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Rates of Progression-Free Survival in MSI-H/dMMR Metastatic Colorectal Cancer Doubled by Pembrolizumab


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Upfront treatment with immunotherapy not only improved results in a subset of patients with metastatic colorectal cancer, it doubled the rates of median progression-free survival. These findings—the first of their kind—arose from the interim analysis of the randomized open-label phase III KEYNOTE-177 trial, which compared the PD-1 antibody pembrolizumab with standard-of-care chemotherapy.

In KEYNOTE-177, patients receiving pembrolizumab had a median progression-free survival of 16.5 months vs 8.2 months with chemotherapy (hazard ratio [HR] = 0.60; P = .0002). The study, therefore, met one of its two co-primary endpoints, as reported at the Plenary Session of the ASCO20 Virtual Scientific Program by ­Thierry André, MD, of Sorbonne University and Saint-Antoine Hospital, Paris.1

­Thierry André, MD

­Thierry André, MD

“Pembrolizumab provided a clinically meaningful and statistically significant improvement in progression-free survival vs chemotherapy in patients with microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) tumors, with fewer treatment-related adverse events, and it should be considered a new standard of care as first-line therapy in these patients,” Dr. André said.

MSI-H/dMMR tumors constitute about 5% of metastatic colorectal cancers and have proved responsive to PD-1 inhibitors in later treatment lines. Pembrolizumab was approved in previously treated MSI-H/dMMR malignancies regardless of the tumor site of origin.

KEYNOTE-177 Details

The study enrolled 307 previously untreated patients with MSI-H/dMMR metastatic colorectal cancer, randomly assigning them to first-line pembrolizumab at 200 mg every 3 weeks for up to 2 years or investigator’s choice of modified FOLFOX6 (fluorouracil [5-FU], leucovorin, and oxaliplatin) or FOLFIRI (5-FU, leucovorin, and 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 confirmation of progressive disease.

The study had two co-primary endpoints: progression-free survival by Response Evaluation Criteria in Solid Tumors (RECIST) and central review, and overall survival. Objective response by central review was a key secondary endpoint. “The study was considered successful if pembrolizumab was superior to chemotherapy for either primary endpoint,” Dr. André said.

The data cutoff date for this interim analysis was February 19, 2020. The study is ongoing, and overall survival data will be presented later. The median study follow-up (time from randomization to data cutoff) was 32.4 months (range = 24.0–48.3 months).

Notable Difference in Progression-Free Survival

Pembrolizumab proved to be superior to chemotherapy by demonstrating a 40% reduction in the risk of disease progression (P = .0002). Progression-free survival rates were 55% with pembrolizumab vs 37% with chemotherapy at 12 months and 48% vs 19%, respectively, at 24 months, Dr. André reported.

OF NOTE

On June 29, 2020, the US Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) colorectal cancer. Approval was based on the KEYNOTE‑177 trial.

The confirmed objective response rates were 43.8% and 33.1%, respectively, with the median duration of response not reached with pembrolizumab (2.3–41.4 months) vs 10.6 months for chemotherapy (2.8–37.5 months). Complete responses were achieved in 11.1% and 3.9%, respectively, and partial responses, in 32.7% vs 29.2%. Best response was stable disease in 30.9% and 42.2% and progressive disease in 29.4% and 12.3%, respectively. At 24 months and beyond, 83% of pembrolizumab responders were still responding, compared with just 35% of the chemotherapy arm.

The ASCO Post asked Dr. André about the 30% of the pembrolizumab arm with progressive disease as the best response. He speculated that the principal cause was primary resistance to pembrolizumab. Alternatively, he suggested, “RECIST version 1.1 criteria may not have been the optimal measure of response, with some pseudoprogression (counting as an event in the progression-free survival curve) and some rare misdiagnosis of MSI-H/dMMR (ie, patients may be proficient).”

Grade 3 to 5 treatment-related adverse events were observed in 22% of the pembrolizumab arm and 66% of the chemotherapy arm. One patient in the chemotherapy arm died due to a treatment-related adverse event. 

DISCLOSURE: KEYNOTE-177 was funded by MSD Oncology. Dr. Andre has received honoraria from Amgen, Bayer, Bristol-Myers Squibb, Pierre Fabre, Roche/Genentech, Sanofi, Servier, and Ventana; has served in a consulting or advisory role for Amgen, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, Clovis Oncology, GIC Advice, Gritstone Oncology, HalioDx, MSD Oncology, Roche/Genentech, Servier, and Tesaro; and has been reimbursed for travel, accommodations, and other expenses by Amgen, Bristol-Myers Squibb, MSD Oncology, Roche/Genentech, and Ventana.

REFERENCE

1. André T, Shiu K-K, Kim TW, et al: Pembrolizumab vs chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. ASCO20 Virtual Scientific Program. Abstract LBA4.

 


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Sharing his perspective on KEYNOTE-177 with The ASCO Post was Axel Grothey, MD, Director of GI Cancer Research at the West Cancer Center, OneOncology, Memphis. “This is a very important, highly anticipated study,” he said.

Axel Grothey, MD

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“It’s the first randomized trial of any checkpoint...

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