CheckMate 8HW

During the 2024 ASCO GU meeting earlier this year, the CheckMate 8HW study demonstrated an unprecedented benefit in progression-free survival (PFS) for patients with MSI-high/dMMR unresectable or metastatic colorectal cancer (CRC) who received first line treatment with nivolumab (nivo) and ipilimumab (ipi) rather than chemotherapy. At ASCO 2024, an expanded efficacy analysis of this trial was presented focusing on the PFS of patients following the first line of subsequent therapy. In this video, Prof Dr Jeroen Dekervel (University Hospitals Leuven) discusses these expanded results with Prof Dr Heinz-Josef Lenz, gastro-intestinal oncologist at the USC Norris Comprehensive cancer center in Los Angeles, and co-investigator of CheckMate 8HW.

CheckMate 8HW randomized patients with unresectable or metastatic CRC and a positive MSI-H/dMMR status by local testing in a 2:2:1 ratio to receive 4 three-weekly cycles of nivolumab (240 mg) + ipilimumab (1 mg/kg) followed by nivolumab monotherapy (480 mg q4w), nivolumab monotherapy (240 mg q2w for 6 cycles, then 480 mg q4w), or chemotherapy (mFOLFOX6 or FOLFIRI) with or without a targeted agent (bevacizumab or cetuximab).

In patients with centrally confirmed MSI-H/dMMR, nivolumab + ipilimumab proved to be associated with a 79% reduced risk for disease progression or death compared to chemotherapy (median not reached vs. 5.9 months; HR[95%CI]: 0.21[0.13-0.55]; p< 0.0001). Of the patients who received chemotherapy in 1^st line, 69% received a subsequent line of therapy, mainly consisting of immunotherapy (56/58). In contrast, only 15% of patients in the nivolumab-ipilimumab required a subsequent treatment line.

Despite this high level of cross-over to immunotherapy in the chemotherapy arm, the clinical benefit obtained with first line nivolumab-ipilimumab was maintained after subsequent therapy. In fact, the median PFS following subsequent therapy (PFS) was not reached in patients who received first line nivolumab-ipilimumab, while it reached 29.9 months in patients who initially received chemotherapy (HR[95%CI]: 0.27[0.17-0.44]). At 24 months, this translated into a PFS2 rate of 83% in the nivolumab-ipilimumab arm as compared to 52% in the control arm.

For Prof Lenz and Prof Dekervel these findings further solidify the combination of nivolumab and ipilimumab as the preferred first line treatment for patients with MSI-H/dMMR unresectable or metastatic CRC. As such, these results also underscore the importance of adequate MSI-H/dMMR testing in clinical practice. With respect to the latter there still seems to be room for improvement given the fact that about 15% of positive local tests for MSI-H/dMMR were not confirmed after central review in this trial.