Pembrolizumab versus chemotherapy showed progression-free survival improvement in the second provisional analysis in patients with the tumor. The study continued until the final overall survival (OS) analysis, planned after 190 OS events or 12 months after the second provisional analysis
The results of the final overall survival (OS) analysis of KEYNOTE-177 (NCT02563002), were presented during the ASCO World Congress 2021. The open-label, randomized, phase III trial compared pembrolizumab versus chemotherapy as first-line treatment in patients with metastatic colorectal cancer (mCRC) whose tumors had repair enzyme deficiency (dMMR) or microsatellite instability (MSI-H).
A total of 307 patients with mCRC MSI-H/dMMR and ECOG 0 or 1 were randomized in a 1:1 ratio to receive pembrolizumab 200mg every three weeks for up to two years or the choice of the investigator (mFOLFOX6 or FOLFIRI every two weeks ± bevacizumab or cetuximab). Treatment continued until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, or completion of 35 cycles (immunotherapy arm only). Patients allocated in the chemotherapy arm could perform crossover after confirmation of disease progression to receive pembrolizumab for up to 35 cycles. The primary endpoints were OS and PFS (RECIST v1.1, central review). Secondary endpoints included ORR, duration of response (DoR) (RECIST v1.1, central review), and safety. For OS significance, the p-value had to meet an α-specified value of 0.0246 (unilateral). Sensitivity analyses to adjust for the crossover effect were performed. The data cutoff for the final analysis was February 19, 2021.
The mean study follow-up was 44.5 months with pembrolizumab versus 44.4 months with chemotherapy. 56 (36%) participants crossover from chemotherapy to pembrolizumab, with 37 receiving anti-PD-1/PD-L1 therapies out-of-trial (60% effective crossover rate in the ITT population).
The hazard ratio (HR) for OS favored pembrolizumab versus chemotherapy with a tendency to reduce the risk of death (HR 0.74; CI 95% 0.53-1.03; P = 0.0359; median not reached [NR] vs 36.7 months); however, the difference did not reach statistical significance.
In the final analysis, the median PFS was 16.5 versus 8.2 months (HR 0.59; CI 95% 0.45 – 0.79) but was not formally tested by the analysis plan. The confirmed ORR was 45.1% (20 complete responses and 49 partial responses) versus 33.1% (6 complete responses and 45 partial responses). The median DoR was not reached versus 10.6 months, respectively.
Treatment-related adverse events (TRAEs) occurred in 79.7% versus 98.6% of patients; and in 21.6% versus 66.4% developed events grade ≥3, respectively.
The authors conclude that as first-line therapy for patients with MSI-H/dMMR mCRC, pembrolizumab versus chemotherapy provides statistically higher PFS gain with fewer adverse events, and it is associated with a trend in mortality reduction that did not reach statistical significance, probably due to the high crossover from chemotherapy to anti-PD1/PD-L1 therapies.