Study of Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-3475-158/KEYNOTE-158)

NCT02628067 | Active Not Recruiting Phase 2 FDA Drug

• 7 other identifiers: 3475-158163196MK-3475-158KEYNOTE-1582022-501253-37-00U1111-1275-83742015-002067-41
• Study Type: interventional
• Target: 1,609
• Locations: 0 countries
• Sites: N/A

Brief Summary

In this study, participants with multiple types of advanced (unresectable and/or metastatic) solid tumors who have progressed on standard of care therapy will be treated with pembrolizumab (MK-3475).

Conditions

Advanced Cancer; Anal Carcinoma; Anal Cancer; Biliary Cancer; Cholangiocarcinoma; Bile Duct Cancer; Neuroendocrine Tumor; Carcinoid Tumor; Endometrial Carcinoma; Endometrial Cancer; Cervical Carcinoma; Cervical Cancer; Vulvar Carcinoma; Vulvar Cancer; Small Cell Lung Carcinoma; Small Cell Lung Cancer (SCLC); Mesothelioma; Thyroid Carcinoma; Thyroid Cancer; Salivary Gland Carcinoma; Salivary Gland Cancer; Salivary Cancer; Parotid Gland Cancer; Advanced Solid Tumors; Colorectal Carcinoma

Keywords

Programmed Cell Death-1 (PD1, PD-1); Programmed Death-Ligand 1 (PDL1, PD-L1); microsatellite instability (MSI); mismatch repair (MMR)

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ at any time during the trial. Responses will be determined by independent central radiologic review, with confirmatory assessment as required per RECIST 1.1. Participants with unknown or missing response information will be treated as non-responders. The percentage of participants who experience a CR or PR based on modified RECIST 1.1 will be presented.

  Up to approximately 10.5 years

Secondary Outcomes (5)

• Duration of Response (DOR)

  Up to approximately 10.5 years

• Progression Free Survival (PFS)

  Up to approximately 10.5 years

• Overall Survival (OS)

  Up to approximately 10.5 years

• Percentage of Participants with Adverse Events (AEs)

  Up to approximately 27 months

• Percentage of Participants who Discontinue Study Intervention due to AEs

  Up to approximately 2 years

Study Arms (2)

Pembrolizumab 200 mg

EXPERIMENTAL

Participants will receive pembrolizumab 200 mg intravenously on Day 1 of each 3-week cycle for up to 35 administrations (up to approximately 2 years of treatment).

Biological: pembrolizumab

Pembrolizumab 400 mg

EXPERIMENTAL

Participants with any advanced solid tumor that has failed at least one line of therapy and is Tumor- Mutational Burden-High (TMB-H), excluding participants with mismatch repair deficient (dMMR/MSI-H) tumors. The dosing regimen for this cohort will be 400 mg every 6 weeks (Q6W) for up to 18 administrations (up to approximately 2 years of treatment).

Biological: pembrolizumab

Interventions

pembrolizumab BIOLOGICAL

intravenous infusion

Also known as: MK-3475, SCH 900475, KEYTRUDA®

Pembrolizumab 200 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- Histologically or cytologically-documented, advanced solid tumor of one of the following types:
• Anal Squamous Cell Carcinoma
• Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater cancers)
• Neuroendocrine Tumors (well- and moderately-differentiated) of the lung, appendix, small intestine, colon, rectum, or pancreas
• Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded)
• Cervical Squamous Cell Carcinoma
• Vulvar Squamous Cell Carcinoma
• Small Cell Lung Carcinoma
• Mesothelioma
• Thyroid Carcinoma
• Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded)
• Any advanced solid tumor, with the exception of colorectal carcinoma (CRC), which is Microsatellite Instability (MSI)-High (MSI-H) OR
• Any advanced solid tumor (including Colorectal Carcinoma \[CRC\]) which is Mismatch Repair Deficient (dMMR)/MSI-H in participants from mainland China who are of Chinese descent. (CRC participants will have a histologically proven locally advanced unresectable or metastatic CRC which is dMMR/MSI-H that has received 2 prior lines of therapy) OR
• Any advanced solid tumor that has failed at least one line of therapy and is TMB-H (≥10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors.
• Note: For participants to be eligible for enrollment they must have failed at least one line of standard of care systemic therapy (ie, not treatment naïve), with the exception of CRC participants who must have failed at least 2 lines of standard of care systemic therapy, as per CRC specific eligibility criteria. Participants must not have melanoma or NSCLC.

You may not qualify if:

• Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
• Active autoimmune disease that has required systemic treatment in the past 2 years
• Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or not recovered from an adverse event caused by mAbs administered more than 4 weeks earlier
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks of study Day 1 or not recovered from adverse events caused by a previously administered agent
• Known additional malignancy within 2 years prior to enrollment with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has known glioblastoma multiforme of the brain stem
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
• Active infection requiring systemic therapy
• Known psychiatric or substance abuse disorders that would interfere with the participant's ability to cooperate with the requirements of the study
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
• Previously participated in any other pembrolizumab (MK-3475) study, or received prior therapy with an anti-programmed cell death (PD)-1, anti-PD-Ligand 1 (anti-PD-L1), anti-PD-Ligand 2 (anti-PD-L2), or any other immunomodulating mAb or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Known history of Human Immunodeficiency Virus (HIV)
• Known active Hepatitis B or C

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (16)

• Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, Geva R, Gottfried M, Penel N, Hansen AR, Piha-Paul SA, Doi T, Gao B, Chung HC, Lopez-Martin J, Bang YJ, Frommer RS, Shah M, Ghori R, Joe AK, Pruitt SK, Diaz LA Jr. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020 Jan 1;38(1):1-10. doi: 10.1200/JCO.19.02105. Epub 2019 Nov 4.

  PMID: 31682550 RESULT

• Marabelle A, O'Malley DM, Hendifar AE, Ascierto PA, Motola-Kuba D, Penel N, Cassier PA, Bariani G, De Jesus-Acosta A, Doi T, Longo F, Miller WH Jr, Oh DY, Gottfried M, Yao L, Jin F, Gozman A, Maio M. Pembrolizumab in microsatellite-instability-high and mismatch-repair-deficient advanced solid tumors: updated results of the KEYNOTE-158 trial. Nat Cancer. 2025 Feb;6(2):253-258. doi: 10.1038/s43018-024-00894-y. Epub 2025 Feb 20.

  PMID: 39979665 RESULT

• Wu X, Mao Y, Xu N, Bai Y, Wang D, Chen X, Yin X, Deng Y, Yang J, Zhang J, Tang J, Huang Y, Li J, Luo S, Zheng H, Zhao W, Xu M, Li N, Mao Y, Gozman A, Xu J. Pembrolizumab in Patients of Chinese Descent with Microsatellite Instability-high/Mismatch Repair Deficient Advanced Solid Tumors: KEYNOTE-158 Final Analysis. Adv Ther. 2025 May;42(5):2480-2489. doi: 10.1007/s12325-025-03142-6. Epub 2025 Mar 22.

  PMID: 40121391 DERIVED

• Oh DY, Algazi A, Capdevila J, Longo F, Miller W Jr, Chun Bing JT, Bonilla CE, Chung HC, Guren TK, Lin CC, Motola-Kuba D, Shah M, Hadoux J, Yao L, Jin F, Norwood K, Lebellec L. Efficacy and safety of pembrolizumab monotherapy in patients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study. Cancer. 2023 Apr 15;129(8):1195-1204. doi: 10.1002/cncr.34657. Epub 2023 Feb 7.

  PMID: 36748723 DERIVED

• O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Amonkar M, Yao L, Jin F, Norwood K, Maio M. Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. Gynecol Oncol. 2022 Aug;166(2):245-253. doi: 10.1016/j.ygyno.2022.06.005. Epub 2022 Jul 11.

  PMID: 35835611 DERIVED

• Even C, Delord JP, Price KA, Nakagawa K, Oh DY, Burge M, Chung HC, Doi T, Fakih M, Takahashi S, Yao L, Jin F, Norwood K, Hansen AR. Evaluation of pembrolizumab monotherapy in patients with previously treated advanced salivary gland carcinoma in the phase 2 KEYNOTE-158 study. Eur J Cancer. 2022 Aug;171:259-268. doi: 10.1016/j.ejca.2022.05.007. Epub 2022 Jun 28.

  PMID: 35777186 DERIVED

• 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. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022 Sep;33(9):929-938. doi: 10.1016/j.annonc.2022.05.519. Epub 2022 Jun 6.

  PMID: 35680043 DERIVED

• Maio M, Amonkar MM, Norquist JM, Ascierto PA, Manzyuk L, Motola-Kuba D, Penel N, Cassier PA, Bariani GM, De Jesus Acosta A, Doi T, Longo F, Miller WH Jr, Oh DY, Gottfried M, Wang R, Norwood K, Marabelle A. Health-related quality of life in patients treated with pembrolizumab for microsatellite instability-high/mismatch repair-deficient advanced solid tumours: Results from the KEYNOTE-158 study. Eur J Cancer. 2022 Jul;169:188-197. doi: 10.1016/j.ejca.2022.03.040. Epub 2022 May 16.

  PMID: 35588692 DERIVED

• Shapira-Frommer R, Mileshkin L, Manzyuk L, Penel N, Burge M, Piha-Paul SA, Girda E, Lopez Martin JA, van Dongen MGJ, Italiano A, Xu L, Jin F, Norwood K, Ott PA. Efficacy and safety of pembrolizumab for patients with previously treated advanced vulvar squamous cell carcinoma: Results from the phase 2 KEYNOTE-158 study. Gynecol Oncol. 2022 Aug;166(2):211-218. doi: 10.1016/j.ygyno.2022.01.029. Epub 2022 Mar 28.

  PMID: 35361487 DERIVED

• Marabelle A, Cassier PA, Fakih M, Kao S, Nielsen D, Italiano A, Guren TK, van Dongen MGJ, Spencer K, Bariani GM, Ascierto PA, Santoro A, Shah M, Asselah J, Iqbal S, Takahashi S, Piha-Paul SA, Ott PA, Chatterjee A, Jin F, Norwood K, Delord JP. Pembrolizumab for previously treated advanced anal squamous cell carcinoma: results from the non-randomised, multicohort, multicentre, phase 2 KEYNOTE-158 study. Lancet Gastroenterol Hepatol. 2022 May;7(5):446-454. doi: 10.1016/S2468-1253(21)00382-4. Epub 2022 Feb 1.

  PMID: 35114169 DERIVED

• O'Malley DM, Bariani GM, Cassier PA, Marabelle A, Hansen AR, De Jesus Acosta A, Miller WH Jr, Safra T, Italiano A, Mileshkin L, Xu L, Jin F, Norwood K, Maio M. Pembrolizumab in Patients With Microsatellite Instability-High Advanced Endometrial Cancer: Results From the KEYNOTE-158 Study. J Clin Oncol. 2022 Mar 1;40(7):752-761. doi: 10.1200/JCO.21.01874. Epub 2022 Jan 6.

  PMID: 34990208 DERIVED

• Yap TA, Nakagawa K, Fujimoto N, Kuribayashi K, Guren TK, Calabro L, Shapira-Frommer R, Gao B, Kao S, Matos I, Planchard D, Chatterjee A, Jin F, Norwood K, Kindler HL. Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study. Lancet Respir Med. 2021 Jun;9(6):613-621. doi: 10.1016/S2213-2600(20)30515-4. Epub 2021 Apr 6.

  PMID: 33836153 DERIVED

• Marabelle A, Fakih M, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, Chung HC, Kindler HL, Lopez-Martin JA, Miller WH Jr, Italiano A, Kao S, Piha-Paul SA, Delord JP, McWilliams RR, Fabrizio DA, Aurora-Garg D, Xu L, Jin F, Norwood K, Bang YJ. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol. 2020 Oct;21(10):1353-1365. doi: 10.1016/S1470-2045(20)30445-9. Epub 2020 Sep 10.

  PMID: 32919526 DERIVED

• Piha-Paul SA, Oh DY, Ueno M, Malka D, Chung HC, Nagrial A, Kelley RK, Ros W, Italiano A, Nakagawa K, Rugo HS, de Braud F, Varga AI, Hansen A, Wang H, Krishnan S, Norwood KG, Doi T. Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies. Int J Cancer. 2020 Oct 15;147(8):2190-2198. doi: 10.1002/ijc.33013. Epub 2020 May 2.

  PMID: 32359091 DERIVED

• Strosberg J, Mizuno N, Doi T, Grande E, Delord JP, Shapira-Frommer R, Bergsland E, Shah M, Fakih M, Takahashi S, Piha-Paul SA, O'Neil B, Thomas S, Lolkema MP, Chen M, Ibrahim N, Norwood K, Hadoux J. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res. 2020 May 1;26(9):2124-2130. doi: 10.1158/1078-0432.CCR-19-3014. Epub 2020 Jan 24.

  PMID: 31980466 DERIVED

• Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3.

  PMID: 30943124 DERIVED

Related Links

• Merck Clinical Trials Information
• Plain Language Summary

MeSH Terms

Conditions

Anus Neoplasms; Biliary Tract Neoplasms; Cholangiocarcinoma; Bile Duct Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Endometrial Neoplasms; Uterine Cervical Neoplasms; Vulvar Neoplasms; Small Cell Lung Carcinoma; Mesothelioma; Thyroid Neoplasms; Salivary Gland Neoplasms; Parotid Neoplasms; Colorectal Neoplasms; Parkinson Disease 4, Autosomal Dominant Lewy Body; Microsatellite Instability

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Rectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases; Biliary Tract Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Bile Duct Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Uterine Cervical Diseases; Vulvar Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Adenoma; Neoplasms, Mesothelial; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Endocrine System Diseases; Thyroid Diseases; Mouth Neoplasms; Mouth Diseases; Stomatognathic Diseases; Salivary Gland Diseases; Parotid Diseases; Colonic Diseases; Genomic Instability; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 9, 2015
• First Posted: December 11, 2015
• Study Start: December 18, 2015
• Primary Completion (Estimated): May 4, 2027
• Study Completion (Estimated): May 4, 2027
• Last Updated: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share