There is a new standard of care in the first-line treatment setting for the subset of patients with advanced colorectal cancer (CRC) that is associated with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR), according to data presented at the ASCO 2020 virtual annual meeting.
In the first study to compare the benefit of a PD-1 inhibitor versus chemotherapy in the front-line treatment of patients with MSI-H or dMMR metastatic CRC, induction with pembrolizumab (Keytruda) doubled the median progression-free survival (PFS).
An interim analysis of the phase 3 KEYNOTE-177 study showed improvement in PFS of >8 months with pembrolizumab, meeting one of the study’s primary end points. The median PFS 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, Sorbonne Université and Hôpital Saint Antoine, Paris, France. “It should be considered a new standard of care as first-line therapy in these patients.”
MSI-H and dMMR tumors comprise approximately 5% of advanced CRC cases and have proved responsive to PD-1 inhibitors in later lines of treatment. Pembrolizumab has been approved for the treatment of any patient with previously treated MSI-H or dMMR malignancies, regardless of tumor site or origin, said Dr André.
This phase 3 study randomized 307 treatment-naïve patients with MSI-H or dMMR metastatic CRC to first-line pembrolizumab 200 mg every 3 weeks for up to 2 years or to the investigator’s choice of modified FOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) every 2 weeks, with or without bevacizumab or cetuximab. Treatment was continued until progressive disease, unacceptable toxicity, patient or investigator decision to withdraw from the trial, or the completion of 35 cycles of pembrolizumab.
Patients who received chemotherapy could cross over to treatment with pembrolizumab for up to 35 cycles after confirmed progressive disease.
Improved Survival, Reduced Toxicity
Findings from the interim analysis showed a clinically meaningful and statistically significant improvement in the median PFS with pembrolizumab (16.5 months) versus chemotherapy (8.2 months). Nearly half (48.3%) of the patients were progression-free at 2 years, said Dr André, compared with only 18.6% of patients who received chemotherapy at that time point.
The overall response rate was 43.8% in patients who received pembrolizumab versus 33.1% in those who received chemotherapy, and the responses were more durable with pembrolizumab. The median duration of response has not been reached with pembrolizumab compared with 10.6 months with chemotherapy. In addition, 36% of the patients in the chemotherapy arm crossed over to the pembrolizumab arm after confirmed disease progression. An additional 35 patients received a PD-1 or PD-L1 inhibitor therapy outside of the study, for an effective crossover rate of 59% in the intent-to-treat population.
At 24 months and beyond, 83% of the patients who had a response with pembrolizumab were still responding, compared with only 35% of patients in the chemotherapy arm.
Pembrolizumab also had an improved safety profile versus chemotherapy. The grade ≥3 treatment-related events were 22% with pembrolizumab versus 66% with chemotherapy. The study is ongoing and overall survival data are not mature yet.
Michael J. Overman, MD, Professor of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, called the 2.5-fold increase in 24-month PFS with pembrolizumab versus chemotherapy (48% vs 19%, respectively) “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%) than with chemotherapy (12%), suggesting that almost 33% of patients had intrinsic resistance to therapy with a PD-1 inhibitor.
“This raises the question of whether patients should receive chemotherapy initially to control disease before receiving immunotherapy,” said Dr Overman. “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 cancer harboring rare dMMR tumors, so that all patients, those with rare or common cancer, “may gain benefit from advances in the use of immunotherapy.”