‘Practice-changing data’ support first-line immunotherapy combination in colorectal cancer
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CHICAGO — Combination immunotherapy significantly improved outcomes vs. first-line chemotherapy for patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer, according to study results.
The combination of nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) reduced risk for progression or death by 79% compared with chemotherapy, findings presented at ASCO Annual Meeting showed.
An analysis of outcomes after subsequent therapy also strongly favored the combination.
“These are practice-changing data,” Heinz-Josef Lenz, MD, professor in the departments of medicine and preventive medicine at Keck Medicine of USC, told Healio. “This is a very important study, and it shows that sequence matters. Patients with newly diagnosed [microsatellite instability-high] tumors should be treated with immunotherapy.”
Background and methods
Nivolumab is an anti-PD-1 antibody and ipilimumab is an anti-CTLA-4 antibody.
Prior phase 2 studies of the nivolumab-ipilimumab combination showed benefit with regard to response rates, PFS and OS, Lenz said.
The randomized phase 3 CheckMate 8HW study assessed three regimens as first-line treatment for patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) unresectable or metastatic colorectal cancer.
Researchers randomly assigned patients in a 2:2:1 ratio to one of the following:
- 240 mg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four doses, followed by 480 mg nivolumab every 4 weeks;
- 240 mg nivolumab every 2 weeks for six doses, followed by 480 mg nivolumab every 4 weeks; or
- chemotherapy with or without targeted therapies.
Patients assigned nivolumab-ipilimumab received the combination for up to 2 years. Otherwise, treatment in all groups continued until disease progression or unacceptable toxicity.
Patients assigned chemotherapy who developed blinded independent central review-documented progression could cross over to treatment with nivolumab-ipilimumab.
PFS by blinded independent central review for nivolumab-ipilimumab vs. first-line chemotherapy, as well as nivolumab-ipilimumab vs. nivolumab in any treatment line, served as dual primary endpoints.
PFS2 — defined as time from randomization to disease progression after subsequent systemic therapy, initiation of second subsequent systemic therapy or death — served as a key exploratory endpoint.
Median treatment duration was 13.5 months with nivolumab-ipilimumab and 4 months with chemotherapy.
Key findings
Previously reported results — after median follow-up of 24.3 months — showed considerably more patients assigned nivolumab-ipilimumab than chemotherapy achieved 2-year PFS (72% vs. 14%).
At ASCO, Lenz presented an expanded efficacy analysis that included 255 patients with centrally confirmed MSI-H/dMMR disease. Two-thirds (n = 171) received nivolumab-ipilimumab and one-third (n = 84) received chemotherapy.
Median follow-up was 31.5 months (range, 6.1-48.4), at which time 31% of patients assigned nivolumab-ipilimumab had completed the planned 2 years of treatment and another 21% remained on treatment.
Updated results showed a 79% improvement in PFS with nivolumab-ipilimumab vs. chemotherapy (median, not reached vs. 5.9 months; HR = 0.21; 97.91% CI, 0.13-0.35).
“That’s one of the highest hazard ratios I’ve seen, and an HR of 0.21 has never been seen in [gastrointestinal] oncology, so we’re very excited about these results,” Lenz said.
Patients assigned chemotherapy appeared more than four times as likely as those assigned nivolumab-ipilimumab to receive subsequent treatment (69% vs. 15%).
In the chemotherapy group, 46% crossed over to nivolumab-ipilimumab and 20% received another form of immunotherapy. In the nivolumab-ipilimumab group, 12% received anti-cancer therapy and 3% underwent surgery.
The PFS2 analysis showed a 73% improvement in the nivolumab-ipilimumab group (median, not reached vs. 29.9 months; HR = 0.27; 95% CI, 0.17-0.44).
“We know nivolumab-ipilimumab is very successful after chemotherapy failure, with response rates of 50% or higher,” Lenz said. “The question was, would outcomes be different with nivolumab-ipilimumab in the first line followed by chemotherapy? The data are very clear: When we include subsequent treatment, we continue to see significantly better progression-free survival with the combination.”
Safety analyses revealed no new signals with the immunotherapy combination.
Results showed a higher rate of any-grade adverse events (94% vs. 80%) and grade 3/grade 4 treatment-related adverse events (48% vs. 23%) in the chemotherapy group.
Two treatment-related deaths occurred in the nivolumab-ipilimumab group. One patient died of myocarditis and another died of pneumonitis.
“Immune-related deaths are rare but they can happen,” Lenz said. “Even though they are not unexpected, they obviously are concerning, and monitoring patients for these side effects is extremely important.”
Next steps and implications
Researchers will continue to follow patients for OS.
“We also are still waiting for data to mature to compare nivolumab-ipilimumab vs. nivolumab,” Lenz said. “There has never been a side-by-side comparison of immune checkpoint inhibitor monotherapy vs. dual inhibition with a CTLA-4 inhibitor. That will be very important to establish the role of CTLA-4 and convince oncologists that dual inhibition is a more effective regimen but not a more toxic one.”
Perspective
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Kanika Nair, MD
CheckMate 8HW is an important, potentially practice-changing study evaluating the use of combination immunotherapy as first-line treatment for metastatic MMR-deficient or MSI-high colorectal cancers. The results show an impressive HR of 0.21, with resposne observed across all subgroups, including those with RAS-mutant disease or different sites of metastatic disease.OS data are not yet reported and, given the high PFS seen so far and the long-term data from immunotherapy use in other cancers, it still may be years until mature OS data are available.
Grade 3/grade 4 treatment-related adverse events were more common with the immunotherapy combination, as expected, and two patients died of immune-related adverse events of myocarditis and pneumonitis. It is important to note that in the study design, ipilimumab — the more potentially toxic of the two drugs — was limited to four doses.
Checkmate 8HW also had a nivolumab-only treatment arm and these results are awaited. Avoiding ipilimumab in the first-line setting is anticipated to have an improved toxicity profile, and adding the anti-CTLA4 antibody could be an option for patients who progress on an anti-PD-1 antibody.
Unfortunately, some patients — despite having MSI-high status or MMR-deficiency — do not respond to immunotherapy. Better biomarkers are needed to identify who is most likely to benefit from immunotherapy. Although many patients have durable responses to immunotherapy, a subset of these patients will progress. Development of second-line targeted treatments is needed as chemotherapy is not effective for this population, as evidenced by a median PFS of 5.9 months.
This study highlights the importance of universal testing for MMR and MSI for colorectal cancers for early identification of patients who will benefit from first-line immunotherapy.
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Lenz H-J, et al. Abstract 3503. Presented at: ASCO Annual Meeting; May 31-June 4, 2024.
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