Accurate Diagnosis of dMMR/MSI-H Status Is Key for Nivolumab/Ipilimumab Treatment in mCRC

Thierry André, MD

Findings from a subgroup analysis of the phase 3 CheckMate 8HW trial (NCT04008030) underscored the importance of accurate molecular testing for patients with metastatic colorectal cancer (mCRC), according to Thierry André, MD, who noted that the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) did not produce an efficacy benefit in patients misdiagnosed as mismatch repair–deficient (dMMR) and microsatellite instability–high (MSI-H) tumors.

Data presented at the 2024 ESMO Congress showed that among patients in the nivolumab/ipilimumab arm (n = 202), 15% did not have centrally confirmed dMMR/MSI-H tumors. In patients with centrally confirmed dMMR/MSI-H tumors, the median progression-free survival (PFS) was not reached (95% CI, 38.4 months–not evaluable [NE]) for nivolumab plus ipilimumab (n = 171) compared with 5.9 months (95% CI, 4.4-7.8) for chemotherapy (n = 84; HR, 0.21; 95% CI, 0.13-0.35; P < .0001).¹ Conversely, patients with misdiagnosed dMMR/MSI-H status treated with the nivolumab combination (n = 27) had a median PFS of 1.9 months (95% CI, 1.5-5.8) vs 11.5 months (95% CI, 2.0-NE) for those given chemotherapy (n = 12; HR, 1.6; 95% CI, 0.7-3.7).

“We need to have the best techniques [to diagnose dMMR/MSI-H status]. You need to have immunochemistry, but you also need to have PCR or next-generation sequencing,” André said. “If you have both [tests], you have the opportunity to avoid misdiagnosis. If you have a discrepancy between the 2 tests, you have the possibility to have an expert team help you to define if a patient’s [tumor] is dMMR/MSI-H.”

Additional data from the analysis showed that the PFS benefit associated with nivolumab plus ipilimumab was consistent across subgroups of patients with centrally confirmed dMMR/MSI-H status, irrespective of age, ECOG performance status, BRAF/RAS mutation status, and the presence of baseline liver metastases. Furthermore, the safety profile of the combination was consistent in patients under 70 years of age and those at least 70 years of age.

In an interview with OncLive^®, André detailed prior data from CheckMate 8HW, expanded on key findings from the subgroup analysis, and discussed the implications of these cumulative data. André is a professor of medical oncology at Sorbonne Université and head of the Medical Oncology Department at Saint Antoine Hospital in Paris, France.

OncLive: What were the efficacy findings previously reported from CheckMate 8HW?

André: [Previous data for] Checkmate 8HW were presented at the 2024 Gastrointestinal Cancers Symposium and the 2024 ASCO Annual Meeting, comparing patients [treated with] first-line nivolumab plus ipilimumab vs chemotherapy.² This was one part of the study. The second part compared nivolumab plus ipilimumab, nivolumab alone, and chemotherapy.

Only data for nivolumab plus ipilimumab vs chemotherapy are known right now. The study is positive concerning [the primary end point] of PFS [HR, 0.21; 95% CI, 0.13-0.34; P < .0001]. It's rare to have this kind of [PFS] curve with 72% of patients [in the nivolumab/ipilimumab arm] without progression [at 24 months].

What updates from the study were presented at the 2024 ESMO Congress?

At the 2024 ESMO Congress, I presented a poster of 3 additional points. The first was the fact that misdiagnoses [of dMMR/MSI-H status] are not rare in this disease. The primary end point was PFS in patients with centrally confirmed dMMR/MSI-H status. In this study, 15% of patients [in the nivolumab/ipilimumab arm] did not have centrally confirmed dMMR/MSI-H [disease], with 10% [of patients with MMR-proficient (pMMR) and microsatellite stable (MSS) disease], 3% with MSS or pMMR disease, and 2% without material to confirm [dMMR/MSI-H] status.

The important thing is the fact that if a patient was misdiagnosed [as dMMR/MSI-H] and received nivolumab plus ipilimumab, the [PFS] results were bad [compared with those given chemotherapy]. It's important to get the [proper] diagnosis and not give the [nivolumab plus ipilimumab] if patients are misdiagnosed as dMMR/MSI-H.

The second point of this poster was a presentation of the subgroup analysis, and [and data showed] the [combination] therapy worked in all subgroups, including age. We had patients with below 50 years of age and others at least 70 years of age [where the combination displayed a PFS benefit]. We also had [patients with or without] liver metastases, [patients with] KRAS-mutated vs wild-type disease, and [patients with] BRAF-mutated vs wild-type disease. Across all subgroups, we saw the benefit of the [nivolumab/ipilimumab] combination.

What was seen regarding updated safety data?

The third point of the presentation was toxicity. The toxicity was not increased in some subgroups. The toxicity was evaluated in male vs female [patients], and no differences were observed between the 2 groups. We also analyzed the differences in toxicity based on the age for patients at least 70 years of age vs younger patients. There were no differences in safety based on age.

What are the implications of these updated data when taken together with previously reported findings?

The conclusion is that nivolumab and ipilimumab [should] now be one of the standard therapies for the [patients with] dMMR/MSI-H mCRC. We are awaiting result of the second part of this study with the comparison between nivolumab alone vs nivolumab plus ipilimumab. We hope to have these data because they will be an important result for the future.

References

1. André T, Lonardi S, Lenz HJ, 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): subgroup efficacy and expanded safety analyses from CheckMate 8HW. Ann Oncol. 2024;35(suppl 2):S451-S452. doi:10.1016/j.annonc.2024.08.610
2. André 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. J Clin Oncol. 2024;42(suppl 3):LBA768. doi:10.1200/JCO.2024.42.3_suppl.LBA768