Nivolumab/Ipilimumab Stands as the SOC for MSI-H/dMMR mCRC

Heinz-Josef Lenz, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is now the preferred treatment regimen for patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC) based on its efficacy and safety profile, according to Heinz-Josef Lenz, MD, although the risk/benefit profile of this regimen should still be considered on an individual patient basis, Van Karlyle Morris, MD, noted.

“I encourage [all oncologists] to try [to use this combination in practice] because it is by far the most effective treatment for this patient population,” Lenz said in an interview with OncLive®.

On April 8, 2025, the FDA approved the combination of nivolumab and ipilimumab for the treatment of adult and pediatric patients at least 12 years of age with dMMR/MSI-H unresectable or metastatic CRC.1 This regulatory decision was backed by data from the phase 3 CheckMate 8HW trial (NCT04008030).

“This FDA approval for nivolumab plus ipilimumab strengthens the level of evidence we have for selecting a dual immune checkpoint blockade approach vs single-agent PD-1 therapy,” Morris added.

Van Karlyle Morris, MD

In the interview, Lenz and Morris discussed the significance of this approval, the evolution of data from CheckMate 8HW, and how the availability of this regimen provides an additional option for individualized CRC treatment considerations.

Lenz is a professor of medicine and cancer biology, a professor of medicine and preventive medicine, section head of GI Oncology in the Division of Medical Oncology, and co-director of the Colorectal Center at the Keck School of Medicine of the University of Southern California (USC) in Los Angeles. He is also the J. Terrence Lanni Chair in Gastrointestinal Cancer Research, co-director of the USC Center for Molecular Pathway and Drug Development, co-director of the USC Norris Center for Cancer Drug Development, associate director for Clinical Research, and co-leader of the Gastrointestinal Cancers Program at the USC Norris Comprehensive Cancer Center.

Morris is an associate and assistant professor in the Department of GI Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: How do the findings from CheckMate 8HW support the clinical use of nivolumab plus ipilimumab for patients with dMMR/MSI-H mCRC?

Lenz: The combination of nivolumab plus ipilimumab is an important step forward for better treatment for MSI-H mCRC. We already saw [in findings] that were published in [2024 in] the New England Journal of Medicine [demonstrating] that nivolumab plus ipilimumab was superior to chemotherapy [in the first-line setting] with a [progression-free survival (PFS)] hazard ratio [HR] of 0.21.2

There was no doubt of the high efficacy of this combination in MSI-H tumors. What was not known was [the efficacy of] nivolumab plus ipilimumab vs nivolumab alone. [In 2020], pembrolizumab [Keytruda] was FDA approved as a single-agent PD-1 inhibitor [for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR CRC], but what would be the direct comparison [between a PD-1 inhibitor and] the PD-1– and CTLA-4–directed combination?

Morris: The [most] recent update from the CheckMate 8HW trial that was reported at the 2025 Gastrointestinal Cancers Symposium [ASCO GI] is important because [the findings support] a new therapeutic option as an FDA-approved treatment for patients with MSI-H or dMMR mCRC, [including those] who have not received prior treatment. We knew last year when the first of the 2 dual primary end points was reported out, comparing the combination of nivolumab and ipilimumab vs chemotherapy, that dual immune checkpoint [blockade] was superior to chemotherapy in patients with untreated MSI-H/dMMR mCRC. We did not have any head-to-head data on whether immunotherapy with 1 immune checkpoint blockade agent—an anti–PD-1 antibody—behaves differently than dual checkpoint [blockade] with a PD-1/CTLA-4 inhibitor combination [in CRC].

What was the design of CheckMate 8HW?

Morris: CheckMate 8HW was a randomized, 3-armed clinical trial where patients were randomly assigned in a 2:2:1 fashion to receive nivolumab at a dose of 1 mg/kg every 3 weeks for 4 doses plus ipilimumab at a dose of 240 mg every 3 weeks for 4 doses, followed by nivolumab at 480 mg every 4 weeks; nivolumab [monotherapy] at a dose of 240 mg every 2 weeks for 6 doses, followed by 480 mg every 4 weeks thereafter; or the control arm of investigator’s choice of mFOLFOX6 [5-fluorouracil, leucovorin, and oxaliplatin] or FOLFIRI [leucovorin, fluorouracil, and irinotecan] chemotherapy [with or without] their choice of biologic with an anti-VEGF or -EGFR antibody.2,3

There were 2 coprimary end points for this trial. One was the comparison of PFS with nivolumab plus ipilimumab vs chemotherapy [in the first-line setting], which had been reported [in 2024], where we saw a significant improvement in median PFS with nivolumab plus ipilimumab compared with chemotherapy. What we did not know until this year was whether there was a difference between 2 vs 1 immunotherapy agents [across all lines of therapy], and that was reported as the second of the 2 coprimary end points this year.

What were the key efficacy findings from the updated analysis of this trial?

Lenz: The presentation at ASCO GI showed a [PFS] benefit with nivolumab plus ipilimumab over nivolumab [HR, 0.62].3 There were significant differences in the 2-year PFS rates from 71% [with the combination] vs 56% [with nivolumab monotherapy]. The overall response rate was also higher [in the combination arm vs the monotherapy arm] at 71% vs 58%, [respectively].

Morris: The 3-year PFS rates were 68% with nivolumab plus ipilimumab vs 51% with nivolumab alone.3 We saw that patients who were randomly assigned to receive the dual immunotherapy combination of nivolumab and ipilimumab were more likely to have sustained disease control and PFS benefit relative to those who received nivolumab alone. We saw lower rates of progressive disease as best overall response in the nivolumab/ipilimumab arm; only 10% of MSI-H patients in CheckMate 8HW who were randomly assigned to receive nivolumab plus ipilimumab progressed as their best response vs 19% of those who received nivolumab alone. We saw improved PFS outcomes and improved best radiographic responses when dual immune checkpoint therapy [was compared] head-to-head with single-agent immunotherapy with nivolumab alone. The results for the efficacy outcomes are promising.

Lenz: We also [included] a new end point called PFS2, which is PFS with subsequent treatment. [The patients in the] nivolumab/ipilimumab arm received chemotherapy if they progressed, and the patients who received chemotherapy received nivolumab plus ipilimumab at progression. We saw sustained efficacy through all the lines of treatment with immunotherapy, so the question is: Does the sequence matter? It does in a significant way.

The data show that the PFS2 is significantly longer when patients start with nivolumab plus ipilimumab followed by chemotherapy than the other way around. Despite the fact that nivolumab plus ipilimumab works well in second- and third-line treatments, the efficacy of chemotherapy is much better after immunotherapy.

Sequence always matters. You always give the best treatment [first]. There are data in different diseases [showing] that prior immunotherapy may sensitize tumors against chemotherapy. Always try to give immunotherapy early. That may also be true for other targeted agents, but [it is definitely true for] immunotherapy. Don't wait for later lines of treatment. [Use immunotherapy] at the time when [it will] have the biggest effect because it may influence the efficacy of subsequent therapies.

Morris: Even though the trial wasn't powered to compare various subpopulations of CRC, between the nivolumab/ipilimumab vs nivolumab arms, there was consistent benefit observed across various ways that we stratify patients with CRC, consistently showing benefit with nivolumab plus ipilimumab. We saw this [benefit] regardless of the sidedness—left vs right colon—of the primary tumor. [Additionally, across] sites of disease—like liver metastases and peritoneal metastases—[outcomes] trended toward benefit with dual immune checkpoint blockade. We also saw this [benefit] even in patients with BRAF V600E mutations, which in general can confer a more unfavorable prognosis for mCRC. This gives us confidence to use dual immune checkpoint blockade as an FDA-approved option for patients with untreated MSI-H mCRC.

What is the safety profile of nivolumab plus ipilimumab?

Morris: We also have to consider the toxicity associated with immunotherapy. It's well known that, in general, the addition of an anti–CTLA-4 antibody can increase the risk of serious immune-related adverse effects [irAEs] for patients. However, the rates of grade 3/4 AEs with nivolumab plus ipilimumab vs nivolumab alone were 22% vs 14%, so we didn't see troubling increases in the rates of AEs with the addition of ipilimumab to nivolumab in CheckMate 8HW.3 There were really no surprises or unexpected observations regarding treatment-related AEs between the 2 immunotherapy arms. By this point, most oncologists are comfortable recognizing and treating irAEs [associated] with these agents [in patients with] CRC and other solid tumors—continue to be mindful of that. However, given that the survival outcomes are so favorable with dual immune checkpoint blockade, the potential for sustained benefit with this approach supports the toxicity signal reported in this study.

Lenz: The quality of life was much higher after week 21 with the combination vs nivolumab alone, meaning there is really no [additional] toxicity concern [with the combination].3 Patients overall do so much better [with the combination]. Since we published [the efficacy of] nivolumab plus ipilimumab in the single-arm phase 2 CheckMate 142 trial [NCT02060188] in the Journal of Clinical Oncology [in 2021, this combination] has been the standard of care for me.

There is really no downside to the combination. Many oncologists’ experiences using ipilimumab at higher doses for melanoma were always associated with significant toxicity concerns, which [are addressed by using] a lower dose. Surprisingly, only 4 doses are needed to have a sustained benefit [in CRC]. There is no doubt in my mind that this combination is the most effective treatment. The [prevalence of] innate resistance to nivolumab plus ipilimumab [among patients with CRC] is approximately 10% to 12%, and it’s more than double that in [patients who receive] nivolumab monotherapy or pembrolizumab monotherapy, also showing the most significant immune response to these tumors using a CTLA-4 inhibitor.

I have been using this combination for the past couple of years, and it is already included in the National Comprehensive Cancer Network Guidelines. It is covered by [many] insurance carriers and providers. Don't be afraid of the toxicity of ipilimumab. The biggest misconception is that this combination is more toxic, and now the data have clearly shown it is not, and it also has shown that 4 doses of ipilimumab is sufficient to [elicit a] long-lasting benefit.

What is your advice for colleagues about further integrating this regimen into clinical practice?

Morris: There are still some patients in whom, whether due to performance status or other clinical considerations, an oncologist may not feel comfortable selecting dual immunotherapy with nivolumab plus ipilimumab for a diagnosis of untreated MSI-H mCRC. These data and this approval will steer more use of dual immune checkpoint blockade, but this has to be considered on a case-by-case basis in selecting who should receive 1 vs 2 immunotherapy agents in this context.

References

1. FDA approves nivolumab with ipilimumab for unresectable or metastatic MSI-H or dMMR colorectal cancer. FDA. April 8, 2025. Accessed April 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-msi-h-or-dmmr-colorectal-cancer
2. Andre T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N Engl J Med. 2024;391(21):2014-2026. doi:10.1056/NEJMoa2402141
3. Andre T, Elez E, Lenz H-J, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4):LBA143. doi:10.1200/JCO.2025.43.4_suppl.LBA143