Frontline Nivolumab/Ipilimumab Provides Superior PFS Benefit Over Chemo in MSI-H/dMMR mCRC

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) significantly reduced the risk of disease progression or death vs chemotherapy in previously untreated patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC), according to preliminary findings from the phase 3 CheckMate-8HW trial (NCT04008030) that were presented during the 2024 Gastrointestinal Cancers Symposium.¹

Results from the prespecified interim analysis showed that among the 303 patients who were randomized to receive nivolumab plus ipilimumab (n = 202) or chemotherapy (n = 101), 171 and 84 patients in each arm had centrally confirmed MSI-H/dMMR result by either immunohistochemistry and/or polymerase chain reaction-based tests.

At a median follow-up of 24.3 months, a clinically meaningful and statistically significant improvement in PFS was observed in the nivolumab/ipilimumab arm (not reached; 95% CI, 38.4 months-not evaluable) vs chemotherapy arm (5.9 months; 95% CI, 4.4-7.8) with a 79% reduction in the risk of disease progression or death (HR, 0.21; 95% CI, 0.13-0.34; P <.0001). The PFS benefit was consistent across all pre-specified subgroups, including patients with KRAS or NRAS mutations, and patients with baseline liver, lung, or peritoneal metastases.

“The study met its primary end point demonstrating statistically significant and clinically meaningful improvement in PFS with [nivolumab] plus [ipilimumab] over chemotherapy. The median PFS was not reached in the [nivolumab] plus [ipilimumab] arm and was 5.9 months in the chemo arm with a hazard ratio of 0.21. There was an early separation of the PFS curve starting at approximately 3 months and so the 24 months PFS rates…were 72% vs 14%,” Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie, head, Medical Oncology Department, St. Antoine Hospital, Paris, explained during his presentation.

This combination is the first dual immunotherapy regimen to show significant efficacy benefit vs chemotherapy as first-line treatment in MSI-H/dMMR mCRC.

Regarding safety, the combination showed a safety profile that was consistent with previously reported data. The combination of nivolumab and ipilimumab was manageable with established protocols and no new safety signals identified.^1,2 Any grade treatment-related adverse events (TRAEs) were seen in 160 of the 200 patients (80%) treated in the nivolumab/ipilimumab arm, and 83 of the 88 (94%) in the chemotherapy arm, and any grade serious TRAEs were seen in 38 (19%) and 17 (19%) patients. In these groups, grade 3-4 TRAEs were observed in 46 (23%) and 42 (48%) patients, and serious grade 3-4 TRAEs were seen in 32 (16%) and 14 (16%) patients.

Any grade and grade 3 or 4 TRAEs that led to discontinuation of the study treatment were reported in 33 (17%) and 23 (12%) of patients in the nivolumab/ipilimumab arm and 28 (32%) and 9 (10%) in the chemotherapy arm. Two treatment-related deaths were reported in the nivolumab and ipilimumab arm, and 1 death was reported during crossover treatment on the chemotherapy arm, but it was determined not to be related to chemotherapy.

About CheckMate-8HW

CheckMate-8HW is a randomized, open-label, phase 3 trial evaluating nivolumab given in combination with ipilimumab vs either nivolumab as a monotherapy or investigator’s choice of chemotherapy in patients with MSI-H or dMMR mCRC.³

Patients were randomized in a 2:2:1 fashion to receive nivolumab 240 mg with ipilimumab 1 mg/kg every 3 weeks for 4 doses, then nivolumab 480 mg every 4 weeks, nivolumab 240 mg every 2 weeks for 6 doses, then nivolumab 480 mg every 4 weeks, or chemotherapy with or without targeted therapies. Patients across all arms continued to receive treatments until disease progression or unacceptable toxicity and for a maximum of 2 years in the nivolumab and ipilimumab arms.¹

The study consists of 2 parts and will include patients with known tumor MSI-H or dMMR status per local standard of practice who have an ECOG performance status of 0 or 1.3 Enrollment in part 1 is open to patients with histologically confirmed recurrent or metastatic CRC not amenable to surgery, irrespective of prior treatment history with chemotherapy and/or targeted agents. In part 2, patients are required to have histologically confirmed recurrent or metastatic CRC not amenable to surgery with no prior treatment history with chemotherapy and/or targeted agents for metastatic disease.

Patients with an active, known, or suspected autoimmune disease’ a history of interstitial lung disease or pneumonitis; or known history of positive test for human immunodeficiency virus or known acquired immunodeficiency syndrome will be excluded from the study.³

“Baseline characteristics of all first-line randomized patients were well balanced. Eighty-five and 83% of patients had centrally confirmed MSI-H or dMMR status. At the data cutoff, 21% in the [nivolumab] plus [ipilimumab] arm and 7% of patients in the chemo arm were still on treatment. Thirty-one percent of patients in the [nivolumab] plus [ipilimumab] arm completed 2 years of treatments and disease progression was the primary reason for treatment discontinuation, 19 in [the nivolumab/ipilimumab] arm and 69 in chemotherapy,” said Andre.

The dual primary end points of the study are PFS per blinded independent central review (BICR) for the experimental combination vs investigator’s choice of chemotherapy in the first-line setting and PFS per BICR for the combination compared with nivolumab alone across all lines of therapy. Evaluation of PFS in patients receiving the combination vs nivolumab alone is ongoing, as well as assessment of the secondary end points of overall response rate, overall survival, disease control rate, and time to response.

“These results support [nivolumab] plus [ipilimumab] as a standard of care, first-line treatment option for patients with MSI-H or dMMR metastatic colorectal cancer,” concluded Andre.

References

1. Andre T, Elez E, Van Cutsem E, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) as first-line (1L) treatment for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): First results of the CheckMate 8HW study. Presented at the 2024 Gastrointestinal Cancers Symposium; San Francisco, CA, January 18-20, 2024. LBA 768.
2. Bristol Myers Squibb announces phase 3 CheckMate-8HW trial evaluating opdivo (nivolumab) plus yervoy (ipilimumab) compared to chemotherapy in microsatellite instability-–high or mismatch repair deficient metastatic colorectal cancer meets primary. News release. Bristol Myers Squibb. December 7, 2023. Accessed January 20, 2024. https://news.bms.com/news/corporate-financial/2023/Bristol-Myers-Squibb-Announces-Phase-3-CheckMate--8HW-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Compared-to-Chemotherapy-in-Microsatellite-InstabilityHigh-or-Mismatch-Repair-Deficient-Metastatic-Colorectal-Cancer-Meets-Primary/default.aspx
3. A study of nivolumab, nivolumab plus ipilimumab, or investigator's choice chemotherapy for the treatment of participants with deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC) (CheckMate 8HW). ClinicalTrials.gov. Updated January 18, 2024. Accessed January 20, 2024. https://www.clinicaltrials.gov/study/NCT04008030