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Significantly Longer PFS with First-line Pembrolizumab for MSI-H/dMMR mCRC

Pembrolizumab led to significantly longer progression-free survival than chemotherapy in KEYNOTE-177 as first-line treatment for MSI-H/dMMR metastatic colorectal cancer
03 Dec 2020
Cancer Immunology and Immunotherapy;  Gastrointestinal cancers;  Personalised medicine

The KEYNOTE-177 study investigators reported on 3 December 2020 in The New England Journal of Medicine that the study data represent another step forward for biomarker-driven studies targeting colorectal cancer (CRC) in patients with microsatellite-instable (MSI) tumours. In particular, first-line treatment with pembrolizumab led to significantly longer progression-free survival (PFS) and fewer treatment-related adverse events (TRAEs) than chemotherapy. 

The authors wrote that programmed death 1 (PD-1) blockade has clinical benefit in MSI–high (MSI-H) or mismatch-repair–deficient (dMMR) tumours after previous therapy. It has emerged as effective therapy for MSI-H/dMMR metastatic CRC (mCRC) refractory to standard chemotherapy combinations. 

One genetic subset of CRC is tumours with dMMR, which are found in 15% of all patients with CRC of whom 12% are sporadic and 3% are hereditary cases. Approximately 80% of cases with sporadic dMMR CRC are caused by methylation of the MLH1 gene promoter, while more than 70% of hereditary cases are associated with germline mutations in the MLH1 and MSH2 genes. Both forms result in the inability of cells to recognise and repair spontaneous mutations, resulting in a very high tumour mutation burden as well as altered microsatellite sequences that render these tumours high in MSI. 

Randomised, phase III, open-label KEYNOTE-177 study (NCT02563002) was conducted to evaluate the efficacy and safety of PD-1 blockade with pembrolizumab compared with standard of care chemotherapy as first-line treatment for MSI-H/dMMR mCRC. In total, 307 patients with MSI-H/dMMR treatment naïve mCRC were randomly assigned in a 1:1 ratio, to receive pembrolizumab every 3 weeks or 5-fluorouracil–based chemotherapy with or without bevacizumab or cetuximab every 2 weeks. Patients who received chemotherapy could cross over to pembrolizumab after disease progression. The study primary endpoints were PFS and overall survival (OS). 

At the second interim analysis, after a median follow-up (calculated from randomisation to data cut-off) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy in terms of PFS (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval 0.45 to 0.80; p = 0.0002). 

The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cut-off date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on OS were still evolving with 66% of required events occurred and remain blinded until the final analysis. 

An overall response (complete or partial response) evaluated according RECIST v1.1 was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group compared with 35% of patients in the chemotherapy group had ongoing responses at 24 months. 

The authors wrote that benefit was observed across key patient subgroups and supports previous data showing the benefit of pembrolizumab monotherapy in MSI-H/dMMR solid tumours. 

Grade 3 or higher TRAEs  occurred in 22% of the patients in the pembrolizumab group compared with 66% (including one patient who died) in the chemotherapy group. 

Improved PFS observed in KEYNOTE-177 study was reflected by clinically meaningful improvements in health-related quality of life that favoured pembrolizumab over chemotherapy, according to findings presented recently at the ESMO Virtual Congress 2020

Axel Grothey wrote in an accompanied editorial article that the durability of response, better safety profile, and improved quality of life associated with immune checkpoint blockade compared with chemotherapy make pembrolizumab the preferred choice of treatment in MSI-H/dMMR mCRC. The KEYNOTE-177 study findings support ongoing studies investigating immune checkpoint inhibitors in the adjuvant and neoadjuvant settings. However, the ultimate goal would be to find active treatment approaches for patients with microsatellite-stable, mismatch repair–proficient tumours that constitute the majority of mCRC cases. 

The KEYNOTE-177 study was supported by Merck Sharp and Dohme and by a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant. 

References

 André T, Shiu K-K, Kim, TW, et al. Pembrolizumab in Microsatellite-Instability–High Advanced Colorectal Cancer. N Engl J Med 2020;383:2207-18. DOI: 10.1056/NEJMoa2017699. 

Grothey A. Pembrolizumab in MSI-H–dMMR Advanced Colorectal Cancer — A New Standard of Care. N Engl J Med 2020; 383:2283-2285. DOI: 10.1056/NEJMe2031294.

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