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FDA Approves First-Line Pembrolizumab: Metastatic MSI-High/dMMR Colorectal Cancer

Killer T cells surround a cancer cell.

Patients with unresectable or metastatic colorectal cancer with high microsatellite instability (MSI) or a deficiency in mismatch repair (dMMR) now have their first frontline immunotherapy option, thanks to the FDA's approval of pembrolizumab (Keytruda®, Merck) in this population.

Efficacy and safety were investigated in an open-label phase 3 trial, KEYNOTE-177 (NCT02563002), for which 307 patients with previously untreated MSI-high/dMMR metastatic colorectal cancer and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomized in a 1:1 ratio to receive pembrolizumab, 200 mg every three weeks for up to two years, or investigator's choice of chemotherapy with mFOLFOX6 (leucovorin calcium [folinic acid]/fluorouracil/oxaliplatin) or FOLFIRI (leucovorin calcium/fluorouracil/irinotecan hydrochloride) every two weeks with or without bevacizumab or cetuximab. Chemotherapy was chosen prior to randomization. Treatment continued until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, or completion of 35 cycles in the case of pembrolizumab. Patients in the chemotherapy arm were permitted to cross over to the pembrolizumab arm for up to 35 cycles after confirmed disease progression. The trial's primary end points were centrally reviewed progression-free survival and overall survival, with key secondary end points of centrally reviewed overall response rate and safety.

As of the interim analysis data cutoff date of February 19, 2020, with a median study follow-up of 28.4 months in the pembrolizumab arm and 27.2 months in the chemotherapy arm, pembrolizumab produced a longer median progression-free survival compared with chemotherapy (16.5 vs 8.2 months), with higher rates of progression-free survival at 12 months (55.3% vs 37.3%) and at 24 months (48.3% vs 18.6%). Pembrolizumab also resulted in a higher confirmed overall response rate (43.8% vs 33.1%) and duration of response (not reached vs 10.6 months). Data on overall survival are not yet mature.

Adverse events of grade 3 or higher were less frequent for pembrolizumab than for chemotherapy (22% vs 66%). Adverse reactions experienced by at least 20% of patients receiving single-agent pembrolizumab are known to include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab can also cause immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. It should be discontinued in the event of a severe or life-threatening infusion-related reaction. Pembrolizumab carries risks of embryo-fetal toxicity and should also be avoided by women who are breastfeeding.

"Pembrolizumab provided a clinically meaningful and statistically significant improvement in progression-free survival versus chemotherapy as first-line therapy for patients with MSI-high/dMMR metastatic colorectal cancer, with fewer treatment-related adverse events observed, and should be the new standard of care for these patients," concluded the investigators in their abstract from the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program, led by Thierry André, MD, Professor of Medical Oncology at the Sorbonne University and Saint-Antoine Hospital, Paris, France.

"Metastatic colorectal cancer is a serious and life-threatening disease with a poor prognosis. Available current therapy with chemotherapy combinations and other biologics are associated with substantial toxicity," commented Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research, in a press release. "Having a nonchemotherapy option available for selected patients is a noteworthy paradigm shift in treatment."

For More Information

Andre T, Shiu KK, Kim TW, et al (2020). Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol (ASCO Virtual Scientific Program Abstracts), 38(suppl_18). Abstract LBA4. DOI:10.1200/JCO.2020.38.18_suppl.LBA4

Clinicaltrials.gov (2020). Study of pembrolizumab (MK-3475) vs standard therapy in participants with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) stage IV colorectal carcinoma (MK-3475-177/KEYNOTE-177). NLM identifier: NCT02563002.

Keytruda® (pembrolizumab) prescribing information (2020). Merck & Co., Inc. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s084lbl.pdf

United States Food and Drug Administration (2020). FDA approves first-line immunotherapy for patients with MSI-H/dMMR metastatic colorectal cancer. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-line-immunotherapy-patients-msi-hdmmr-metastatic-colorectal-cancer

Image credit: Alex Ritter, Jennifer Lippincott Schwartz, and Gillian Griffiths. Courtesy of the National Institutes of Health

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