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Nature reviews | CliniCal OnCOlOgy The antiPD-1 antibody pembrolizumab was approved by the FDA for patients with previously treated advancedstage mismatch repair deficient (dMMR) or microsatellite instabilityhigh (MSIH) solid tumours in May 2017. This landmark approval, the first for a tissueagnostic indication in oncology, was based on data from 149 patients with 1 of 15 cancer types, including 90 patients with colorectal cancer (CRC). Indeed, ~15% of patients with CRC have dMMR/MSIH disease. Now, results of the KEYNOTE-177 trial show the efficacy of firstline pembrolizumab in these patients. Patients were randomly assigned to receive pembrolizumab (n = 153) or physician’s choice of one of four standard chemotherapy regimens (n = 154). Patients in the latter group could cross over to receive pembrolizumab after confirmed RECIST progression. The percentage of patients with an overall or complete response, or progressive disease, was 43.8%, 11% and 29.4%, respectively, with pembrolizumab, and 33.1%, 4% and 12.3% with chemotherapy. At a median followup duration of 32.4 months, the median progressionfree survival (PFS) duration was longer with pembrolizumab than with chemotherapy: 16.5 months versus 8.2 months (HR 0.60, 95% CI 0.45–0.80; P = 0.0002). The estimated PFS was 55.3% versus 37.3% at 12 months and 48.3% versus 18.6% at 24 months. This PFS benefit with pembrolizumab was consistent across the majority of prespecified subgroups (mutated or wildtype BRAF, wildtype RAS, and right or left primary tumour location). The only exception was the subgroup of patients with RASmutant CRC, who did not seem to derive greater benefit from immunotherapy than from chemotherapy. Overall survival (OS) data were not mature at the time of data cutoff. At this time, 56 of 154 patients receiving chemotherapy had crossed over to the pembrolizumab group, and an additional 35 patients received an antiPD-1 or antiPDL1 antibody outside of the trial. Owing to this high rate of crossover (59% overall), a statistically significant difference in OS might not be demonstrated in this trial. The incidence of grade 3–4 adverse events (AEs) was 56% versus 78% with pembrolizumab and chemotherapy, respectively, and that of grade 5 AEs was 4% versus 5%. Immunerelated AEs of grade 3–4 occurred in 9% versus 2% of patients; none of grade 5 was reported. “KEYNOTE-177 confirms the prognostic and predictive value of MSIH status for a more personalized and effective management of CRC,” opines Josep Tabernero, who was not involved in this trial. “Importantly, fewer treatmentrelated adverse events were observed with pembrolizumab. Therefore, the results of this trial are potentially practice changing and promise to substantially improve outcomes for those who matter the most — our patients,” Tabernero adds. Previous trials showing benefit from antiPD-1 antibodies in patients with dMMR/MSIH CRC, such as MK-3475 and KEYNOTE-164 (testing pembrolizumab) and CheckMate 142 (testing nivolumab), were noncomparative. “Now we have shown that immunotherapy is superior to chemotherapy in these patients in terms of response rates and PFS,” summarizes lead investigator Luis Diaz. In June 2020, these results led to the FDA approval of pembrolizumab for the firstline treatment of patients with metastatic dMMR/MSIH CRC. “This is not only the first major approval in CRC in over a decade, but also the first of firstline immunotherapy in this malignancy,” he concludes. Ongoing trials are comparing the efficacy of chemotherapy with or without the antiPDL1 antibody atezolizumab in patients with dMMR/MSIH CRC, at different disease stages (NCT02997228 and NCT02912559). Diaz and collaborators are also involved in trials “investigating the efficacy of pembrolizumab in the adjuvant setting in patients with dMMR/MSIH solid tumours, with circulating tumour DNA guidance (NCT03832569), and of neoadjuvant TSR-042, another antiPD-1 antibody, in patients with dMMR/MSIH rectal cancer (NCT04165772)”. Finally, KEYNOTE-177 co-investigator Thierry André highlights “the ongoing phase III study CheckMate 8HW comparing nivolumab alone or in combination with ipilumumab versus chemotherapy in patients with metastatic dMMR/MSIH CRC”. The results of these studies could help to establish additional settings in which patients with dMMR/ MSIH tumours might benefit from immunecheckpoint inhibition. Diana Romero I M M U N OT H E R A P Y