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While many patients are treated beyond progression (TBP), the magnitude and duration of clinical benefit in these patients have not been fully quantified. Data from 799 patients with melanoma (n = 176), non-small cell lung cancer (NSCLC; n = 146), gastric cancer (GC; n = 87), head and neck squamous cell carcinoma (HNSCC; n = 112), clear-cell renal cell carcinoma (ccRCC; n = 51), and urothelial carcinoma (UC; n = 227) TBP were included. Patients had received pembrolizumab beyond confirmed progressive disease (PD) per RECIST v1.1. A subset of patients displays a 30% reduction in the sum of lesion diameters in the post-progression period (melanoma 24.4%, NSCLC 11.6%, 12.6% GC, 8.9% HNSCC, 15.7% ccRCC, and 13.2% UC). Most patients show stable target lesion dynamics in the post-progression period (melanoma, 64.8%; NSCLC, 72.6%; GC, 69.0%, 75.9% HNSCC, 72.5% ccRCC, 75.3% UC). Pembrolizumab generates meaningful efficacy in a subset of patients treated beyond RECIST v1.1 progression., Competing Interests: Declaration of interests B.G.T. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. M.C. has nothing to disclose. K.M. is a stockholder of Merck & Co., Inc., Rahway, NJ, USA, and holds a leadership role (Vice President, Clinical Pharmacology, Clinical Development) at Generate Biomedicines. DPd.A. is a stockholder of Merck & Co., Inc., Rahway, NJ, USA, and holds a leadership role (Senior Vice President, Clinical Drug Development) at Generate Biomedicines. E.R. is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; owns stock in Merck & Co., Inc., Rahway, NJ, USA; and holds a leadership role (Senior Vice President, Clinical Oncology) at Merck & Co., Inc., Rahway, NJ, USA. A.S. reports advisory/consultancy to Two River, Inc, holds a leadership role at Generate Biomedicines (CMO), and is an officer/on the board of directors for Navigating Cancer. J.D.W. reports a role of consultant for Adaptive Biotech, Amgen, Apricity, Ascentage Pharma, Astellas, AstraZeneca, Bayer, Beigene, Bristol Myers Squibb, Celgene, Chugai, Eli Lilly and Company, F Star, Imvaq, Kyowa Hakko Kirin, Linneaus, MedImmune, Merck, Neon Therapeutics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Takara Bio, Trieza, Truvax, Serametrix, Surface Oncology, Syndax, and Syntalogic; research support from AstraZeneca and Bristol Myers Squibb; and equity in Adaptive Biotechnologies; BeiGene; Imvaq; Linneaus; Potenza Therapeutics; Tizona Pharmaceuticals; and Trieza. A.R. reports leadership for PACT Pharma, Arcus Biosciences, and Lutris; stock and other ownership interests for Compugen, CytomX Therapeutics, Advaxis, Acrus Biosciences, Tango Therapeutics, PACT Pharma, Merus, ImaginAb, Lutris Pharma, Highlight, MapKure, 4c Biomked, Kite/Gilead, Isoplexis, Appia, Synthekine, Pluto, Inspirna, RAPT Therapeutics, and ImmPACT-Bio; honoraria from Merck Sharp & Dohme, Novartis, Amgen, Chugai/Roche, Genentech/Roche, Sanofi, Vedanta Biosciences, and AstraZeneca; a consulting or advisory role for Merck, Amgen, Novartis, Chugai Pharma, and Sanofi; research funding to institution from Agilent and Bristol Myers Squibb; and patents, royalties, other intellectual property for nonviral gene editing to Arsenal Bio., (Copyright © 2023 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier Inc. All rights reserved.)

A quantitative systems pharmacology model for metastatic melanoma was developed for immuno-oncology with the goal of predicting efficacy of combination checkpoint therapy with pembrolizumab and ipilimumab. This literature-based model is developed at multiple scales: (i) tumor and immune cell interactions at a lesion level; (ii) multiple heterogeneous target lesions, nontarget lesion growth, and appearance of new metastatic lesion at a patient level; and (iii) interpatient differences at a population level. The model was calibrated to pembrolizumab and ipilimumab monotherapy in patients with melanoma from Robert et al., specifically, waterfall plot showing target lesion response and overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), which additionally considers nontarget lesion growth and appearance of new metastatic lesions. We then used the model to predict waterfall and RECIST version 1.1 for combination treatment reported in Long et al. A key insight from this work was that nontarget lesions growth and appearance of new metastatic lesion contributed significantly to disease progression, despite reduction in target lesions. Further, the lesion level simulations of combination therapy show substantial efficacy in warm lesions (intermediary immunogenicity) but limited advantage of combination in both cold and hot lesions (low and high immunogenicity). Because many patients with metastatic disease are expected to have a mixture of these lesions, disease progression in such patients may be driven by a subset of cold lesions that are unresponsive to checkpoint inhibitors. These patients may benefit more from the combinations which include therapies to target cold lesions than double checkpoint inhibitors., (© 2021 Merck Sharp & Dohme Corporation & Vantage Research LLC. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy. This revised model structure provided a framework to efficiently evaluate the impact of covariates and pembrolizumab exposure. Both models indicated that exposure to the drug was not a significant predictor of tumor size response, demonstrating that the dose range evaluated (2 and 10 mg/kg every 3 weeks) is likely near or at the plateau of maximal response., (© 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)