U.S. Full Prescribing Information for Opdivo.

The Opdivo plus Yervoy vs. chemotherapy arm of the CheckMate-8HW trial showed that the combination regimen reduced the risk of cancer progression or death by 79% compared to chemotherapy in first-line patients (HR 0.21; 95% CI: 0.14-0.32; P<0.0001). This arm also assessed the other dual primary endpoint of PFS, where median PFS was not reached with Opdivo plus Yervoy (95% CI: 38.4-NE) compared to 5.8 months with chemotherapy (95% CI: 4.4-7.8). PFS rates were numerically higher with Opdivo plus Yervoy vs. chemotherapy at 12- and 24-months (79% vs. 21% and 72% vs. 14%, respectively). KM curves comparing PFS with Opdivo plus Yervoy vs. chemotherapy showed an early separation at three months, which was sustained through two years.

The regimen of Opdivo plus Yervoy represents the first-ever dual immune checkpoint inhibitor combination to demonstrate significant efficacy benefit compared to Opdivo monotherapy and chemotherapy in MSI-H/dMMR mCRC patients.

“This approval marks our ninth indication for an Opdivo-based treatment in the gastrointestinal space. We are witnessing the transformative potential of dual immunotherapy in treating GI cancers,” said Wendy Short Bartie, senior vice president of Oncology Commercialization at Bristol Myers Squibb. “People with MSI-H/dMMR metastatic colorectal cancer face high unmet need, and Opdivo plus Yervoy is an important new approach in the first-line setting. This milestone can offer hope, and it underscores our commitment to continue reaching more patients with new treatment options.”

“Colorectal cancer is the third most commonly diagnosed cancer and the second most common cause of cancer-related death for men and women combined in the U.S., and concerning trends show that incidence is increasing in people younger than 50,” said Nicole Sheahan, President of the Global Colon Cancer Association. “Despite the prevalence of CRC, there remains a high unmet need, highlighting the urgency for additional treatment options. We are thrilled with this FDA approval as Opdivo plus Yervoy offers an exciting new first-line approach for patients with MSI-H/dMMR metastatic colorectal cancer.”

Opdivo as a single agent, or in combination with Yervoy, was previously granted accelerated approval in MSI-H/dMMR CRC adult and pediatric patients (12 years and older) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Today’s FDA decision converts this second-line indication to full approval for Opdivo monotherapy and expands the indication for Opdivo plus Yervoy into the first-line setting based on the CheckMate-8HW trial.

About CheckMate-8HW

CheckMate-8HW is a Phase III, randomized, multicenter, open-label trial evaluating Opdivo plus Yervoy compared to Opdivo alone or chemotherapy (mFOLFOX-6 or FOLFIRI with or without bevacizumab or cetuximab) in patients with unresectable MSI-H/dMMR mCRC. In the CheckMate-8HW study, 839 patients were randomized to receive either Opdivo monotherapy (Opdivo 240 mg Q2W for six doses, followed by Opdivo 480 mg Q4W), Opdivo plus Yervoy (Opdivo 240 mg plus Yervoy 1 mg/kg Q3W for four doses, followed by Opdivo 480 mg Q4W), or investigator’s choice of chemotherapy. The dual primary endpoints of the trial were PFS for Opdivo plus Yervoy compared to Opdivo alone across all lines of therapy and PFS for Opdivo plus Yervoy compared to chemotherapy in the first-line setting, as assessed by Blinded Independent Central Review (BICR). The study is ongoing to assess various secondary endpoints, including overall survival (OS), and BMS will continue to work with the study investigators to present these data and longer-term follow-up in the future.

Select Safety Profile from CheckMate-8HW

The safety analysis in CheckMate-8HW included 288 patients, of whom 200 received Opdivo plus Yervoy. Serious adverse reactions occurred in 46% of patients receiving Opdivo plus Yervoy. The most frequent serious adverse reactions reported in ≥1% of patients who received Opdivo plus Yervoy were adrenal insufficiency (2.8%), hypophysitis (2.8%), diarrhea (2.0%), abdominal pain (2.0%), small intestinal obstruction (2.0%), pneumonia (1.7%), acute kidney injury (1.4%), immune mediated enterocolitis (1.4%), pneumonitis (1.4%), colitis (1.1%), large intestinal obstruction (1.1%), and urinary tract infection (1.1%). The most common adverse reactions reported in ≥ 20% of patients treated with Opdivo plus Yervoy were fatigue, diarrhea, pruritis, abdominal pain, musculoskeletal pain, and nausea. Fatal adverse reactions occurred in 2 (0.6%) patients who received Opdivo plus Yervoy; these included myocarditis and pneumonitis, 1 each. Opdivo and/or Yervoy were discontinued in 19% of patients and were delayed in 48% of patients for an adverse reaction.