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Dual Immunotherapy Shows Promise in MSI-H/dMMR Metastatic Colorectal Cancer
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Key Takeaways
- Nivolumab plus ipilimumab significantly improved PFS in MSI-H/dMMR mCRC compared to nivolumab monotherapy, reducing disease progression or death risk by 38%.
- The overall response rate was higher with the combination therapy (71% vs 58%), indicating enhanced efficacy over monotherapy.
Nivolumab plus ipilimumab demonstrated a 38% reduction in the risk of disease progression or death.
A phase 3 CheckMate-8HW (NCT04008030) trial evaluating nivolumab (Opdivo; Bristol Myers Squibb) plus ipilimumab (Yervoy; Bristol Myers Squibb) versus nivolumab monotherapy, met the primary end point of progression free survival (PFS) for the treatment of microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).1
3D image of a tumor in the colon | Image credit: Sebastian Kaulitzki - stock.adobe.com
“The results from this analysis of the CheckMate -8HW trial answer affirmatively an important question about whether dual I/O therapy with Opdivo plus Yervoy can also improve outcomes for patients with MSI-H/dMMR mCRC compared with Opdivo alone,” Dana Walker, MD, MSCE, vice president, global program lead, late development, oncology, Bristol Myers Squibb, said in a news release.1
The randomized, open label, 3-arm phase 3 trial included a total of 839 individuals that were randomly assigned to receive 240 mg of nivolumab monotherapy for 6 doses, followed by an additional 480 mg; or, 240 mg of nivolumab plus 1 mg of ipilimumab for 4 doses, followed by an additional 480 mg of nivolumab; or investigator’s choice of chemotherapy (CT). The study aimed to compare treatments across all lines of therapy, including first-line to treat MSI-H/dMMR mCRC.1
CRC is the third most diagnosed cancer globally, which develops in the colon or the rectum. MSI-H and dMMR in colorectal cancer both indicate a type of tumor with a defective DNA repair system. Approximately 5% to 7% of individuals with metastatic CRC have MSI-H or dMMR tumors and are less likely to benefit from conventional chemotherapy, resulting in a poor prognosis. Immunomodulating drugs are a key treatment for dMMR/MSI-H colorectal cancer, but many patients develop resistance due to still-unknown molecular factors.1,2
Nivolumab has furthered treatment options across various forms of cancer as a PD-1 immune checkpoint inhibitor. The immunotherapy uses the body’s own immune system to help restore anti-tumor immune response. Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). The immunotherapy drug blocks CTLA-4, boosting T-cell activation, proliferation, and anti-tumor immune responses by preventing CTLA-4 from binding to its ligands and reducing T-regulatory cell function.1
“The benefit of dual inhibition of PD-1 and CTLA-4 has been well established in phase 3 trials of Opdivo plus Yervoy across a broad range of tumor types, including in MSI-H/dMMR mCRC compared to chemotherapy,” Walker discussed.1
At a median follow-up of 47 months, the results of the phase 3 trial showed that individuals treated with nivolumab plus ipilimumab achieved a 38% reduction in the risk of disease progression or death compared to nivolumab monotherapy, meeting the dual primary end point of PFS as assessed by Blinded Independent Central Review (BICR). Additionally, the secondary end point of overall response rate was meaningly higher with nivolumab plus ipilimumab compared to nivolumab monotherapy (71% vs 58%; P = .0011).1
The safety profile of the combination immunotherapies was consistent with previous safety data. The study authors noted that grade 3 and 4 adverse events were reported in 22% of individuals treated with nivolumab plus ipilimumab and 14% in individuals treated with nivolumab monotherapy.1
The study authors noted that the trial is ongoing to evaluate further secondary end points, including overall survival.1
The combination of nivolumab plus ipilimumab demonstrated a reduced risk of disease progression or death by 79% compared with investigator’s choice of chemotherapy in previous results from the CheckMate – 8HW trial. The current results further indicate how the dual therapy can improve outcomes for individuals with MSI-H/dMMR mCRC.1
