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Background: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers., Methods: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance., Findings: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively., Conclusion: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Interpretation: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer., Competing Interests: Competing interests: CN reports grant support and personal fees from General Electric Healthcare, outside the submitted work. SB reports grant support from National Institutes of Health, outside the submitted work. JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, Ipsen, from null, outside the submitted work. VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work. JH reports grants from Immune Deficiency Foundation, Jeffery Modell Foundatoin and Chao Physician-Scientist, and Baxalta, and has served as an advisory board member for Takeda, CSL Behring, and Horizn Pharma outside the submitted work. AN reports research support and non-financial support from Merck Sharp & Dohme Corp., grants from NCI/NIH, research support from The University of Texas MD Anderson Cancer Center, during the conduct of the study; grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, and Surface Oncology, non-financial support for travel and accommodation from ARMO BioSciences, and has served as an advisory board member for Novartis, CytomX Therapeutics, Genome and Company, STCube Pharmaceuticals, OncoSec KEYNOTE-695, and Kymab outside the submitted work. RRC, CR, MAk, MAyoub, SA, NE, PM, POZ, RV, CP, BS, DDK declare no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite approval of immunotherapy for a wide range of cancers, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer., Methods: To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in an unbiased manner, we performed genome-wide CRISPR immune screens and integrated our results with multi-omics clinical data to evaluate the role of tumor intrinsic factors in regulating two rate-limiting steps of cancer immunotherapy, namely, T cell tumor infiltration and T cell-mediated tumor killing., Results: Our studies revealed two distinct types of immune resistance regulators and demonstrated their potential as therapeutic targets to improve the efficacy of immunotherapy. Among them, PRMT1 and RIPK1 were identified as a dual immune resistance regulator and a cytotoxicity resistance regulator, respectively. Although the magnitude varied between different types of immunotherapy, genetically targeting PRMT1 and RIPK1 sensitized tumors to T-cell killing and anti-PD-1/OX40 treatment. Interestingly, a RIPK1-specific inhibitor enhanced the antitumor activity of T cell-based and anti-OX40 therapy, despite limited impact on T cell tumor infiltration., Conclusions: Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations., Competing Interests: Competing interests: WP received honoraria and travel support from Bristol-Myers Squibb (BMS). PH is on the scientific advisory boards for Immatics, Dragonfly, Sanofi and GlaxoSmithKline (GSK). JR received consulting and/or travel fees from European Journal of Cancer, Vall d'Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GSK, Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners (including serving on the scientific advisory board from 2015 to present), received research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and served as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium and GSK. No potential conflicts of interest were disclosed by other authors., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with advanced rare cancers have poor prognosis and few treatment options. As immunotherapy is effective across multiple cancer types, we aimed to assess pembrolizumab (programmed cell death 1 (PD-1) inhibitor) in patients with advanced rare cancers., Methods: In this open-label, phase 2 trial, patients with advanced rare cancers whose tumors had progressed on standard therapies, if available, within the previous 6 months were enrolled in nine tumor-specific cohorts and a 10th cohort for other rare histologies. Pembrolizumab 200 mg was administered intravenously every 21 days. The primary endpoint was non-progression rate (NPR) at 27 weeks; secondary endpoints were safety and tolerability, objective response rate (ORR), and clinical benefit rate (CBR)., Results: A total of 127 patients treated between August 15, 2016 and July 27, 2018 were included in this analysis. At the time of data cut-off, the NPR at 27 weeks was 28% (95% CI, 19% to 37%). A confirmed objective response (OR) was seen in 15 of 110 (14%) evaluable patients (complete response in one and partial response in 14). CBR, defined as the percentage of patients with an OR or stable disease ≥4 months, was 38% (n=42). Treatment was ongoing in 11 of 15 patients with OR at last follow-up. In the cohort with squamous cell carcinoma (SCC) of the skin, the NPR at 27 weeks was 36%, ORR 31%, and CBR 38%. In patients with adrenocortical carcinoma (ACC), NPR at 27 weeks was 31%, ORR 15%, and CBR 54%. In the patients with carcinoma of unknown primary (CUP), NPR at 27 weeks was 33%, ORR 23%, and CBR 54%. In the paraganglioma-pheochromocytoma cohort, NPR at 27 weeks was 43%, ORR 0%, and CBR 75%. Treatment-related adverse events (TRAEs) occurred in 66 of 127 (52%) patients, and 12 (9%) had grade ≥3 TRAEs. The most common TRAEs were fatigue (n=25) and rash (n=17). There were six deaths, all of which were unrelated to the study drug., Conclusions: The favorable toxicity profile and antitumor activity seen in patients with SCC of skin, ACC, CUP, and paraganglioma-pheochromocytoma supports further evaluation of pembrolizumab in this patient population., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: AN reports research support and non-financial support from Merck Sharpe grants from NCI, research support from EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor, Amplimmune, Armo BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera BioSciences, TopAlliance BioSciences, Eli Lilly, Kymab, and PsiOxus, non-financial support for travel and accommodation from Armo BioSciences, and has served as an advisory board member for Novartis and CytomX Therapeutics outside the submitted work; FM-B reports grants from Novartis/Aduro, Calithera, Bayer, Jounce, CytoMx, eFFECTOR, PUMA Biotechnology, Curis, Millennium, GlaxoSmithkline, Daiichi Sankyo, Abbvie, Guardant Health, Takeda, and Aileron, personal fees for advisory from Inflection Biosciences, Darwin Health and Spectrum, personal fees for consulting from GRAIL, Clearlight Diagnostics, Dialectica, Samsung Bioepis, Aduro, Xencor, Jackson Laboratory, personal fees from OrigiMed, Kolon Life Science and Parexel International, personal fees for consulting/travel related from Pieris, Sumitomo Dainippon, and OrigMed, personal fees for advisory/travel related from Mersana, grants and personal fees for travel related from Taiho, grants and personal fees for Consulting/travel related from Genentech, Debio, and Pfizer, grants and personal fees for consulting from Zymeworks, grants and personal fees for advisory from Seattle Genetics, grants from AstraZeneca outside the submitted work; JH reports grant from Immune Deficiency Foundation, outside the submitted work; JRA reports personal fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, and Merck Sharpe, on the advisory board for Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharma, Peptomyc, Merck Sharpe & Dome, Kelun Pharma/Klus Pharma, Pfizer, Roche Pharma, and Elipses Pharma, research funding from Bayer, Novartis, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GlaxoSmithkline, Ipsen, from null, outside the submitted work. SAP-P reports grants from AbbVie, Inc., Aminex Therapeutics, BioMarin Pharmaceutical, Inc., Boehringer Ingelheim, Bristol Myers Squibb, Cerulean Pharma, Inc., Chugai Pharmaceutical Co., Ltd, Curis, Inc., Five Prime Therapeutics, Flex Bio, Inc., Genmab A/S, GlaxoSmithkline, Helix BioPharma Corp., Incyte Corp., Jacobio Pharmaceuticals Co., Ltd, Medimmune, LLC, Medivation, Inc., Merck Sharpe & Dome Corp., NewLink Genetics Corporation/Blue Link Pharmaceuticals, Novartis Pharmaceuticals, Pieris Pharmaceuticals, Inc., Pfizer, Principia Biopharma, Inc., Puma Biotechnology, Inc., Seattle Genetics, Taiho Oncology, Tesaro, Inc., Transthera Bio, and XuanZhu Biopharma, outside the submitted work; RF reports personal fees for serving on advisory board from Ayala and Regeron-Sanofi, personal fees for consultation from Cellestia, and other from Merck, outside the submitted work; MC reports personal fees for consulting from Pfizer Inc., Genentech, Inc., and Apricity Health LLC, personal fees for serving as scientific/advisory committee member from EMD Serono, Inc., and Genentech, Inc., outside the submitted work; SHS reports personal fees from Angiodynamics, non-financial support from Neuwave Medical, Medtronic, and Merit Medical, outside the submitted work; CT reports salary support from Merck, during the conduct of the study; salary support from Merck, and for contract work to perform correlatives from Armo Bioscience, outside the submitted work; MF reports personal fees and non-financial support for speaking engagements and research funding from Stryker, personal fees for serving on advisory board from Biom’Up, Genetech, and Ipsen, outside the submitted work; VS reports clinical trial research funding from Novartis, Bayer, GlaxoSmithkline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Takeda and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, outside the submitted work; DSH reports research/grant funding from Abbvie, Adaptimmune, Amgen, Astra-Zeneca, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genmab, Ignyta, Kite, Kyowa, Lilly, Medimmune, Merck, Merrimack, Mirati, MIRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer; personal fees from Axiom, Baxter, GLG, Group H, Guidepoint Global, Jannsen, Medscape, Numab, Trieza Therapeutics; research/grant funding and personal fees from Bayer, Genentech, Infinity, LOXO, Seattle Genetics, Takeda; and other from Molecular Match, OncoResponse, Presagia Inc, during the conduct of the study; SP reports personal fees and other for financial relationship/speakers bureau consultant from Tyme, Inc., and 4-D Pharma, outside the submitted work; TAY reports personal fees and other for research support, consulting, speakers bureau from AstraZeneca and Pfizer, personal fees and other for research support, consulting from Bayer, Seattle Genetics, and Vertex Pharmaceuticals, personal fees and other for research support, speakers bureau from Tesaro, personal fees for consultant, speakers bureau from Merck, research support from Jounce, Eli Lilly and Kyowa, personal fees for consultant services from Aduro, Almac, Atrin, Bristol-Meyers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, Ignyta, Jansen, and Roche, outside the submitted work; AMT reports grants from NIH/NCI, during the conduct of the study; grants from EMD Serono, Boston Biomedical, Inc., Verastem Oncology, Karus Therapeutics, Ltd., Immatics Biotechnologies, CPRIT, Tvardi Therapeutics, OBI Pharma, Parker Institute, Tempus, Foundation Medicine, and Placon Therapeutics, for consulting/advisory role from Genentech, Roche Europe, and Covance, outside the submitted work; FJ reports grants from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Piqur, Symphogen, Bayer, and Fujifilm Corporation and Upsher-Smith Laboratories, research funding & SAB from Deciphera, SAB from IFM Therapeutics, Synlogic, Gaurdant Health, services as paid consultant & ownership interests in Trovagene, and paid consultant in Immunomet, outside the submitted work; SF reports clinical trial research support from Polaris Pharmaceuticals, Inc., Takeda., Lilly, Astra Zeneca, Endocyte, Novartis NIH/NCI, Aprea Therapeutics, Aneropharma Science, OncoMed Pharmaceuticals, Huya Bioscience International, Parexel International, LLC, Medivir AB, New Pharma, Inc, BioAtla LLC, MacroGenics, BeiGene, IMV, Inc, and Tolero Pharmaceuticals, outside the submitted work; RMS reports fees for consulting services from Amgen, Bristol-Myers Squibb, Jansen, Abbvie, Pfizer, Innocrin Therapeutics, Tessa Therapeutics during the conduct of the study; MAH reports grants from Exelixis Inc, grants and personal fees from Eisai Inc, and HRA Pharma, outside the submitted work. BS, DDK, RRC, CJ, KPR, S-MT, LW, CB, NT, VR, SK, JMP, AA (Abonofal), JG, AA (Alshawa), LMM, MX, SA, EEID, KRH, and GRV declare no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS - and BRAF -mutated cell lines including BRAF -mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively ( N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue ( n = 15), nausea ( n = 12), dermatitis acneiform ( n = 10), decreased appetite ( n = 7), and maculopapular rash ( n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed., (©2019 American Association for Cancer Research.)