Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

Abstract

Purpose: Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer.

Patients and methods: Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review.

Results: Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events.

Conclusion: Our study demonstrates the clinical benefit of anti-programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

Trial registration: ClinicalTrials.gov NCT02628067.

Conflict of interest statement

Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/journal/jco/site/ifc.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Aurelien Marabelle

Stock and Other Ownership Interests: Pegascy

Honoraria: Bristol-Myers Squibb, AstraZeneca, MedImmune, Oncovir, Merieux

Consulting or Advisory Role: Lytix Biopharma, Eisai, Pierre Fabre, Merck Serono, Novartis, Amgen, Pfizer, Symphogen, AstraZeneca, Servier, Gritstone Oncology, Molecular Partners, Bayer, Partner Therapeutics, Sanofi, Roche, Boehringer Ingelheim, Redx Pharma, Sotio, Innate Pharma, Imcheck, Cerenis Therapeutics, MSD, OSE Immunotherapeutics, Bioncotech

Speakers' Bureau: MSD, Bristol-Myers Squibb, AstraZeneca, Roche

Research Funding: Mersu (Inst), Bristol-Myers Squibb (Inst), Boehringer Ingelheim (Inst), Transgene (Inst), MSD (Inst)

Patents, Royalties, Other Intellectual Property: Monoclonal antibodies against CD81 (Stanford University)

Travel, Accommodations, Expenses: Bristol-Myers Squibb, MSD, Roche, AstraZeneca

Other Relationship: Pegascy

Dung T. Le

Honoraria: Merck

Consulting or Advisory Role: Merck, Bristol-Myers Squibb

Research Funding: Merck, Bristol-Myers Squibb, Aduro Biotech, Curegenix, Medivir

Patents, Royalties, Other Intellectual Property: Inventor of technology, Microsatellite Instability as a Pharmacogenomic Marker of Therapeutic Response to Immune Checkpoint Inhibition

Paolo A. Ascierto

Stock and Other Ownership Interests: PrimeVax

Consulting or Advisory Role: Bristol-Myers Squibb, Genentech, Merck Sharp & Dohme, Novartis, Amgen, Array BioPharma, Merck Serono, Pierre Fabre, Newlink Genetics, Genmab, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC

Research Funding: Bristol-Myers Squibb (Inst), Genentech (Inst), Array BioPharma (Inst)

Travel, Accommodations, Expenses: Merck Sharp & Dohme

Anna Maria Di Giacomo

Consulting or Advisory Role: Bristol-Myers Squibb, Incyte, Pierre Fabre, MSD Oncology

Ana De Jesus-Acosta

Consulting or Advisory Role: Merck

Research Funding: Merck (Inst), AstraZeneca (Inst)

Jean-Pierre Delord

Consulting or Advisory Role: Novartis, Genentech, Bristol-Myers Squibb, MSD Oncology

Research Funding: Genentech (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst)

Ravit Geva

Leadership: Pyxis

Honoraria: Bristol-Myers Squibb, MSD, Medison, Roche, Novartis, Janssen, Pfizer, Takeda

Consulting or Advisory Role: Bayer, Novartis, MSD, BOL Pharma

Patents, Royalties, Other Intellectual Property: Options, BOL Pharma

Travel, Accommodations, Expenses: Bristol-Myers Squibb, Merck Serono, Bayer, Medison

Maya Gottfried

Consulting or Advisory Role: Pfizer, Boehringer Ingelheim, Roche

Travel, Accommodations, Expenses: Pfizer, Roche, Boehringer Ingelheim

Nicolas Penel

Research Funding: Bayer (Inst)

Travel, Accommodations, Expenses: Astellas Pharma, Janssen-Cilag

Other Relationship: PharmaMar

Aaron R. Hansen

Honoraria: Merck, AstraZeneca, MedImmune, Pfizer, GlaxoSmithKline, Novartis, Bristol-Myers Squibb

Consulting or Advisory Role: Genentech, Merck, GlaxoSmithKline, Bristol-Myers Squibb, Novartis, Boston Biomedical, Boehringer Ingelheim

Research Funding: Karyopharm Therapeutics (Inst), Merck (Inst), Bristol-Myers Squibb (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Genentech (Inst), Janssen (Inst)

Sarina A. Piha-Paul

Research Funding: AbbVie (Inst), Aminex (Inst), BioMarin Pharmaceutical (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squib (Inst), Cerulean Pharma (Inst), Chugai Pharmaceutical (Inst), Curis (Inst), Five Prime Therapeutics (Inst), Genmab (Inst), GlaxoSmithKline (Inst), Helix BioPharma (Inst), Incyte (Inst), Jacobio Pharmaceuticals (Inst), MedImmune (Inst), Medivation (Inst), Merck Sharp & Dohme (Inst), New Link Genetics Corp (Inst), Blue Link Pharmaceuticals (Inst), Novartis Pharmaceuticals (Inst), Pieris Pharmaceuticals (Inst), Pfizer (Inst), Principia Biopharma (Inst), Puma Biotechnology (Inst), Rapt Therapeutics (Inst), Seattle Genetics (Inst), Taiho Oncology (Inst), Tesaro (Inst), TransThera Bio (Inst), XuanZhu Biopharma (Inst)

Toshihiko Doi

Consulting or Advisory Role: MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer, Boehringer Ingelheim, Rakuten Medical

Research Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Merck Serono (Inst), MSD (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Eli Lilly (Inst), Sumitomo Group (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Bristol-Myers Squibb (Inst), AbbVie (Inst), Quintiles (Inst), Eisai (Inst)

Bo Gao

Consulting or Advisory Role: MSD

Hyun Cheol Chung

Consulting or Advisory Role: Taiho Pharmaceutical, Celltrion, MSD, Eli Lilly, Quintiles, Bristol-Myers Squibb, Merck Serono

Speakers' Bureau: Merck Serono, Eli Lilly, Foundation Medicine

Research Funding: Eli Lilly, GlaxoSmithKline, MSD, Merck Serono, Bristol-Myers Squibb, Taiho Pharmaceutical

Jose Lopez-Martin

Stock and Other Ownership Interests: PharmaMar

Consulting or Advisory Role: Novartis, Eli Lilly, Roche, GlaxoSmithKline, MSD Oncology, Celgene, Caris Life Sciences, Bayer, Pfizer, Pierre Fabre, Bristol-Myers Squibb, Bristol-Myers Squibb (Inst), Roche Molecular Diagnostics (Inst), Amgen, PharmaMar

Patents, Royalties, Other Intellectual Property: PharmaMar

Travel, Accommodations, Expenses: Roche, MSD Oncology, Roche, Bristol-Myers Squibb

Yung-Jue Bang

Consulting or Advisory Role: Samyang, BeiGene, Green Cross, Taiho Pharmaceutical, Merck Serono, AstraZeneca, MedImmune, Novartis, MSD Oncology, Bayer, Hanmi, Genentech, Eli Lilly, Daiichi Sankyo, Astellas Pharma, Bristol-Myers Squibb, Genexine

Research Funding: AstraZeneca (Inst), MedImmune (Inst), Novartis (Inst), Genentech (Inst), MSD (Inst), Merck Serono (Inst), Bayer (Inst), GlaxoSmithKline (Inst), Bristol-Myers Squibb (Inst), Pfizer (Inst), Eli Lilly (Inst), Boehringer Ingelheim (Inst), Macrogenics (Inst), Boston Biomedical (Inst), Five Prime Therapeutics (Inst), CKD (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), BeiGene (Inst), Curis (Inst), Green Cross (Inst), Daiichi Sankyo (Inst), Astellas Pharma (Inst), Genexine (Inst)

Ronnie Shapira Frommer

Honoraria: MSD Oncology, Bristol-Myers Squibb, Novartis, Roche, AstraZeneca, Medison, Neopharm

Consulting or Advisory Role: VBL Therapeutics, Clovis Oncology, MSD Oncology

Manisha Shah

Consulting or Advisory Role: Eisai, Loxo, Novartis, Ignyta

Research Funding: Eisai, Merck, Loxo

Razi Ghori

Employment: Merck

Andrew K. Joe

Employment: Merck Sharp & Dohme, Sanofi

Stock and Other Ownership Interests: Merck Sharp & Dohme, Sanofi

Travel, Accommodations, Expenses: Merck Sharp & Dohme, Sanofi

Scott K. Pruitt

Employment: Merck Sharp & Dohme

Stock and Other Ownership Interests: Merck Sharp & Dohme

Luis A. Diaz Jr

Leadership: Personal Genome Diagnostics, Jounce Therapeutics

Stock and Other Ownership Interests: PapGene, Personal Genome Diagnostics, Jounce Therapeutics, Zydecom Corporation, Thrive Detect, Neophore, Amgen (I)

Consulting or Advisory Role: Merck, Personal Genome Diagnostics, Cell Design Labs, Lyndra, Caris Life Sciences, Genocea Biosciences, Zydecom, Neophore

Research Funding: Merck (Inst)

Patents, Royalties, Other Intellectual Property: US-2010041048-A1, Circulating mutant DNA to assess tumor dynamics; US-2015344970-A1, Personalized tumor biomarkers; WO-2010118016-A2, Digital quantification of DNA methylation; US-2005202465-A1, Thymidylate synthase gene and metastasis; US-2014227271-A1, Somatic mutations in ATRX in brain cancer; WO-2012094401-A2, Genes frequently altered in pancreatic neuroendocrine tumors; US-2013323167-A1, Detecting and treating solid tumors through selective disruption of tumor vasculature; EP-2912468-B1, Papanicolaou test for ovarian and endometrial cancers; US-9976184-B2, Mutations in pancreatic neoplasms; US-2017267760-A1, Checkpoint blockade and microsatellite instability; US-2018171413-A1, Head and neck squamous cell carcinoma assays; US-2018171413-A1, Head and neck squamous cell carcinoma assays; US-2018171413-A1, Head and neck squamous cell carcinoma assays; US-2018086832-A1, HLA-restricted epitopes encoded by somatically mutated genes; US-2018258490-A1, Assaying ovarian cyst fluid; US-2016208340-A1, TERT promoter mutations in urothelial neoplasia; US-2015252415-A1, Arid1b and neuroblastoma; WO-2018071796-A2, Compositions and methods for identifying functional antitumor T-cell responses; EP-3322824-A1, Detection of tumor-derived DNA in cerebrospinal fluid; US-2016273049-A1, Systems and methods for analyzing nucleic acid (Inst); US-2018135044-A1, Nonunique barcodes in a genotyping assay (Inst); and US-2017016075-A1, Neoantigen analysis (Inst)

Travel, Accommodations, Expenses: Merck

No other potential conflicts of interest were reported.

Figures

FIG 1.

(A) Duration of response by RECIST version 1.1 per independent central radiologic review. Tick marks represent censored patients. Analysis included all patients with a confirmed complete or partial response. Patients with an ongoing response are those whose disease had not progressed, had not initiated a new anticancer treatment, and had not died at the time of analysis. (B) Best percentage change from baseline in tumor size by RECIST version 1.1 per independent central radiologic review. Analysis included all patients who received at least one dose of study treatment and had at least one evaluable postbaseline tumor assessment.

FIG 2.

Kaplan-Meier analysis of (A) progression-free survival and (B) overall survival. Tick marks represent censored patients. Analysis included all patients who received at least one dose of study treatment. NR, not reached.

FIG A1.

Study profile. Data cutoff date for analyses was December 6, 2018. Efficacy and safety analyses included all patients who received at least one dose of study treatment. MSI-H/dMMR, mismatch repair deficient/microsatellite instability high.

FIG A2.

Distribution of tumor cohorts included in KEYNOTE-158.