Pirtobrutinib, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma: Updated Results from the Phase 1/2 BRUIN Study
Authors: Wang Michael , Shah Nirav N. , Alencar Alvaro J. , Gerson James N. , Patel Manish R. , Fakhri Bita , Jurczak Wojciech , Tan Xuan Ni , Lewis Katharine , Fenske Timothy S. , Coombs Catherine C. , Flinn Ian W. , Lewis David John , Le Gouill Steven , Palomba M. Lia , Woyach Jennifer A. , Pagel John M. , Lamanna Nicole , Cohen Jonathon B. , Barve Minal A. , Ghia Paolo , Eyre Toby A. , Zinzani Pier Luigi Luigi , Ujjani Chaitra S. , Koh Youngil , Izutsu Koji , Lech-Marańda Ewa , Tam Constantine S. , Sundaram Suchitra , Yin Ming , Nair Binoj , Balbas Minna , Tsai Donald , Mato Anthony R. , Cheah Chan Yoon 
Published: November 2021

Background: Covalent BTK inhibitors (BTKi) have transformed the management of mantle cell lymphoma (MCL), but these treatments are not curative and the majority of patients (pts) will require additional treatment. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as MCL. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. In the phase 1/2 BRUIN study, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated and demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts, most of whom had prior treatment with a covalent BTKi (Mato et al. Lancet 2021;397, 10277:892-901).

Methods: BRUIN is a multicenter phase 1/2 study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received &gt;2 prior therapies. Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS), safety and tolerability, and pharmacokinetics. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification. Safety was assessed in all pts (CLL/SLL and NHL).

Results: As of 27 September 2020, 323 pts (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other NHL [other transformation, B-PLL and hairy cell leukemia]) were treated on 7 dose levels (25-300mg QD). Median age was 69 (range 50-87) years for MCL pts. Among the 61 MCL pts, median number of prior lines of therapy was 3 (range, 1-8) and a majority of them had received a prior BTKi (93%), an anti-CD20 antibody (98%) or chemotherapy (92%). No DLTs were reported and MTD was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%), and contusion (13%) were the most frequent treatment-emergent adverse events regardless of attribution or grade seen in &gt;10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. Five (1%) pts discontinued due to treatment-related adverse events. At the efficacy cutoff date, 52 prior BTKi treated MCL pts were efficacy evaluable with an ORR of 52% (95% CI 38-66; 13 CR [25%], 14 PR [27%], 9 SD [17%], 11 PD [21%] and 5 [10%] pts discontinued prior to first response assessment). Median follow up was 6 months (range 0.7-18.3+). Responses were observed in 9/14 pts (64%) with prior autologous or allogeneic stem cell transplant, and 2 of 2 with prior CAR-T cell therapy.

Conclusion: Pirtobrutinib demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL following multiple prior lines of therapy, including a covalent BTKi. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 60 new pts with MCL and an additional 10 months since the prior data cut will be presented.

Disclosures

Wang: Juno: Consultancy, Research Funding; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Lilly: Research Funding; Moffit Cancer Center: Honoraria; Newbridge Pharmaceuticals: Honoraria; VelosBio: Consultancy, Research Funding; OMI: Honoraria; BGICS: Honoraria; Mumbai Hematology Group: Honoraria; BioInvent: Research Funding; CStone: Consultancy; Hebei Cancer Prevention Federation: Honoraria; Celgene: Research Funding; Oncternal: Consultancy, Research Funding; Molecular Templates: Research Funding; Epizyme: Consultancy, Honoraria; InnoCare: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Clinical Care Options: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Chinese Medical Association: Honoraria; Scripps: Honoraria; Imedex: Honoraria; Physicians Education Resources (PER): Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Dava Oncology: Honoraria; Genentech: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Bayer Healthcare: Consultancy; Loxo Oncology: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Shah: Epizyme: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Incyte: Consultancy; Umoja: Consultancy; Kite: Consultancy; Legend: Consultancy. Alencar: Amgen: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Epizyme: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Kite Pharma: Consultancy; Seattle Genetics: Consultancy. Gerson: Abbvie, Genentech: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology at Lilly: Research Funding. Patel: Hutchinson MediPharma: Research Funding; Florida Cancer Specialists: Research Funding; Mirati Therapeutics: Research Funding; Lycera: Research Funding; Millennium Pharmaceuticals: Research Funding; Mabspace: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Daiichi Sankyo: Research Funding; Effector Therapeutics: Research Funding; Cyteir Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Vedanta: Research Funding; Loxo Oncology: Research Funding; Forma Therapeutics: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; GlaxoSmithKline: Research Funding; LSK Biopartners: Research Funding; ModernaTX: Research Funding; ORIC Pharmaceuticals: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Phoenix Molecular Designs: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Evelo Biosciences: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Eli Lilly: Research Funding; Curis: Research Funding; Jacobio: Research Funding; Acerta Pharma: Research Funding; AstraZeneca: Research Funding; Ciclomed: Research Funding; BioNTech: Research Funding; Clovis: Research Funding; Checkpoint Therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Calithera: Research Funding; Bicycle Therapeutics: Research Funding; Artios Pharma: Research Funding; TopAlliance: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Taiho: Research Funding; H3 Biomedicine: Research Funding; Vigeo: Research Funding; Tesaro: Research Funding; Aileron Therapeutics: Research Funding; Agenus: Research Funding; Ignyta: Research Funding; Xencor: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Incyte: Research Funding; Kymab: Research Funding; Hengrui: Research Funding; Verastem: Research Funding; Takeda: Research Funding; Klus Pharma: Research Funding; Jounce Therapeutics: Research Funding. Fakhri: Loxo/Lilly: Research Funding. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; Jagiellonian University: Ended employment in the past 24 months; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment. Lewis: AstraZeneca: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria. Fenske: Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; Servier Pharmaceuticals: Consultancy; Kite (Gilead): Speakers Bureau; MorphoSys: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; Seattle Genetics: Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Lewis: Loxo Oncology at Lilly: Membership on an entity's Board of Directors or advisory committees. Palomba: Pluto: Honoraria; Priothera: Honoraria; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Notch: Honoraria, Other: Stock; Ceramedix: Honoraria; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; Lygenesis: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Juno: Patents & Royalties; Nektar: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Magenta: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Pagel: Pharmacyclics/AbbVie: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Actinium Pharmaceuticals: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Gilead: Consultancy. Lamanna: Juno Therapeutics, Inc.: Research Funding; Pharmacyclics: Consultancy; MingSight Pharmaceuticals, Inc.: Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy; TG Therapeutics, Inc: Research Funding; Oncternal Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Celgene Corporation: Consultancy; Genentech, Inc.: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy; Verastem Oncology: Research Funding. Cohen: Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy. Ghia: AbbVie: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; Celgene/Juno/BMS: Consultancy, Honoraria; Gilead: Consultancy, Research Funding. Eyre: Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding. Zinzani: Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ujjani: Gilead: Honoraria; TG Therapeutics: Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Bio: Consultancy; Loxo: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Izutsu: Yakult: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Lech-Marańda: Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Tam: Loxo: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Roche: Consultancy, Honoraria; Pharmacyclics: Honoraria. Yin: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Nair: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Balbas: Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tsai: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Mato: LOXO: Consultancy, Research Funding; Genmab: Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cheah: Novartis: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Ascentage Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Research Funding; BMS: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other: travel, Research Funding.