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Stereotactic ablative body radiation (SABR) delivers high rates of local control in early-stage non-small cell lung cancer (NSCLC); however, systemic immune effects are poorly understood. Here, we evaluate the early pathologic and immunologic effects of SABR. Blood/core-needle tumor biopsies were collected from six patients with stage I NSCLC before and 5-7 days after SABR (48 Gy/4 or 50 Gy/5 fractions). Serial blood was collected up to 1-year post-SABR. We used immunohistochemistry to evaluate pathological changes, immune-cell populations (CD8, FoxP3), and PD-L1/PD-1 expression within the tumor. We evaluated T-cell receptor (TCR) profile changes in the tumor using TCR sequencing. We used the MANAFEST (Mutation-Associated Neoantigen Functional Expansion of Specific T-cells) assay to detect peripheral neoantigen-specific T-cell responses and dynamics. At a median follow-up of 40 months, 83% of patients (n=5) were alive without tumor progression. Early post-SABR biopsies showed viable tumor and similar distribution of immune-cell populations as compared with baseline samples. Core-needle samples proved insufficient to detect population-level TCR-repertoire changes. Functionally, neoantigen-specific T-cells were detected in the blood prior to SABR. A subset of these patients had a transient increase in the frequency of neoantigen-specific T-cells between 1 week and 3-6 months after SABR. SABR alone could induce a delayed, transient neoantigen-specific T-cell immunologic response in patients with stage I NSCLC., Competing Interests: Competing interests: KRV has received consulting from AstraZeneca; CH has received consulting fees from Johnson & Johnson and D1 Medical Technology; PTT has received consulting fees from RefleXion Medical Inc, Natsar Pharm, Bayer Healthcare, Regeneron & J&J, has a patent (9114158) licensed to Natsar Pharmaceuticals; JRB receives research funding from AstraZeneca and BMS. CT receives research grants from Siemens Medical Solutions and Carestream Health; JRB has advisory board or consulting agreements with Amgen, AstraZeneca (AZ), Bristol-Myers Squibb (BMS), Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi, Regeneron, Janssen, Johnson & Johnson and Data and Safety Monitoring Board (DMSB) relationships with Janssen; PMF receives research funding from AstraZeneca, BMS, Novartis, Regeneron, Kyowa, BioNTech. PMF has advisory board or consulting agreements with AstraZeneca, AbbVie, Amgen, BMS, Novartis, Genentech, Sanofi, Surface, Janssen, G1, Merck and DSMB relationships with Polaris, Flame. JN receives consulting fees from AZ, Roche, Amgen, BMS, Mirati, Merck, Arcus Biosciences, AbbVie, Daiichi Sankyo, Elevation Oncology, Bayer, NGM Pharmaceutical, Regeneron, Pfizer, Takeda, Kaleido Biosciences. JN has DSMB relationships with AZ, BMS, Daiichi Sankyo; VA receives research funding to Johns Hopkins University from AstraZeneca, Personal Genome Diagnostics and Delfi Diagnostics and has received research funding to Johns Hopkins University from Bristol-Myers Squibb in the past 5 years. VA is an inventor on patent applications (63/276,525, 17/779,936, 16/312,152, 16/341,862, 17/047,006 and 17/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that have been licensed to one or more entities. Under the terms of these license agreements, the University and inventors are entitled to fees and royalty distributions; KNS has filed for patent protection on the MANAFEST technology (serial No. 16/341,862), has received travel support/honoraria from Illumina, Inc., receives research funding from Bristol-Myers Squibb, Anara, and AstraZeneca, and owns founder’s equity in ManaT Bio, Inc. The terms of these arrangements are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies., (© 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.)

Background: Combination therapies that aim to improve the clinical efficacy to immune checkpoint inhibitors have led to the need for non-invasive and early pharmacodynamic biomarkers. Positron emission tomography (PET) is a promising non-invasive approach to monitoring target dynamics, and programmed death-ligand 1 (PD-L1) expression is a central component in cancer immunotherapy strategies. [ 18 F]DK222, a peptide-based PD-L1 imaging agent, was investigated in this study using humanized mouse models to explore the relationship between PD-L1 expression and therapy-induced changes in cancer., Methods: Cell lines and xenografts derived from three non-small cell lung cancers (NSCLCs) and three urothelial carcinomas (UCs) were used to validate the specificity of [ 18 F]DK222 for PD-L1. PET was used to quantify anti-programmed cell death protein-1 (PD-1) therapy-induced changes in PD-L1 expression in tumors with and without microsatellite instability (MSI) in humanized mice. Furthermore, [ 18 F]DK222-PET was used to validate PD-L1 pharmacodynamics in the context of monotherapy and combination immunotherapy in humanized mice bearing A375 melanoma xenografts. PET measures of PD-L1 expression were used to establish a relationship between pathological and immunological changes. Lastly, spatial distribution analysis of [ 18 F]DK222-PET was developed to assess the effects of different immunotherapy regimens on tumor heterogeneity., Results: [ 18 F]DK222-PET and biodistribution studies in mice with NSCLC and UC xenografts revealed high but variable tumor uptake at 60 min that correlated with PD-L1 expression. In MSI tumors treated with anti-PD-1, [ 18 F]DK222 uptake was higher than in control tumors. Moreover, [ 18 F]DK222 uptake was higher in A375 tumors treated with combination therapy compared with monotherapy, and negatively correlated with final tumor volumes. In addition, a higher number of PD-L1+ cells and higher CD8 + -to-CD4 + cell ratio was observed with combination therapy compared with monotherapy, and positively correlated with PET. Furthermore, spatial distribution analysis showed higher [ 18 F]DK222 uptake towards the core of the tumors in combination therapy, indicating a more robust and distinct pattern of immune cell infiltration., Conclusion: [ 18 F]DK222-PET has potential as a non-invasive tool for monitoring the effects of immunotherapy on tumors. It was able to detect variable PD-L1 expression in tumors of different cancer types and quantify therapy-induced changes in tumors. Moreover, [ 18 F]DK222-PET was able to differentiate the impact of different therapies on tumors., Competing Interests: Competing interests: SN, MGP and DK are co-inventors on pending patents covering [18F]DK222, and as such are entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement was reviewed and approved by Johns Hopkins University in accordance with its conflict-of-interest policies. SN, MGP and SPR received funding and were consultants for Precision Molecular, Inc., the licensee of [18F]DK222. SN, MGP and SPR have equity in D&D Pharmatech, the parent company of Precision Molecular, Inc. All other authors declare no conflicts pertaining to the described work., (© 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.)

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade., Competing Interests: Competing interests: TZ reports grants or contracts from Acerta, Novartis, Merrimack, Abbvie/StemCentrx, Merck, Regeneron, Mirati Therapeutics, Janssen, AstraZeneca, Pfizer, OmniSeq, Personal Genome Diagnostics, Astellas, Eli Lilly, Exelixis, BMS, and Tempus; advisory board/consulting fees from Merck, Exelixis, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Amgen, BMS, Pharmacyclics, SeaGen, Calithera, QED Therapeutics, Eisai, Aveo, Eli Lilly, Aravive, and Bayer; honoraria from MJH Associates, Vaniam, Aptitude Health, Peerview, Clinical Care Options, KCA, SIU, and ASCO; all unrelated to submitted work. DB reports grants from BMS, Exelixis, AVEO Pfizer, Eisai, EMD Serono, leadership or fiduciary role in KCCure (President), NCI GU Steering Committee, and Alliance Cooperative Group GU Committee, all outside the submitted work. WS reports support for the present manuscript from LUNGevity Foundation paid to her company WSCollaborative. Outside the submitted publication, she reports consulting fees from LUNGevity Foundation, National Brain Tumor Society, Ovarian Cancer Research Alliance, Cholangiocarcinoma Foundation, Pfizer, Daiichi Sankyo, Target Cancer Foundation, CancerCare, Childhood Cancer Coalition, and TriSalus Life Sciences paid to her company; honoraria from American Institutes of Cancer Research; leadership or fiduciary role in Rising Tide Foundation for Clinical Cancer Research; and owns stock in TriSalus Life Sciences. EB reports grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech, Johnson&Johnson, Merck (MSD), and Natera outside the submitted work. RJS reports grants from Merck, loyalty to Up-to-date, consulting fees from AstraZeneca, Merck, BMS, Novartis, Eisai, Pfizer, and Iovance; and participation on a data safety monitoring/advisory board for Yale and Duke Universities, all outside the submitted work. MBA reports grants from the NCI (P30CA051008, R21CA270585, P50CA101942, R01CA231291, and DoD (KC170216), consultant fees from BMS, Merck, Novartis, Eisai, Aveo, Pfizer, Werewolf, Fathom, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda, Roche, SAB Bio, Exelixis, Iovance, COTA, Idera, Agenus, Asher Bio, AstraZeneca, Calithera, SeaGen, Sanofi, OncoRena, and GSK; honoraria from Medscape, OncLive, PRIME, Clinical Education Alliance, LivDerm, and ASCO; participation on a data safety monitoring board or advisory board for Novartis, BMS, Pfizer, SIMCHA, Genentech/Roche, and Melanoma Research Foundation; and owns stock in Werewolf, Pyxis Oncology, and Elpis, all outside the submitted work. PMF reports research funding to his affiliated institution from AstraZeneca, BMS, Corvus, Kyowa, Novartis, and Regeneron; consultant fees from Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Genentech, Janssen, Iteos, Merck, Sanofi, Novartis, and Surface; and participation on a data safety monitoring board for Polaris, outside the submitted work. GF owns stock in Bristol Myers Squibb and works for BMS. MSH is the CEO of the Melanoma Research Alliance. SE is an employee of Merck&Co. The remaining authors report 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.)

Definitive management of locoregionally advanced solid tumors presents a major challenge and often consists of a combination of surgical, radiotherapeutic and systemic therapy approaches. Upfront surgical treatment with or without adjuvant radiotherapy carries the risks of significant morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of local or distant disease relapse despite the use of standard adjuvant therapy. Preoperative neoadjuvant systemic therapy has the potential to significantly improve clinical outcomes, particularly in this era of expanding immunotherapeutic agents that have transformed the care of patients with metastatic/unresectable malignancies. Tremendous progress has been made with neoadjuvant immunotherapy in the treatment of several locoregionally advanced resectable solid tumors leading to ongoing phase 3 trials and change in clinical practice. The promise of neoadjuvant immunotherapy has been supported by the high pathologic tumor response rates in early trials as well as the durability of these responses making cure a more achievable potential outcome compared with other forms of systemic therapy. Furthermore, neoadjuvant studies allow the assessment of radiologic and pathological responses and the access to biospecimens before and during systemic therapy. Pathological responses may guide future treatment decisions, and biospecimens allow the conduct of mechanistic and biomarker studies that may guide future drug development. On behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group, this article summarizes the current state of neoadjuvant immunotherapy of solid tumors focusing primarily on locoregionally advanced melanoma, gynecologic malignancies, gastrointestinal malignancies, non-small cell lung cancer and head and neck cancer including recent advances and our expert recommendations related to future neoadjuvant trial designs and associated clinical and translational research questions., Competing Interests: Competing interests: AAT reports grants from Bristol Myers Squib, grants from Genentech-Roche, grants from Regeneron, grants from Sanofi-Genzyme, grants from Nektar, grants from Clinigen, grants from Merck, grants from Acrotech, grants from Pfizer, grants from Checkmate, grants from OncoSec, personal fees from Bristol Myers Squibb, personal fees from Merck, personal fees from Easai, personal fees from Instil Bio, personal fees from Clinigin, personal fees from Regeneron, personal fees from Sanofi-Genzyme, personal fees from Novartis, personal fees from Partner Therapeutics, personal fees from Genentech/Roche, personal fees from BioNTech, outside the submitted work. RLF reports grants from AstraZeneca/MedImmune, grants from Bristol Myers Squibb, grants from Merck, grants from Novasenta, grants from Tesaro, stock from Novasenta, personal fees from Aduro Biotech, personal fees from Bicara Therapeutics, personal fees from Bristol Myers Squibb, personal fees from Brooklyn Immunotherapeutics, personal fees from Catenion, personal fees from Coherus BioSciences, personal fees from Everest Clinical Research Corporation, personal fees from F. Hoffmann-La Roche, personal fees from Genocea Biosciences, personal fees from Hookipa Biotech, personal fees from Instil Bio, personal fees from Kowa Research Institute, personal fees from Lifescience Dynamics Limited, personal fees from MacroGenics, personal fees from Merck, personal fees from Mirati Therapeutics, personal fees from Mirror Biologics, personal fees from Nanobiotix, personal fees from Novasenta, personal fees from Numab Therapeutics AG, personal fees from OncoCyte Corporation, personal fees from Pfizer, personal fees from PPD Development LP, personal fees from Rakuten Medical, personal fees from Sanofi, personal fees from Seagen, personal fees from Vir Biotechnology, personal fees from Zymeworks, outside of the submitted work. KNM reports advisory board participation and reimbursement from Aravive, Alkemeres, AstraZeneca, Blueprint pharma, Eisai, EMD/Serono, GSK/Tesaro, Genentech/Roche, Hengrui, Immunogen, IMXmed, IMab, Lilly, Mersana, Mereo, Myriad, Merck, Novarits, OncXerna, Onconova, VBL Therapeutics. Research funding from PTC therapeutics, Lilly, Merck, GSK/Tesaro. GOG Partners Associate director. VT-L does not have any competing interest to report. PMF reports advisory board participation and reimbursement from Amgen, AstraZeneca, BMS, Daiichi, F-Star, G1, Genentech, Iteos, Janssen, Merck, Novartis, Sanofi, Surface, and research grants to his institution from AstraZeneca, BioNTech, BMS, Corvus, Kyowa, Novartis, and Regeneron. JRE reports employment at Bristol Meyers Squibb (spouse) and Janssen (spouse), honoraria for Pfizer, consulting for Lexicon, advisory boards for Ipsen, Advanced Accelerator Applications, and research support from Xencor, Tarveda, Genentech, Amgen, AstraZeneca, Medimmune, Hutchison, Incyte, Oncolys, Seagen. Neither JW nor members of his immediate family have a financial interest or obligation related to the information transmitted in this publication. None of them have received any compensation, salary, gifts, promises of employment or reimbursement for travel., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite treatment advancements with immunotherapy, our understanding of response relies on tissue-based, static tumor features such as tumor mutation burden (TMB) and programmed death-ligand 1 (PD-L1) expression. These approaches are limited in capturing the plasticity of tumor-immune system interactions under selective pressure of immune checkpoint blockade and predicting therapeutic response and long-term outcomes. Here, we investigate the relationship between serial assessment of peripheral blood cell counts and tumor burden dynamics in the context of an evolving tumor ecosystem during immune checkpoint blockade., Methods: Using machine learning, we integrated dynamics in peripheral blood immune cell subsets, including neutrophil-lymphocyte ratio (NLR), from 239 patients with metastatic non-small cell lung cancer (NSCLC) and predicted clinical outcome with immune checkpoint blockade. We then sought to interpret NLR dynamics in the context of transcriptomic and T cell repertoire trajectories for 26 patients with early stage NSCLC who received neoadjuvant immune checkpoint blockade. We further determined the relationship between NLR dynamics, pathologic response and circulating tumor DNA (ctDNA) clearance., Results: Integrated dynamics of peripheral blood cell counts, predominantly NLR dynamics and changes in eosinophil levels, predicted clinical outcome, outperforming both TMB and PD-L1 expression. As early changes in NLR were a key predictor of response, we linked NLR dynamics with serial RNA sequencing deconvolution and T cell receptor sequencing to investigate differential tumor microenvironment reshaping during therapy for patients with reduction in peripheral NLR. Reductions in NLR were associated with induction of interferon-γ responses driving the expression of antigen presentation and proinflammatory gene sets coupled with reshaping of the intratumoral T cell repertoire. In addition, NLR dynamics reflected tumor regression assessed by pathological responses and complemented ctDNA kinetics in predicting long-term outcome. Elevated peripheral eosinophil levels during immune checkpoint blockade were correlated with therapeutic response in both metastatic and early stage cohorts., Conclusions: Our findings suggest that early dynamics in peripheral blood immune cell subsets reflect changes in the tumor microenvironment and capture antitumor immune responses, ultimately reflecting clinical outcomes with immune checkpoint blockade., Competing Interests: Competing interests: VA receives research funding to her institution from Bristol-Myers Squibb and Astra Zeneca. PMF has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Novartis, Corvus, Kyowa. He has also served as a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Iteos, Janssen, Mirati, Novartis, Sanofi and as a DSMB member for Polaris and Flame Therapeutics. KNS receives research funding to her institution from Bristol-Myers Squibb, Astra Zeneca, and Enara Bio, and holds founder’s equity in manaT Bio. VEV is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the Board of Directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy. Additionally, Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. VEV is an inventor of multiple licensed patents related to technologies from Johns Hopkins University. Some of these licenses and relationships are associated with equity or royalty payments directly to Johns Hopkins and VEV. VEV is an advisor to Bristol-Myers Squibb, Danaher, Genentech, and Takeda Pharmaceuticals. Within the last five years, VEV has been an advisor to Merck and Ignyta. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. JW is a consultant for Personal Genome Diagnostics, is the founder and owner of Resphera Biosciences and holds patents, royalties or other intellectual property from Personal Genomic Diagnostics. JER is in the advisory board/consultant of Oncocyte, receives speaking fees for Astrazeneca, and has received research funding to his institution from Genetech/Roche, and Verastem. JB is in the advisory board/consultant of Amgen, AstraZeneca, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron, receives grant research funding from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Inc and Revolution Medicines and is in the Data and Safety Monitoring Board/Committees of GlaxoSmithKline, Sanofi and Janssen. TS is in the advisory board/consultant of Cue Biopharma, Dracen, Innate, Nanobiotix, Merck, Sanofi, Synthekine, receives grant research funding from AstraZeneca, BMS, Cue Biopharma, Genentech/Roche, Merck, Nanobiotix, Synthekine, and is in the Data and Safety Monitoring Board/Committees of Astra Zeneca, and Nektar. VL has received research funding to his institution from AstraZeneca, Bristol-Myers Squibb, Merck, SeaGen. He has also served as a consultant for Takeda, SeaGen, Bristol-Myers Squibb, AstraZeneca, and Guardant Health., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)- either as monotherapy or in combination with other ICIs or chemotherapy-have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC's 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma., Competing Interests: Competing interests: CA—Consulting fees: AstraZeneca, Celgene, Eli Lilly, Genetech, Merck. SJA—Advisory board: Bristol Myers Squibb, Celsius, Merck, Samyang Biopharma, AstraZeneca/Medimmune; Consultant: Bristol Myers Squibb, Celsius, Merck, Samyang Biopharma, AstraZeneca/Medimmune, CBMG, Memgen, RAPT, Venn, Achilles Therapeutics, GlaxoSmithKline, Amgen; Scientific advisory board: CBMG, Memgen, RAPT, Venn, Achilles Therapeutics, GlaxoSmithKline, Amgen. MD—Speaker bureaus: Genentech, Merck, Bristol Myers Squibb and AstraZeneca (all have been discontinued as of November 2019). SMD—Scientific advisory boards: Johnson & Johnson Scientific, T-Cure Bioscience, LungLife AI, Early Diagnostics; Contracted research: Jansen. PMF—Consulting fees: Amgen, AstraZeneca, Bristol Myers Squibb, Iteos, Novartis, Janssen; Contracted research: AstraZeneca, Bristol Myers Squibb, Kyowa, Novartis; DSMB: Polaris, Flame. EBG—Consulting fees: ABL-Bio, Boehringer Ingelheim, Bristol Myers Squibb, Dracen, EMD Serono, Eisai, GlaxoSmithKline, Merck, Novartis; Contracted research: AstraZeneca, Bristol Myers Squibb, Dynavax, EMD Serono, Eli Lilly, Genentech, Merck, Iovance Biotherapeutics, Mirati Therapeutics, Neon, Novartis. SBG—Consulting fees: AstraZeneca, Blueprint Medicine, Bristol Myers Squibb, Boehringer Ingelheim, Genentech, Sanofi Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen; Contracted research: AstraZeneca, Boehringer Ingelheim. RG—Consulting fee: Achilles, GenePlus, Inivata, Roche. RH—Contracted research: My institution receives funds for conducting clinical trials from Bayer and TCR2 under a cooperative research and development agreement with NCI. MDH—Consulting fees: Merck, Bristol Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, Arcus; Contracted research: Bristol Myers Squibb; IP rights: A patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx; Ownership interest: Arcus, Shattuck Labs, Immunai. RSH—Consulting fees: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bolt Biotherapeutics, Bristol Myers Squibb, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologic, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck and Company; Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Ribbon Therapeutics, Ventana Medical Systems, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, WindMIL Therapeutics, Xencor; Contracted research: AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company; Board member (non-executive/independent): Immunocore Holdings Limited, Junshi Pharmaceuticals. FRH—Consulting fees: Merck, Bristol Myers Squibb, Genentech/Roche, Lilly/Loxo, Daiichi, Novartis, AstraZeneca, Boehringer Ingelheim, OncoCyte, Amgen, Sanofi/Regeneron; Contracted research through University of Colorado: Amgen, AbbVie, Biodesix, Rain Therapeutics, Aurora Oncology, Mersana; IP rights through University of Colorado: EGFR protein and EGFR Gene Copy Number as Predictive Biomarker for EGFR Therapy. MLJ—Consulting fees – all payments made to my institution: Achilles Therapeutics, Amgen, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, EMD Serono, G1 Therapeutics, Roche/Genentech, GlaxoSmithKline, Gritstone, Incyte, Janssen, Lilly, Merck, Mirati, Novartis, Pfizer, Sanofi-Aventis, WindMIL Therapeutics; Contracted research – all payments made to my institution: AbbVie, Adaptimmune, Amgen, Apexigen, Array Biopharma, AstraZeneca, Atreca, BeiGene, BerGenBio, Boehringer Ingelheim, Calithera, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Lilly, EMD Serono, Roche/Genentech, Genmab, Genocea, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce, Mirati, Neovia Oncology, Novartis, Pfizer, Regeneron, Sanofi, Shattuck Labs, Syndax, Takeda, Tarveda, University of Michigan, WindMIL Therapeutics, TCR2 Therapeutics, Arcus, Ribon, Rubius Therapeutics, Tmunity Therapeutics, Seven and Eight Biosciences, Foundation Medicine; Partner consulting Fees: Otsuka. DM—Consulting fees: Gilead, G1 Therapeutics, AbbVie. JWN—Grants and personal fees: Takeda (during the conduct of the study), AstraZeneca; Grants (non-financial support): Genentech/Roche, Exelixis, Jounce Therapeutics, Eli Lilly and Company, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera; Grants and non-financial support: Merck, Novartis, Boehringer Ingelheim, Nektar Therapeutics, Adaptimmune, GSK, Janssen, AbbVie. JDP—Consulting fees: AstraZeneca, AbbVie, Takeda; Contracted research: Bristol Myers Squibb, Takeda, RAIN. DLR—Consulting fees: AstraZeneca, Agendia, Amgen, BMS, Cell Signaling Technology, Cepheid, Danaher, Daiichi Sankyo, Genoptix/Novartis, GSK, Konica Minolta, Merck, NanoString, PAIGE.AI, Perkin Elmer, Roche, Sanofi, Ventana and Ultivue; Laboratory support: Amgen, Cepheid, NavigateBP, NextCure, and Konica Minolta. SS—Gift cards: Healthcasts-Syneos, ZOOM RX Surveys, Schlesinger Group, Impact Rx; Monetary compensation: Global M3. LHS—Contracted research: Merck, Bristol Myers Squibb, Regeneron. BS—Consulting fees: Bristol Myers Squibb. SITC staff: SMW—Shares owned: Pacific Biosciences, Editas Medicine; AK, LL, CG--Nothing to disclose, (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: There is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials [DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505)] combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial., Methods and Analysis: This multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m 2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m 2 ) 4-6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4-6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18-70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma., Ethics and Dissemination: The protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences., Drug Supply: AstraZeneca., Protocol Version: CTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021., Trial Registration Number: ClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909., Competing Interests: Competing interests: ZS, CB, AC, SY, KaF, KarF, AB, MMC have nothing to disclose. PSK reports grants and fees from AstraZeneca and Pfizer, she is a consultant/ advisory board member of MSD, outside the submitted work; PMF reports grants and fees from AstraZeneca, BMS, Corvus, Novartis, Kyowa; he is a consultant/ advisory board member of Amgen, AstraZeneca, BMS, Novartis, Janssen, Iteos, Mirati, Sanofi; he is a Data Safety Monitoring Board member of Polaris, Flame, outside the submitted work; BH is a consultant/ advisory board member of MSD, BMS, Roche, Pfizer, AstraZeneca, Eisai, Takeda; his institution received grants from Amgen, outside the submitted work; SR reports grants and fees from Amgen, AstraZeneca, Genmab, Eisai, Lilly, Roche, Merck, Takeda and GSK; he is a Data Safety Monitoring Board member of Jansen; a member of Board for Gergia Society of Oncology and IASLC; his institution received grants from AstraZenca, Amgen, BMS, Merck, Genmab, Takeda, Advaxis and Pfizer, outside the submitted work; WJL reports grants and fees from Douglas Pharmaceuticals, and patents relating to immune checkpoint therapy, unrelated to this study, outside the submitted work; KO'B has received advisory board and/or speaker bureau and/or meeting travel/registration support from BMS, MSD, LillyOncology, Boehringer-Ingelheim, Pfizer, Novartis, Roche-Genentech,Teva, Mundipharma, Astrazeneca, Janssen, Natera and TriStar. He is a board member and stock holder for Carpe Vitae Pharmaceuticals and a stock holder for RepLuca Pharmaceuticals and DGC Diagnostics and holds patents for novel therapeutics and diagnostic tests, outside the submitted work; NP reports grants and fees from Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche, Takeda and Ipsen; he is an advisory board member of Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Pfizer and Roche; his institution received grants from Bayer, Pfizer and Roche, outside the submitted work; JB reports grants and fees from AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines, Amgen, Eli Lilly, GlaxoSmithKline, Sanofi, Regeneron; she is a Data Safety Monitoring Board member of GlaxoSmithKline, Sanofi, Janssen; she is an advisory board member of IASLC; outside the submitted work; VA institution received grants from BMS and AstraZeneca; outside the submitted work; MS institution received grants from the following competitive funding bodies: Australian National Health and Medical Research Council, Canadian Cancer Trials Group, Cancer Australia, Medical Research Future Fund of Australia; and the following pharmaceutical companies: Astellas, Amgen, Astra Zeneca, Bayer, Beigene, Bionomics, Bristol-Myers Squibb, Celgene, Medivation, Merck, Merck Sharp & Dohme, Pfizer, Roche, Sanofi, Tilray, outside the submitted work; AKN reports grants and fees from Bayer Pharmaceuticals; Roche Pharmaceuticals; Boehringer Ingelheim; Merck Sharpe Dohme; Douglas Pharmaceuticals, Atara Biotherapeutics, Astra Zeneca (payment to institution); Pharmabcine; Trizell Ltd; Seagen; honoraria from Bristol Myers Squibb and her institution received grants from AstraZeneca and Douglas Pharmaceuticals, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown., Methods: We undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0-1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines., Results: Thirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22-79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together., Conclusions: Pembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study., Trial Registration Number: NCT03091478., Competing Interests: Competing interests: JN: research funding: Merck, AstraZeneca; consulting: AstraZeneca, Bristol-Myers Squibb; Takeda, Daiichi Sankyo, Roche/Genentech; Honoraria: Merck, AstraZeneca, Bristol-Myers Squibb, Roche/Genentech. CD: consultant: Depuy-Synthes, Bionaut Labs; royalties: Thrive (through Johns Hopkins University). CH: research funding: NCI/NIH; consultant: Merck & Co. CAS-M: research funding: NCI/NIH, Pfizer, AstraZeneca, Novartis, BMS, Tesaro/GSK; consultant: BMS, Seattle Genetics, Genomic Health, Athenex, Polyphor, Halozyme. MH: consultant: BTG International, NewLink Genetics, Celgene, AbbVie. PMF: consultant: AstraZeneca, Abbvie, Amgen, BMS, Janssen; research funding: AstraZeneca, BMS. CD, KWK, NP, CB, and BP are founders of, hold equity in, and are consultants to Thrive and Personal Genome Diagnostics. KWK and NP are on the Board of Directors of Thrive. KWK is a consultant to Sysmex, Eisai, and CAGE Pharma. KWK and NP are consultants to Neophore. CB is a consultant to Depuy-Synthes and Bionaut Labs. CD is a consultant to Thrive and is compensated with income and equity. The companies named above as well as other companies have licensed previously described technologies related to the work described in this paper from Johns Hopkins University. CD, CB, KWK, and NP are inventors on some of these technologies. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to Johns Hopkins University. The terms of all of these arrangements are being managed by Johns Hopkins University in accordance with its conflict of interest policies. KJR: research funding: Accuray, Elekta AB; travel expenses: Brainlab, Accuray, Elekta AB; honoraria: Elekta AB; data safety monitoring board: BioMimetixRC; research funding to institution from Novartis, Genentech, Merck, Macrogenics, Puma Biotechnology. Unrestricted educational grant from Pfizer., (© 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: Immune-checkpoint inhibitor (ICI)-pneumonitis that does not improve or resolve with corticosteroids and requires additional immunosuppression is termed steroid-refractory ICI-pneumonitis. Herein, we report the clinical features, management and outcomes for patients treated with intravenous immunoglobulin (IVIG), infliximab, or the combination of IVIG and infliximab for steroid-refractory ICI-pneumonitis., Methods: Patients with steroid-refractory ICI-pneumonitis were identified between January 2011 and January 2020 at a tertiary academic center. ICI-pneumonitis was defined as clinical or radiographic lung inflammation without an alternative diagnosis, confirmed by a multidisciplinary team. Steroid-refractory ICI-pneumonitis was defined as lack of clinical improvement after high-dose corticosteroids for 48 hours, necessitating additional immunosuppression. Serial clinical, radiologic (CT imaging), and functional features (level-of-care, oxygen requirement) were collected preadditional and postadditional immunosuppression., Results: Of 65 patients with ICI-pneumonitis, 18.5% (12/65) had steroid-refractory ICI-pneumonitis. Mean age at diagnosis of ICI-pneumonitis was 66.8 years (range: 35-85), 50% patients were male, and the majority had lung carcinoma (75%). Steroid-refractory ICI-pneumonitis occurred after a mean of 5 ICI doses from PD-(L)1 start (range: 3-12 doses). The most common radiologic pattern was diffuse alveolar damage (DAD: 50%, 6/12). After corticosteroid failure, patients were treated with: IVIG (n=7), infliximab (n=2), or combination IVIG and infliximab (n=3); 11/12 (91.7%) required ICU-level care and 8/12 (75%) died of steroid-refractory ICI-pneumonitis or infectious complications (IVIG alone=3/7, 42.9%; infliximab alone=2/2, 100%; IVIG + infliximab=3/3, 100%). All five patients treated with infliximab (5/5; 100%) died from steroid-refractory ICI-pneumonitis or infectious complications. Mechanical ventilation was required in 53% of patients treated with infliximab alone, 80% of those treated with IVIG + infliximab, and 25.5% of those treated with IVIG alone., Conclusions: Steroid-refractory ICI-pneumonitis constituted 18.5% of referrals for multidisciplinary irAE care. Steroid-refractory ICI-pnuemonitis occurred early in patients' treatment courses, and most commonly exhibited a DAD radiographic pattern. Patients treated with IVIG alone demonstrated an improvement in both level-of-care and oxygenation requirements and had fewer fatalities (43%) from steroid-refractory ICI-pneumonitis when compared to treatment with infliximab (100% mortality)., Competing Interests: Competing interests: None declared., (© 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: We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab., Methods: Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint., Results: While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations., Conclusions: Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response., Competing Interests: Competing interests: JER has received grants from Conquer Cancer: The ASCO Foundation. VA has received grants from the National Institutes of Health, The LUNGevity Foundation, The V Foundation, Swim Across America, The Allegheny Health Network – Johns Hopkins Research Fund and the Maryland Department of Health and Mental Hygiene Cigarette Restitution Fund Program, Bristol-Myers Squibb, and Personal Genomic Diagnostics. KS has received personal fees from Illumina. JRW is the founder and owner of Resphera Biosciences LLC. SB has received personal fees from Bristol-Myers Squibb. DJ has been on the advisory boards of Diffusion Pharmaceuticals, Merck, and AstraZeneca. TM has received grants from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive BioTechnologies, Leap Therapeutics, and Aprea; has received personal fees from Leap Therapeutics, Immunos Therapeutics, and Pfizer; is co-founder and holds equity in Imvaq Therapeutics; and has filed patents for work related to PD-1 and CTLA-4. JT has received grants from Akoya Biosciences and Bristol-Myers Squibb, has received non-financial support from Akoya Biosciences, and has been on the advisory boards of Bristol-Myers Squibb, Merck, AstraZeneca, Compugen, and Regeneron. VEV has received grants from the National Institutes of Health, The Commonwealth Foundation, and Bloomberg–Kimmel Institute for Cancer Immunotherapy; has been on the advisory boards of Bristol-Myers Squibb, Genentech, Merck, and Takeda Pharmaceuticals; and is the founder, serves on board of directors and owns stock in Delfi Diagnostics and Personal Genome Diagnostics. GR has received personal fees from Medicago and owns stock in Johnson & Johnson. PI has received grants from Bristol-Myers Squibb and Biomarker Strategies, LLC; has received personal fees from AbbVie, AstraZeneca, Bayer, Veran Medical Technologies Inc., and Roche Diagnostics; and has been on the advisory boards of AstraZeneca and Guardant Health. DMP and ST have received research grants from Bristol-Myers Squibb and Compugen; have received personal fees from Aduro Biotech, Five Prime Therapeutics, Tizona Therapeutics, DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Amgen, MedImmune, Merck, Compugen, Dynavax, Immunomic Therapeutics, Janssen Oncology, Immunocore, Bristol-Myers Squibb, Arbor Pharmaceuticals, and NexImmune; and own equity in Aduro Biotech, Potenza Therapeutics, Five Prime Therapeutics, Tizona Therapeutics, DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, and Trieza Therapeutics. JN has received grants from AstraZeneca and Merck; has been on the advisory boards of AstraZeneca, Bristol Myers-Squibb, and Genentech/Roche; and has received personal fees from AstraZeneca, Bristol-Myers Squibb, and Merck. BL has received grants from Eli Lilly, Genentech, Bristol-Myers Squibb, AstraZeneca, Turning Point Therapeutics, and Amgen; and has received personal fees from Eli Lilly, Genentech, AstraZeneca, Celgene, Pfizer, Merck, Novartis, and Takeda. MH has received grants from Bristol-Myers Squibb; has received personal fees from Bristol-Myers Squibb, Merck, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, Arcus, and Eli Lilly; owns equity in Shattuck Labs, Immunai, and Arcus; and has filed patents related to the use of tumor mutation burden to predict response to immunotherapy. JRB has received grants from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Inc., and Revolution Medicines; has received personal fees from Genentech/Roche; has been on the advisory boards of Amgen, Bristol-Myers Squibb, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, and Sanofi; and has been on the Data and Safety Monitory boards of GlaxoSmithKline and Sanofi. JEC has received grants from the National Institutes of Health; and has also received grants and personal fees from Merck, Bristol-Myers Squibb, Genentech, and AstraZeneca. PMF has received grants from the LUNGevity Foundation, Stand Up To Cancer, AstraZeneca, Bristol-Myers Squibb, Kyowa, Novartis, and Corvus; and has been on the advisory boards of Abbvie, AstraZeneca, and Bristol-Myers Squibb. The remaining authors declare no conflicts of interest., (© 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: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression., Methods: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available., Results: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper., Conclusions: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features., Competing Interests: Competing interests: JN: research funding: AstraZeneca, Merck, Consulting/Advisory Board: AstraZeneca, Merck, Bristol-Myers Squibb, Honoraria: AstraZeneca, Merck, Bristol-Myers Squibb. EL: research funding: Bristol-Myers Squibb, Merck, Regeneron, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, Novartis, EMD Serono, Array BioPharma, MacroGenics, Sanofi. PMF: research funding: AstraZeneca, Bristol-Myers Squibb, Corvus, Kyowa, Novartis, Consulting/Advisory Board: AstraZeneca, Bristol-Myers Squibb, Janssen, Merck, Novartis, Lilly, Boehringer. LBY: research funding: Rocket Medical, Consulting/Advisory Board: Boston Scientific. HL: Consulting/Advisory Board: Boston Scientific; DFK/Advisory Board: Consulting: Boston Scientific. JT: research funding: Bristol-Myers Squibb, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, AstraZeneca. JRB: research funding: Bristol-Myers Squibb, Consulting/Advisory Board: Bristol-Myers Squibb, Merck, AstraZeneca, and Genentech, and reports receiving commercial., (© 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.)

Immune-related (IR)-pneumonitis is a rare and potentially fatal toxicity of anti-PD(L)1 immunotherapy. Expert guidelines for the diagnosis and management of IR-pneumonitis include multidisciplinary input from medical oncology, pulmonary medicine, infectious disease, and radiology specialists. Severe acute respiratory syndrome coronavirus 2 is a recently recognized respiratory virus that is responsible for causing the COVID-19 global pandemic. Symptoms and imaging findings from IR-pneumonitis and COVID-19 pneumonia can be similar, and early COVID-19 viral testing may yield false negative results, complicating the diagnosis and management of both entities. Herein, we present a set of multidisciplinary consensus recommendations for the diagnosis and management of IR-pneumonitis in the setting of COVID-19 including: (1) isolation procedures, (2) recommended imaging and interpretation, (3) adaptations to invasive testing, (4) adaptations to the management of IR-pneumonitis, (5) immunosuppression for steroid-refractory IR-pneumonitis, and (6) management of suspected concurrent IR-pneumonitis and COVID-19 infection. There is an emerging need for the adaptation of expert guidelines for IR-pneumonitis in the setting of the global COVID-19 pandemic. We propose a multidisciplinary consensus on this topic, in this position paper., Competing Interests: Competing interests: JN: research funding: Merck, AstraZeneca; consulting/advisory board: Bristol-Myers Squibb, AstraZeneca, Roche/Genentech; honoraria: Bristol-Myers Squibb, Merck, AstraZeneca. DBJ: advisory boards/consulting: Array Biopharma, BMS, Jansen, Merck, Novartis; research funding: BMS, Incyte. JRB: advisory boards/consulting: Amgen, BMS, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi; research funding: AstraZeneca, BMS, Genentech/Roche, Merck, RAPT Therapeutics Inc., Revolution Medicines; data and safety monitoring board/committees: GlaxoSmithKline, Sanofi. MN: advisory boards/consulting: Daiichi Sankyo, AstraZeneca; research funding: Merck, Canon Medical Systems, AstraZeneca, Daiichi Sankyo; honorarium: Roche. PMF: advisory boards/consulting: Abbvie, AstraZeneca, BMS; research funding: AstraZeneca, BMS, Kyowa, Novartis, Corvus., (© 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: Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors., Methods: In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W)., Results: Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities were observed, and adverse events included those typical of other PD-1 antibodies. The most common treatment-related adverse events of any grade were fatigue (22%), diarrhea (17%), pruritus (14%), hypothyroidism (10%), and nausea (10%). Partial responses occurred in two patients (response rate 3.4%); one with atypical carcinoid tumor of the lung and one with anal cancer. Paired tumor biopsies from patients taken at baseline and on treatment suggested an on-treatment increase in CD8+ lymphocyte infiltration in patients with clinical benefit., Conclusions: Spartalizumab was well tolerated at all doses tested in patients with previously treated advanced solid tumors. On-treatment immune activation was seen in tumor biopsies; however, limited clinical activity was reported in this heavily pretreated, heterogeneous population. The phase 2 part of this study is ongoing in select tumor types., Trial Registration Number: NCT02404441., Competing Interests: Competing interests: AN received research funding from NCI, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Regeneron, Merck, BMS, Pfizer, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse); travel/accommodation expense from ARMO BioSciences; and consultancy fees and research funding from CytomX Therapeutics and Novartis. JG received grant funding from Array, Tesaro, Moderna, Adaptimmune, and Alexo; personal fees from Oncorus, Regeneron, Pfizer, Incyte, Agios, Amgen, and Ironwood Pharmaceuticals; and grant funding and personal fees from Bristol-Myers Squibb, Genentech/Roche, Takeda, Blueprint, Loxo, Novartis, and Merck. PMF received research funding from Corvus and Kyowa; consultancy fees from AbbVie, Boehringer, EMD Serono, Inivata, Janssen, Lilly, and Merck; and research funding and consultancy fees from AstraZeneca, BMS, and Novartis. MOB received funding from Novartis, personal fees from BMS, Adaptimmune, GSK, Novartis, EMD Serono, Sanofi, Immunocore, and Turnstone; grant funding from Takara Bio; and personal fees and grant funding from Merck. C-CL received personal fees from BeiGene, Daiichi Sankyo, Roche, and Novartis. SS received research funding from GSK, Millennium, MedImmune, Johnson & Johnson, Gilead, Plexxikon, Onyx, Bayer, Blueprint, XuanZhu, Incyte, Toray, Celgene, Hengrui, OncoMed, Tesaro, AADi, Merck, Inhibrx, AMAL, and Syndax; personal fees and research funding from Novartis; equity from Iterion Therapeutics, Proterus Therapeutics, ConverGene, and Stingray Therapeutics; honoraria from Exelixis, Loxo Oncology, Natera, Hengrui Therapeutics, Tarveda Therapeutics, Dracen Pharmaceuticals, and Barricade Therapeutics; and owns stock with LSK BioPharma and Salarius Pharmaceuticals. MT received consultancy fees from Eisai, Bristol-Myers Squibb, Array Biopharma, Blueprint Medicines, Arqule, Loxo Oncology, Bayer, Novartis, and Genentech. JHMS received personal fees from Modra Pharmaceuticals. TMB received grant funding from Daiichi Sankyo, Medpacto, Incyte, Mirati Therapeutics, MedImmune, AbbVie, AstraZeneca, MabVax, Stemline Therapeutics, Merck, Lilly, GlaxoSmithKline, Novartis, Genentech, Deciphera, Merrimack, Immunogen, Millennium, Phosplatin Therapeutics, Calithera Biosciences, Kolltan Pharmaceuticals, Principa Biopharma, Peleton, Immunocore, Roche, Aileron Therapeutics, Bristol-Myers Squibb, Amgen, Onyx, Sanofi, Boehringer-Ingelheim, Astellas Pharma, Five Prime Therapeutics, Jacobio, Top Alliance BioScience, Janssen, Clovis Oncology, Takeda, Karyopharm Therapeutics, Foundation Medicine, and ARMO Biosciences; grant funding and consultancy fees from Leap Therapeutics; grant funding, consultancy fees, and non-financial support from Ignyta and Moderna Therapeutics; grant funding, personal fees, and consultancy fees from Pfizer; grant funding, personal fees, and non-financial support from Loxo and Bayer; personal fees and non-financial support from Guardant Health; and personal fees from Exelesis. HW, HS, and JM are employees of Novartis. APS and JF are employees of Novartis and own stock with Novartis. SC is an employee of Novartis and has patents with Novartis., (© 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: Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently., Case Presentation: We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment., Conclusions: These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.

Background: The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described., Case Presentations: In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked., Conclusions: This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation.