There’s a new standard of care in the first-line setting for a subset of patients with advanced colorectal cancer.
In the first study to compare a PD-1 inhibitor with chemotherapy as frontline treatment of patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer, induction pembrolizumab doubled median progression-free survival.
Interim analysis of the phase 3 KEYNOTE-177 study showed improvement in progression-free survival of more than 8 months with pembrolizumab, meeting one of its primary end points. According to data presented at the ASCO20 Virtual Scientific Program, median progression-free survival was 16.5 months with the checkpoint inhibitor versus 8.2 months with chemotherapy (hazard ratio, 0.60; P = .0002).
“Pembrolizumab provided a clinically meaningful and statistically significant improvement in progression-free survival versus chemotherapy in patients with MSI-H or dMMR tumors, with fewer treatment-related adverse events,” said Thierry André, MD, of Sorbonne University and Saint-Antoine Hospital, Paris, France. “It should be considered a new standard of care as first-line therapy in these patients.”
As Dr André reported, MSI-H/dMMR tumors comprise approximately 5% of advanced colorectal cancers and have proved responsive to PD-1 inhibitors in later lines of treatment. Pembrolizumab has been approved for the treatment of previously treated MSI-H/dMMR malignancies regardless of tumor site or origin, said Dr André.
For this phase 3 study, Dr André and colleagues randomized 307 previously untreated patients with MSI-H/dMMR metastatic colorectal cancer to first-line pembrolizumab 200 mg every 3 weeks for up to 2 years or investigator’s choice of modified FOLFOX6 (5-fluorouracil/leucovorin/oxaliplatin) or FOLFIRI (5-fluorouracil/leucovorin/irinotecan) every 2 weeks, with or without bevacizumab or cetuximab. Treatment was continued until progressive disease, unacceptable toxicity, patient/investigator decision to withdraw, or completion of 35 cycles of pembrolizumab. Patients receiving chemotherapy could cross over to pembrolizumab for up to 35 cycles after confirmed progressive disease.
Significant Differences in Survival and Toxicity
As Dr André reported, findings from the interim analysis showed clinically meaningful and statistically significant improvement in median progression-free survival on pembrolizumab (16.5 months) versus chemotherapy (8.2 months). Whereas nearly half of patients (48.3%) were progression free at 2 years, only 18.6% of patients treated with chemotherapy had not progressed at the same time point, said Dr André.
The overall response rate was 43.8% for patients on pembrolizumab versus 33.1% on chemotherapy, and the responses were also more durable. Median duration of response has not been reached on pembrolizumab compared with 10.6 months on chemotherapy, said Dr André, who noted that 36% of patients in the chemotherapy arm crossed over to receive pembrolizumab after confirmed disease progression. An additional 35 patients received anti–PD-1 or anti–PD-L1 therapy outside the study for an effective crossover rate of 59% in the intent-to-treat population, he added.
At 24 months and beyond, 83% of pembrolizumab responders were still responding, compared with only 35% on the chemotherapy arm.
Pembrolizumab also demonstrated an improved safety profile versus chemotherapy. There was a lower incidence of grade 3 or higher treatment-related events on pembrolizumab (22%) versus chemotherapy (66%), Dr André reported.
The study is ongoing, and overall survival data will be presented at a later date.
Michael J. Overman, MD, professor at The University of Texas MD Anderson Cancer Center, Houston, called the 2.5-fold increase in 24-month progression-free survival on pembrolizumab versus chemotherapy (48% vs 19%) “clinically meaningful” and said that these results should change clinical practice.
Despite the improved survival with immunotherapy, however, Dr Overman noted that the rate of progressive disease was higher with pembrolizumab (29%) versus chemotherapy (12%), suggesting that almost one-third of patients demonstrate intrinsic resistance to PD-1–based therapy.
“This raises the question of whether patients should receive chemotherapy initially to control disease before receiving immunotherapy,” Dr Overman said. “In the meantime, it is critical that we develop biomarkers of resistance to identify those patients who are not benefiting from pembrolizumab.”
However, given the consistent benefits of targeting PD-1 and PD-L1, irrespective of histology or deficient mismatch repair, Dr Overman encouraged pharmaceutical companies and clinical investigators to conduct trials in a tumor-agnostic fashion for patients with deficient mismatch repair cancers, “so that all patients, rare or common, may gain benefit from advances in the use of immunotherapy.”