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Résumé Le congrès Targeted Anticancer Therapies (TAT) s’est déroulé cette année du 2 au 4 mars à Paris. Encore une fois l’immunothérapie y était à l’honneur avec les anticorps anti-PD-1/PD-L1, les anticorps anti-CSF-1R, l’immunothérapie adoptive et le développement de combinaisons d’immunothérapies. Le challenge actuel reste de parvenir à identifier les patients susceptibles d’en retirer le plus grand bénéfice. Parmi les molécules prometteuses présentées par ailleurs, on peut citer les agents ciblant les cyclines dépendantes kinases (CDK) ou les empreintes épigénétiques ainsi que les inhibiteurs de PARP et des systèmes de réparation de l’ADN tels qu’ATR. Enfin, une troisième génération d’inhibiteurs de tyrosines-kinases (ITK) est actuellement en cours d’évaluation afin de contourner les résistances acquises aux premiers ITK ; comme le rociletinib actif sur la mutation de résistance T790M dans les cancers bronchiques. Sur le plan des techniques, le criblage moléculaire affirme son intérêt en routine clinique dans le cadre du développement de la médecine personnalisée avec les résultats de l’essai MOSCATO-01, et de nouveaux critères radiologiques et « radiomics » d’évaluation de la réponse tumorale sont en cours de validation pour s’adapter notamment à l’immunothérapie et aux thérapies ciblées.

BackgroundImmune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs). Although the incidence and prevalence of irAEs have been well characterized in the literature, less is known about the cumulative incidence rate of irAEs. We studied the cumulative incidence of irAEs, defined as the probability of irAE occurrence over time and the risk factors for irAE development in metastatic urothelial carcinoma (mUC) and renal cell carcinoma (mRCC) patients treated with ICIs.MethodsWe identified a cohort of patients who received ICIs for mUC and mRCC. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) V.5.0 guidelines. The monthly incidence of irAEs over time was reported after landmark duration of therapy. Cumulative incidence of irAEs was calculated to evaluate the time to the first occurrence of an irAE accounting for the competing risk of death. Prognostic factors for irAE were assessed using the Fine and Gray method.ResultsA total of 470 patients were treated with ICIs between July 2013 and October 2018 (mUC: 199 (42.3%); mRCC: 271 (57.7%)). 341 (72.6%) patients received monotherapy, 86 (18.3%) received ICIs in combination with targeted therapies, and 43 (9.2%) received dual ICI therapy. Overall, 186 patients (39.5%) experienced an irAE at any time point. Common irAEs included hypothyroidism (n=42, 22.6%), rush and pruritus (n=36, 19.4%), diarrhea/colitis (n=35, 18.8%), transaminitis (n=32, 17.2%), and pneumonitis (n=14, 7.5%). Monthly incidence rates decreased over time; however, 17 of 109 (15.6%, 95% CI: 9.4% to 23.8%) experienced their first irAE at least 1 year after treatment initiation. No differences in cumulative incidence were observed based on cancer type, agent, or irAE grade. On multivariable analysis, combined ICI therapy with another ICI or with targeted therapy (p<0.001), first-line ICI therapy (p=0.011), and PD-1 inhibitor therapy (p=0.007) were all significantly associated with irAE development.ConclusionsThis study quantitates the incidence of developing irAEs due to ICI conditioned on time elapsed without irAE development. Although the monthly incidence of irAEs decreased over time on therapy, patients can still develop delayed irAEs beyond ICI discontinuation, and thus, continuous vigilant monitoring is warranted.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1−3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD−L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors. Competing Interest Statement ZB: reported nonfinancial support from Bristol-Myers Squibb and Genentech/ImCore. D.A.B. reported nonfinancial support from, Bristol-Myers Squibb, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.A.S. reported nonfinancial support from Bristol-Myers Squibb, and equity in 152 Therapeutics outside the submitted work. X.G: Research Support to Institution: Exelixis. X.X.W: Research Support: BMS. B.A.M is a consultant for Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. L.C.H reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, and Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech. M.B.A: Advisory Board participation: BMS, Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf, Fathom, Pneuma, Leads BioPharma; Consultant: BMS, Merck, Novartis, Pfizer, Genentech-Roche, Exelixis, Eisai, Aveo, Array, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, Pharma, Surface, Alexion, Acceleron, Cota, Amgen; Research Support to institution: BMS, Merck, Pfizer, Genentech. C.J.W: Co-founder of Neon Therapeutics, and is a member of its SAB. Receives research funding from Pharmacyclics. T.H.H: Advisory board participation: Surface Therapeutics, Exelixis, Genentech, Pfizer, Ipsen, Cardinal Health; research support-Novartis. D.F.M reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; and reports that his home institution receives research funding from Prometheus Laboratories. D.H: consulting or research funding from Pfizer, Novartis, BMS, Ipsen, Exelixis, and Merck. S.S: Research support to Institution: Bristol-Myers Squibb, AstraZeneca, Novartis, Exelixis; Consultant: Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; royalties: Biogenex. E.M.V: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Illumina, Ervaxx; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Ervaxx, Microsoft; Travel reimbursement: Roche/Genentech; Patents: Institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. T.K.C: Research (Institutional and personal): AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda, National Cancer Institute (NCI), National Institute of Health (NIH), Department of Defense (DOD).; Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly, ASCO, ESMO ; Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest.; No speaker bureau; Stock ownership: Pionyr, Tempest.; No leadership or employment in for-profit companies. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); Patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response, filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others); The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; CV provided upon request for scope of clinical practice and research; Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components: Asmar Wood S.A.L. is a private company based in Beirut, Lebanon that will provide a total of $100,000 in salary support to Dr. Sarah Abou Alaiwi from 7/1/2018 to 7/1/2020 during her post-doctoral research fellowship at DFCI; Fondation Arc Pour La Recherche Sur Le Cancer is a not-for-profit foundation based in Villejuif, France that provides 2561.04 Euros per month in salary support to Dr. Ronan Flippot during his clinical training at DFCI from 5/2/2018 to 11/4/2018. The other authors declare no potential conflicts of interest.