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Pembrolizumab Benefit Demonstrated In KEYNOTE-177 Trial

Metastatic colorectal cancer patients with microsatellite instability-high or mismatch repair-deficient disease have longer progression-free survival with pembrolizumab than chemotherapy
07 Dec 2020
Colon and Rectal Cancer;  Immunotherapy;  Personalised/Precision Medicine

Author: By Lynda Williams, Senior medwireNews Reporters 

 

medwireNews: The KEYNOTE-177 trial results support the use of pembrolizumab for the treatment of patients with microsatellite instability-high or mismatch repair-deficient (MSI-H–dMMR) metastatic colorectal cancer (CRC). 

The second interim analysis of the phase III open-label trial was performed after a median follow-up of 32.4 months. At this time, median progression-free survival (PFS) was 16.5 months for the 153 patients randomly assigned to receive pembrolizumab 200 mg every 3 weeks compared with 8.2 months for the 154 patients instead given 5-fluorouracil-based chemotherapy at 2-week intervals, with or without bevacizumab or cetuximab. 

This gave a significant hazard ratio (HR) for disease progression or death of 0.60 in favour of the PD-1 inhibitor, the investigators report in The New England Journal of Medicine

As the PFS curves were not parallel, the proportional-hazards assumption was violated and a restricted mean survival time analysis was performed; after 2 years of follow-up the estimated mean PFS was 13.7 months with pembrolizumab versus 10.8 months with chemotherapy, with 56 and 69 deaths in the two groups, respectively. 

And PFS was “consistently longer with pembrolizumab” in the key prespecified patient subgroups, say the researchers, including a significant benefit for BRAF wild type and BRAF V600E mutation carriers, patients who were wild type for KRAS or NRAS, and those with right-side tumours or recurrent metachronous disease. 

The overall survival data are “still evolving”, with the final analysis planned when 190 deaths have occurred or after a further 12 months, explain Luis Diaz, from Memorial Sloan Kettering Cancer Center in New York, USA, and co-authors. 

Median duration of treatment was 11.1 months for pembrolizumab and 5.7 months for chemotherapy. 

A radiographic response was reported for 43.8% of the pembrolizumab-treated patients, including a complete response in 11.0%, compared with rates of 33.1% and 4.0%, respectively, in the chemotherapy arm. 

However, the pembrolizumab arm did have a higher rate of progressive disease as a best response than the chemotherapy group (29.4 vs 12.3%) and a lower rate of stable disease (20.9 vs 42.2%). 

Among responding patients, 83% of the pembrolizumab arm had an ongoing response at 24 months versus 35% of their chemotherapy-treated counterparts, with median durations not reached and 10.6 months, respectively. 

Treatment-related grade 3 or more severe adverse events occurred in 22% of patients given pembrolizumab versus 66% of the chemotherapy group, and grade 5 events occurred in 4% and 5% of the trial arms, respectively 

Grade 3–4 events of special interest were reported for 9% of patients given pembrolizumab, most commonly colitis or hepatitis, and for 2% of patients given chemotherapy, who had infusion or severe skin reactions. 

“These data represent another step forward for biomarker-driven studies targeting MSI-H–dMMR colorectal cancers”, the KEYNOTE-177 investigators say.

“Treatment with pembrolizumab led to significantly longer progression-free survival 

and fewer treatment-related adverse events than chemotherapy”, Luis Diaz et al summarise.

“As a result, pembrolizumab should be considered an option for initial therapy for patients with MSI-H–dMMR metastatic colorectal cancer.” 

Reference 

André T, Shiu K-K, Kim TW, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med 2020;383:2207–2218. DOI: 10.1056/NEJMoa2017699.

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature group

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