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Ref Type Journal Article
PMID (35680043)
Authors Maio M, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH, Oh DY, Gottfried M, Xu L, Jin F, Norwood K, Marabelle A
Title Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.
Journal Vol Issue Date Pages Journal Short Title
Annals of oncology : official journal of the European Society for Medical Oncology 33 9 2022 Sep 929-938 Ann Oncol
URL
Abstract Text Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study.Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review.Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each).Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MSH2 negative biliary tract cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 40.9% (9/22, 3 complete responses and 6 partial responses), a duration of response of 30.5 mo, a median progression-free survival of 4.2 mo, and a median overall survival of 19.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) biliary tract cancer (PMID: 35680043; NCT02628067). 35680043
PMS2 negative small intestine cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 48.0% (12/25, 3 complete responses and 8 partial responses), a duration of response and a median overall survival that was not reached, and a median progression-free survival of 23.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) small intestine cancer (PMID: 35680043; NCT02628067). 35680043
MLH1 negative small intestine cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 48.0% (12/25, 3 complete responses and 8 partial responses), a duration of response and a median overall survival that was not reached, and a median progression-free survival of 23.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) small intestine cancer (PMID: 35680043; NCT02628067). 35680043
PMS2 negative ovarian cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 33.3% (8/24, 3 complete responses and 5 partial responses), a duration of response that was not reached, a median progression-free survival of 2.2 mo, and a median overall survival of 33.6 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian cancer (PMID: 35680043; NCT02628067). 35680043
MLH1 negative biliary tract cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 40.9% (9/22, 3 complete responses and 6 partial responses), a duration of response of 30.5 mo, a median progression-free survival of 4.2 mo, and a median overall survival of 19.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) biliary tract cancer (PMID: 35680043; NCT02628067). 35680043
MSH6 negative small intestine cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 48.0% (12/25, 3 complete responses and 8 partial responses), a duration of response and a median overall survival that was not reached, and a median progression-free survival of 23.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) small intestine cancer (PMID: 35680043; NCT02628067). 35680043
MLH1 negative pancreatic cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 18.2% (4/22, 1 complete response and 3 partial responses), a duration of response that was not reached, a median progression-free survival of 2.1 mo, and a median overall survival of 3.7 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) pancreatic cancer (PMID: 35680043; NCT02628067). 35680043
MSH2 negative small intestine cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 48.0% (12/25, 3 complete responses and 8 partial responses), a duration of response and a median overall survival that was not reached, and a median progression-free survival of 23.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) small intestine cancer (PMID: 35680043; NCT02628067). 35680043
MSH6 negative biliary tract cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 40.9% (9/22, 3 complete responses and 6 partial responses), a duration of response of 30.5 mo, a median progression-free survival of 4.2 mo, and a median overall survival of 19.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) biliary tract cancer (PMID: 35680043; NCT02628067). 35680043
PMS2 negative pancreatic cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 18.2% (4/22, 1 complete response and 3 partial responses), a duration of response that was not reached, a median progression-free survival of 2.1 mo, and a median overall survival of 3.7 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) pancreatic cancer (PMID: 35680043; NCT02628067). 35680043
MLH1 negative ovarian cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 33.3% (8/24, 3 complete responses and 5 partial responses), a duration of response that was not reached, a median progression-free survival of 2.2 mo, and a median overall survival of 33.6 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian cancer (PMID: 35680043; NCT02628067). 35680043
MSH6 negative pancreatic cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 18.2% (4/22, 1 complete response and 3 partial responses), a duration of response that was not reached, a median progression-free survival of 2.1 mo, and a median overall survival of 3.7 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) pancreatic cancer (PMID: 35680043; NCT02628067). 35680043
MLH1 negative stomach cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 31.0% (13/42, 4 complete responses and 9 partial responses), a duration of response that was not reached, a median progression-free survival of 3.2 mo, and a median overall survival of 11.0 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) gastric cancer (PMID: 35680043; NCT02628067). 35680043
PMS2 negative biliary tract cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 40.9% (9/22, 3 complete responses and 6 partial responses), a duration of response of 30.5 mo, a median progression-free survival of 4.2 mo, and a median overall survival of 19.4 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) biliary tract cancer (PMID: 35680043; NCT02628067). 35680043
MSH2 negative stomach cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 31.0% (13/42, 4 complete responses and 9 partial responses), a duration of response that was not reached, a median progression-free survival of 3.2 mo, and a median overall survival of 11.0 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) gastric cancer (PMID: 35680043; NCT02628067). 35680043
MSH6 negative ovarian cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 33.3% (8/24, 3 complete responses and 5 partial responses), a duration of response that was not reached, a median progression-free survival of 2.2 mo, and a median overall survival of 33.6 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian cancer (PMID: 35680043; NCT02628067). 35680043
MSH2 negative pancreatic cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 18.2% (4/22, 1 complete response and 3 partial responses), a duration of response that was not reached, a median progression-free survival of 2.1 mo, and a median overall survival of 3.7 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) pancreatic cancer (PMID: 35680043; NCT02628067). 35680043
PMS2 negative stomach cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 31.0% (13/42, 4 complete responses and 9 partial responses), a duration of response that was not reached, a median progression-free survival of 3.2 mo, and a median overall survival of 11.0 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) gastric cancer (PMID: 35680043; NCT02628067). 35680043
MSH2 negative ovarian cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 33.3% (8/24, 3 complete responses and 5 partial responses), a duration of response that was not reached, a median progression-free survival of 2.2 mo, and a median overall survival of 33.6 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) ovarian cancer (PMID: 35680043; NCT02628067). 35680043
MSH6 negative stomach cancer sensitive Pembrolizumab Phase II Actionable In a Phase II trial (KEYNOTE-158), Keytruda (pembrolizumab) treatment resulted in an objective response rate of 31.0% (13/42, 4 complete responses and 9 partial responses), a duration of response that was not reached, a median progression-free survival of 3.2 mo, and a median overall survival of 11.0 mo in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) gastric cancer (PMID: 35680043; NCT02628067). 35680043