Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes

Cancers harboring mutations in the Kirsten rat sarcoma homolog (KRAS) gene have been associated with poor prognosis and lack of targeted therapies. KRAS mutations occur in approximately one in four patients diagnosed with non-small cell lung cancer (NSCLC) with KRAS G12C mutations harbored at approximately 11–16%. Research into KRAS-driven tumors and analytical chemistry have borne a new class of selective small molecules against the KRAS G12C isoform. Phase II data for sotorasib (AMG510) has demonstrated a 37.1% overall response rate (ORR). Adagrasib (MRTX849) has demonstrated a 45% ORR in an early study. While single agent efficacy has been seen, initial data suggest combination approaches are an opportunity to improve outcomes. Here, we present perspectives on the initial progress in targeting KRAS G12C, examine co-mutations evident in KRAS G12C NSCLC, and comment on potential future combinatorial approaches including SHP2, SOS1, MEK, EGFR, mTOR, CDK, and checkpoint blockade which are currently being evaluated in clinical trials. As of May 28, 2021, sotorasib has achieved US FDA approval for patients with KRAS G12C mutant lung cancer after one line of a prior therapy.

Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice

Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

An Open-Label Phase II Trial of the Combination of Decitabine, SQ Bortezomib and Pegylated Liposomal Doxorubicin for the Treatment of Patients with Relapsed/Refractory Acute Myelogenous Leukemia

Background Relapsed/refractory (R/R) acute myeloid leukemia (AML) remains a challenge to cure. Prior studies of hypomethylating agent (HMA) decitabine (DEC), proteasome inhibitor bortezomib (BTZ), and anthracycline (AC) pegylated liposomal doxorubicin (PLD) monotherapy, as well as DEC + BTZ and BTZ + PLD regimens, have demonstrated safety and modest activity in R/R AML. Inhibition of NF-κB signaling by BTZ and DEC could prevent AC resistance resulting from NF-κB activity. Thus, we hypothesized that the DEC + BTZ + PLD (DBP) regimen would have activity in R/R AML. Methods We performed a phase II trial of DBP, with a safety lead-in cohort, in patients aged 18-90 with R/R AML. The original protocol called for 1-4 28-day (D) cycles of induction with intravenous (IV) DEC 20mg/m 2 on D1-10, subcutaneous (SQ) BTZ 1.3mg/m 2 on D1, 4, 8, and 11, and IV PLD 40mg/m 2 on D4. Dose-limiting toxicity (DLT) of grade 3 peripheral neuropathy (G3 PN) in the first 2 patients led to a revised schedule of BTZ on D5, 8, 12, and 15 and PLD on D12, eliminating simultaneous DBP dosing on any 1 day. Patients achieving a bone marrow blast count <5% after any course of induction proceeded to the continuation regimen: 28-D cycles of DEC on D1-5, BTZ on D1 and 8, and PLD on D12. Treatment continued until progression, intolerance, bone marrow transplant (BMT), study withdrawal, or administration of 12 cycles. Patients reaching lifetime maximum AC exposure could remain on trial with PLD removed from their regimen. Primary endpoint was objective response rate (ORR), defined as complete remission (CR) + CR with incomplete hematological recovery (CRi) + partial remission. Response was based on International Working Group criteria and determined by blood count values between cycles. Secondary endpoints of overall and event-free survival (OS, EFS) were estimated by Kaplan-Meier method. Toxicity was monitored per Common Terminology Criteria for Adverse Events (AEs) v4.03. Results Ten patients were enrolled from May 2016 to February 2018, after which the sponsor closed the protocol. Median age was 57 years [range 27-69]. Patients were 50% female, 60% White, 10% African American/Black, 30% other/mixed race, and 40% Hispanic/Latino, with median baseline ECOG score of 1 [0-1] and median 2 [1-3] lines of prior therapy. Sixty percent had de novo and 40% had secondary disease. By WHO subtype, 30% had AML with MRC, 20% NPM1 mutation, 10% inv(3), 10% therapy-related, and 30% not otherwise specified. European LeukemiaNet 2017 risk was favorable in 20%, intermediate in 40%, and adverse in 40%. Median number of cycles completed was 2 [1-7] with a median time on study of 100.5 days [35-678]. One patient achieved CR and 2 achieved CRi for an ORR of 30%. An additional patient likely had a CR with <5% blasts and count recovery but had a suboptimal aspirate differential. Including this unconfirmed CR, ORR was 40%. An additional 2 (20%) achieved morphological leukemia-free state (MLFS). Of the 6 patients with any response (CR + CRi + MLFS), 2 achieved best response after cycle 1, 2 after cycle 2, 1 after cycle 3, and 1 after cycle 4. Relapse occurred in 2 of 5 (40%) while on study, at 425 days after CRi and 83 days after MLFS. All 3 patients with prior HMA exposure were non-responders. All patients discontinued treatment. Reasons included BMT (40%), AE (30%), progression (20%) and insurance loss (10%). Half planned to bridge to BMT as next-line therapy following study treatment. When taken off study, 50% were alive while 20% had died from AML complications, 20% from graft-versus-host-disease post-BMT, and 10% after relapse post-BMT. Median OS was 6.67 months (95% confidence interval [CI] 6.07 to not reached [NR]). Median EFS was 3.22 months (95% CI 1.50 to NR), with a maximum EFS of 16.93 months. Following G3 PN in the first 2 patients, no DLTs occurred on the modified regimen. Seventy percent of patients experienced at least possibly related G3+ AEs or serious AEs (SAEs). Of the 22 related G3+ AEs, anemia and decreased platelet count were seen in 50% and dizziness in 20%. Of the 22 related SAEs, anorexia, fatigue, PN, febrile neutropenia, and bacteremia were most common, each occurring in 20%. Conclusion The DBP triplet demonstrated preliminary anti-AML activity in a R/R AML patient cohort. Staggered dosing was better tolerated than simultaneous DBP. DBP may serve as an effective bridge to BMT for some patients. This study supports further evaluation of DBP, or related combinations, in R/R AML. Disclosures Rosenberg: Takeda, Janssen: Speakers Bureau. Abedi: Seattle Genetics: Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Speakers Bureau. Tuscano: BMS, Seattle Genetics, Takeda, Achrotech, Genentech, Pharmacyclics, Abbvie: Research Funding. Jonas: AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie: Other: Travel reimbursement. OffLabel Disclosure: Bortezomib is FDA-approved for the treatment of multiple myeloma in patients who have already been treated with 2 lines of prior therapy and progressed on the most recent therapy. Decitabine is indicated for treatment of patients with myelodysplastic syndromes. Doxorubicin is approved in AML among other cancers.

A Meta-Analysis of Pivotal Pralatrexate Studies in Relapsed/Refractory Mature T-Cell Lymphoma (r/r TCL)

Introduction While patients with r/r TCL have a poor prognosis, significant progress has been made over the past decade in developing new drugs and regimens for the disease. All of the approved agents have their own distinct advantages and issues, making it essential to critically assess the merits and limitations of each. It is well accepted that the development of acquired drug resistance to conventional chemotherapy reduces efficacy with each subsequent line of therapy. However in the era of novel single agents, less is known about the role of these new drugs in patients with chemo-sensitive and chemo-refractory disease. Based on results of the PROPEL trial in 111 treated patients, pralatrexate was the first drug approved as a novel single agent in the US for r/r TCL (O'Connor et al. J Clin Oncol. 2011). Drug registration and approval of pralatrexate was subsequently attained in many healthcare ministries around the world, including Japan, China and Taiwan based on the results of PROPEL and/or locally conducted studies (Maruyama et al. Cancer Sci 2017; Hong et al. Target Oncol 2019; Wang et al. EHA 2019). A meta-analysis of these four trials was undertaken to better understand those factors influencing efficacy and safety of pralatrexate in this patient population. Methods Patient- or summary-level data presented in the individual clinical study reports from the four regulatory-mandated prospective clinical trials of pralatrexate monotherapy in patients with r/r TCL were included in this meta-analysis. Pooled studies (phase 2 PDX-008 [PROPEL], phase 3 FOT12-CN-301, phase 4 FOT14-TW-401, phase 2 part of PDX-JP1) collected data on the primary efficacy endpoint of objective response rate (ORR) as assessed by central review. Secondary efficacy endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Data were collected in accordance with the original protocol and updated with longer survival follow-up where available. Relapse was defined as achieving a complete response (CR) or partial response (PR) on prior therapy lasting for > 3 months, and refractory was defined as stable disease or progressive disease on prior therapy or relapsed disease <3 months of achieving CR or PR. Both the fixed effect model (includes within study variations) and random effects model (includes within study and between study variations) were considered in this meta-analysis. Results A total of 221 patients were included in the efficacy analysis set for this meta-analysis. The median age was 59 years (range 21-89) and 67% were male. Histological subtypes as assessed by the central review included PTCL-not otherwise specified (108 pts, 49%), angioimmunoblastic T-cell lymphoma (47 pts, 21%), anaplastic large cell lymphoma (ALK-negative; 26 pts, 12%), transformed mycosis fungoides (12 pts, 5%), extranodal NK/T cell lymphoma, nasal type (7 pts, 3%), and other/missing (10/11 pts, 5% each). Patients had a median of 2 prior lines of systemic therapies (range 1-14). At the most recent line of therapy prior to pralatrexate, 68 (31%) and 103 (47%) patients were classified as relapsed and refractory respectively, with the remaining 50 (23%) unable to be determined due to response to the prior therapy being unavailable or not evaluable. Ten percent (n=24) of patients had stem cell transplant prior to receiving pralatrexate. Pooled ORR of the entire cohort was 40.7% (95% CI, 34.2, 47.5), including 30 in CR (13.6%) and 60 in PR (27.2%). The median DOR was 9.1 months (95% CI, 7.4-10.8). Median PFS was 4.6 months (95% CI, 4.0-5.2) while median OS was 16.3 months (95% CI, 13.1-22.6). Conclusions This meta-analysis confirms significant clinical activity of pralatrexate in heavily treated patients with r/r TCL, with an ORR of 40.7% at a median of two lines of prior therapy. These findings meaningfully bolster the original observations from PROPEL with 3 additional regulatory mandated clinical studies and suggest that earlier use may be associated with improved outcome. Further details on the efficacy by prior lines of systemic therapy as well as safety data will be presented. Disclosures O'Connor: TG Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Research Funding; BMS: Research Funding; Astex: Research Funding; Kymera: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Mundipharma: Honoraria; Myeloid Therapeutics: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Maruyama: Novartis: Research Funding; Chugai: Honoraria, Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Astellas Pharma,: Research Funding; Otsuka: Research Funding; MSD: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria; Kyowa Kirin: Honoraria; Zenyaku: Honoraria; AstraZeneca: Honoraria; Nippon: Honoraria; SymBio: Honoraria. Yeoh: Mundipharma: Current Employment. Tobinai: Celgene: Consultancy, Honoraria; Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria; Solasia Pharma: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria; Yakult: Honoraria; Zenyaku Kogyo: Consultancy, Honoraria.

Compassionate Use of Belantamab Mafodotin for Treatment of Patients with Relapsed/Refractory Multiple Myeloma Heavily Treated. Spanish Experience

Background: Heavily pretreated relapsed and refractory multiple myeloma (RR MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short (Richardson et al. 2007). Belantamab Mafodotin (BM), a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin F, showed single-agent activity in the phase 1 DREAMM-1 and phase 2 DREAMM-2 studies in heavily pre-treated patients with RRMM (Lonial et al, 2019 & 2021). We aim to assess efficacy and safety of BM treatment administered via the expanded access compassionate care program for triple class MMRR patients in the region of Madrid (Spain). Methods: An observational, retrospective and multicenter study has been performed including all patients who received at least one dose of BM under the expanded access program in the region of Madrid (Spain) from Nov 2019 to Jun 2021. Hematology centers provided data from the medical records and entered them in a case report form distributed to the sites. Primary endpoint was overall response rate (ORR). Secondary endpoints were progression free survival (PFS), overall survival (OS) and the incidence of treatment emergent adverse events (TEAEs), with a major focus on ocular and hematologic toxicity. Results: A total of 33 patients (pts), from 14 different centers, were included from February 2020 till May 2021. Median age was 70 (46-79) years. 55% of the pts were women. Median time from diagnosis was 71 (10-858) months. 30.3% were high-risk cytogenetic features. Median of prior therapy lines was 5 (3-8) and at least 88% of the pts were triple class refractory. The median number of BM doses per patient was 3 (1-16) and the median follow-up was 11 months (95%CI 6.34-15.66). ORR was 42.2%, and 18.2% achieved ≥VGPR. Median PFS was 3 months (95%CI 0.92-5.08). Median PFS for patients who achieved ≥PR was 11 months (HR 0,26; 95% CI 0,10-0,68). No significant differences were found in PFS according to age, cytogenetic risk and prior therapy lines. OS was 424 days (95% CI 107-740). The incidence of non-hematological TEAEs was 57.6% and the most common of which was ocular toxicity (45.5%). The incidence of ≥G3 non-hematological TEAEs was 30.3%. 51.5% of the pts were diagnosed of keratopathy and 21.2% was ≥G3. 30.3% of the pts showed a reduced visual acuity, but this event was resolved in 92.9% of the pts. The most common symptoms were blurry vision (30.3%, n=10) and dry eye (24.2%, n=8). The incidence of ≥G3 hematological TEAEs was 18.2% and thrombocytopenia was the most frequent (21.2%). Dose reductions of BM were required in 30.3% of the pts and delayed in 36.4% due to TEAEs. Main causes for treatment discontinuation (81%, n=27) were disease progression (54.5%, n=18), toxicity (15.2%, n=5), death (6.1%, n=3) and due to patient's decision (3%, n=1). Conclusion: Compassionate use of BM in heavily pretreated RR MM pts showed a relevant anti-myeloma activity with a manageable safety profile.These results are similar to those observed in the DREAMM-1 and DREAMM-2 clinical trials. Disclosures No relevant conflicts of interest to declare.

BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today's standard of care. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population. Study Design and Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure). Eligible patients are adults with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi. The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Disclosures Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Genmab: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding. Wierda: GSK/Novartis: Research Funding; Xencor: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Gilead Sciences: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy. Davids: Astra-Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding. Zinzani: ROCHE: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; MSD: Consultancy, Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau. Lu: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Liu: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tam: Beigene: Honoraria; Loxo: Honoraria; Abbvie: Research Funding; Janssen: Research Funding; Beigene: Research Funding; Janssen: Honoraria; Abbvie: 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. Eyre: Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding.