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Background: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past., Patients and Methods: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion Torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3)., Results: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs., Conclusion: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs., Competing Interests: Competing interests: TL was employed as a research scientist by Thermo Fisher Scientific during the time of study. JH declares research funding from The Texas Medical Center Digestive Diseases Center, Jeffery Modell Foundation, Immune Deficiency Foundation, Baxalta US Inc, Chao Physician-Scientist Foundation, is Consultant/Advisory board: Takeda, Pharming Healthcare Inc, and Horizon Therapeutics USA, Inc. and Ad hoc consultancy speaker: Alfaisal University. SS is a full-time employee of Thermo Fisher Scientific, Inc. DYD received honorarium from Chrysalis Biomedical. JMC is an employee of OmniSeq and shareholder of Labcorp. SPP declares institutional funding for clinical trial from NCI, Bristol Myers Squibb, Novartis, Consulting fees: Immunocore; Payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events: Delcath (non-promotional), Merck & Co (non-promotional), Support for attending meetings and/or travel: Merck & Co, Cardinal Health, TriSalus LifeSciences, Participation on a Data Safety Monitoring Board or Advisory Board: Reata, Immunocore, Immatics, Bristol Myers Squibb, Cardinal Health, Castle Biosciences, Delcath, Novartis, Stock or stock options: Pfizer, Amgen. YY reports personal fees from AbbVie, personal fees from Amgen, personal fees from Bexion Pharmaceuticals, personal fees from BeyondSpring Pharmaceuticals, personal fees from Boehringer Ingelheim Pharmaceuticals, personal fees from Bristol Myers Squibb, personal fees from Century Therapeutics, personal fees from Enliven Therapeutics, personal fees from Repare Therapeutics, personal fees from Servier Pharmaceuticals, personal fees from Starpax Pharmaceuticals, personal fees from Vertex Pharmaceuticals, during the conduct of the study. JRA is on the advisory board of Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA, declares research funding (to institution): Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, Vall d'Hebron Institute of Oncology/Cancer Core Europe, clinical research (to institution): Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati Linnaeus Therapeutics, travel reimbursement: European Society for Medical Oncology and Other: Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC. SF receives Clinical Trial Research Support/Grant Funding through the institution from the following sources: NIH/NCI P30CA016672 – Core Grant (CCSG Shared Resources); Abbisko; BeiGene; BioAtla, LLC.; Boehringer Ingelheim; CUE Biopharma, Inc.; Eli Lilly & Co.; Exelisis; Greenfire Bio, Inc.; Hookipa Biotech; IMV, Inc.; Innovent Biologics, Co., Ltd.; K-Group Beta; Lyvgen Biopharm, Co., Ltd.; MacroGenics; MediLink Therapeutics, Co. Ltd.; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; NeuPharma, Inc.; NextCure, Inc.; Ningbo NewBay Technology Development Co., Ltd.; Novartis; NovoCure; Nykode Therapeutics AS.; Parexel International, LLC; Pionyr Immunotherapeutics, Inc.; PureTech Health, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; SQZ Biotechnologies; Sumitomo Dainippon; Taiho Oncology and NCCN; Treadwell Therapeutics; Turnstone Biologics; Tyligand Bioscience, Ltd.; Virogin Biotech, Ltd. FM-B (36 months) declares: consulting <5,000/year: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks, advisory committee <5,000/year: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis, sponsored research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co., honoraria <5,000/year: Chugai Biopharmaceuticals, and other (travel related): none. GML is an employee/shareholder of Thermo Fisher Scientific. AN declares research funding from NCI, EMD Serono, MedImmune, Healios Onc. Nutrition, Atterocor/Millendo, 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, Immune-Onc Therapeutics, Surface Oncology, Monopteros Therapeutics, BioNTech SE, Seven & Eight Biopharma, and SOTIO Biotech AG, on advisory board/Consulting fees from Deka Biosciences, NGM Bio, PsiOxus Therapeutics, Immune-Onc Therapeutics, STCube Pharmaceuticals, OncoSec KEYNOTE-695, Genome & Company, CytomX Therapeutics, Nouscom, Merck Sharp & Dohme Corp, OncoNano, Servier, Lynx Health, AbbVie, PsiOxus, received travel and accommodation expense from ARMO BioSciences, NeoImmuneTech and honoraria for speaking engagements from AKH Inc, The Lynx Group, Society for Immunotherapy of Cancer (SITC), Korean Society of Medical Oncology (KSMO), Scripps Cancer Care Symposium, ASCO Direct Oncology Highlights, European Society for Medical Oncology (ESMO), CME Outfitters. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pituitary carcinoma is an aggressive tumor characterized by metastatic spread beyond the sellar region. Symptoms can be debilitating due to hormonal excess and survival is poor. Pituitary carcinomas recur despite conventional multimodality treatments. Given the recent advances in the use of immune checkpoint inhibitors (CPIs) to treat various solid cancers, there has been interest in exploring the role of immunotherapy for treating aggressive, refractory pituitary tumors. We treated 4 patients with pituitary carcinoma with pembrolizumab as part of a phase II clinical trial. Two patients (patients 1 and 2) with functioning corticotroph pituitary carcinomas (refractory to surgery, radiotherapy and chemotherapy) had partial radiographic (60% and 32% per Immune-Related Response Evaluation Criteria In Solid Tumors, respectively) and hormonal responses. Patient 1's response continues 42 months after initiation of pembrolizumab and his tumor tissue obtained after treatment with temozolomide demonstrated a hypermutator phenotype with MSH2 and MSH6 gene mutations. Patient 2's tumor after exposure to temozolomide was not sampled, but prior somatic mutational testing was negative. One patient with a non-functioning corticotroph tumor (patient 3) had a best response of stable disease for 4 months. One patient with a prolactin-secreting carcinoma (patient 4) had progressive disease. The latter 2 patients' tumors did not demonstrate a hypermutator phenotype after treatment with temozolomide. Programmed death-ligand 1 staining was negative in all tumors. We report 2 cases of corticotroph pituitary carcinoma responsive to pembrolizumab after prior exposure to alkylating agents. The role of CPIs in treating patients with pituitary carcinoma, the relationship between tumor subtype and response to immunotherapy and mechanisms of hypermutation in this orphan disease require further study.Trial registration number: NCT02721732., Competing Interests: Competing interests: No, there are 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.)

Background: Decreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab., Methods: A total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors., Results: A decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies., Conclusion: Patients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies., Trial Registration Number: NCT02721732., Competing Interests: Competing interests: Merck was the sponsor of the drug pembrolizumab. CT had salary support on this study., (© 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.)

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.)