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Background: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical activity in patients with RET fusion-positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study., Patients and Methods: ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator's decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety., Results: Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion-positive NSCLC were enrolled. The ORR was 72% [54/75; 95% confidence interval (CI) 60% to 82%] for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion-positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs., Conclusions: Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion-positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending., Competing Interests: Disclosure FG has consulted or provided expert opinion for Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; has received fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda; and has received funding for scientific research from Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Celgene, GSK, Lilly, MSD, Novartis, Pfizer, Roche, Siemens, and Takeda. GC has consulted and/or had advisory roles for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Foundation Medicine, GlaxoSmithKline, Lilly, Novartis, Pfizer, Roche/Genentech, Samsung, and Seattle Genetics; served on speakers’ bureaus for Daiichi Sankyo, Foundation Medicine, Lilly, Novartis, Pfizer, Roche/Genentech, and Samsung; received travel, accommodations, and expenses from Pfizer, Roche/Genentech; received honoraria from Ellipses Pharma and research funding from Merck; and is supported by the OPTIMA [grant number 101034347]. MT has received honoraria for scientific meetings (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; advisory-board honoraria (self) from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; travelling support (self) from AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; and has received research funding (institution) from AstraZeneca, BMS, Roche, and Takeda. VS reports research funding/grant support for clinical trials from AbbVie, Agensys, Alfa-sigma, Altum, Amgen, Bayer, Berg Health, Biotherapeutics, Blueprint Medicines Corporation, Boston Biomedical, Boston Pharmaceuticals, Celgene, D3, Dragonfly Therapeutics, Exelixis, Fujifilm, GSK, Idera Pharma, Incyte, Inhibrx, Loxo Oncology, MedImmune, MultiVir, Nanocarrier, National Comprehensive Cancer Network, NCI-CTEP, Novartis, Northwest Biotherapeutics, Pfizer, PharmaMar, Roche/Genentech, Takeda, Turning Point Therapeutics, UT MD Anderson Cancer Center, and Vegenics; travel support from ASCO, ESMO, Helsinn, Incyte, Novartis, and PharmaMar; consultancy/advisory board participation for Helsinn, Incyte, Loxo Oncology/Eli Lilly, MedImmune, Novartis, R-Pharma US, QED Pharma; and other relationship with Medscape. CSB has received consulting fees from AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Turning Point Therapeutics, Guardant, Regeneron, Silverback, and Takeda; and has received research funding to their institution from AbbVie, AstraZeneca, Blueprint Medicines Corporation, Daiichi Sankyo, Genentech Inc., Janssen, Lilly, Loxo Oncology, Novartis, Pfizer, Rain Therapeutics, Spectrum Pharmaceuticals, and Turning Point Therapeutics. DSWT has consulted and/or had advisory roles for AstraZeneca, Bayer, Lilly, Loxo Oncology, Merrimack, Novartis, Pfizer, and Takeda; received honoraria from Boehringer Ingelheim, Merck, and Roche; and research funding to their institution from AstraZeneca, Bayer, GSK, and Novartis. DHL has received personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Chong Keun Dang, CJ Healthcare, Genexine, Janssen, Lilly, Merck, Menarini, MSD, Mundipharma, Novartis, Ono, Pfizer, Roche, Samyang Biopharm, ST Cube, and Takeda; and non-financial support from Blueprint Medicines Corporation and Takeda. DM has consulted and/or had advisory roles at scientific meetings for AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi, and Takeda (institution, no personal honoraria). EG has consulted and/or had advisory roles for Alkermes, BMS, Boehringer Ingelheim, Ellipses Pharma, Janssen, NeoMed, Roche, Seattle Genetics, TFS, Thermo Fisher Scientific; served on speakers’ bureaus for MSD, Roche, and Thermo Fisher Scientific; received travel and accommodation expenses from BMS, Glycotope GmbH, Menarini, and MSD; research funding to their institution from Novartis, Roche, and Thermo Fisher Scientific; and is supported by a grant from the ‘la Caixa’ Foundation [grant number LCF/PR/CE07/50610001]. DWK has received travel and accommodation expenses from Amgen and Daiichi Sankyo; and research funding to their institution from Alpha Biopharma, Amgen, AstraZeneca/MedImmune, Boehringer Ingelheim, Daiichi Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. AJvdW reports research funding/grant support for clinical trials from AstraZeneca [grant number ESR-16-12212], Boehringer Ingelheim, Pfizer, Roche, and Takeda [grant number 2019N0853/2020N0366]; and consultancy/advisory board participation for AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Pfizer, Roche, and Takeda. JFG has an immediate family member who is an employee of Ironwood Pharmaceuticals; has consulted and/or had advisory roles for Agios, Amgen, Array BioPharma, Blueprint Medicines Corporation, BMS, Genentech, Gilead Sciences, Jounce Therapeutics, Lilly, Loxo Oncology, Merck, Mirati, Silverback Therapeutics, GlydeBio, Moderna Therapeutics, Oncorus, Regeneron, Takeda, and Theravance; has stock and ownership in Ironwood Pharmaceuticals; has received honoraria from ARIAD, Incyte, Merck, Novartis, Pfizer, and Takeda; and research funding from Adaptimmune, ALX Oncology, ARIAD, Array BioPharma, AstraZeneca, Blueprint Medicines Corporation, BMS, Genentech, Jounce Therapeutics, Merck, Novartis, and Tesaro. LPA has a leadership role in ALTUM Sequencing and Genomica; served on speakers’ bureaus for AstraZeneca, BMS, Lilly, MSD Oncology, Merck Serono, Pfizer, Roche/Genentech; received travel, accommodation, and expenses from AstraZeneca, BMS, MSD, Pfizer, Roche, and Takeda; honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines Corporation, BMS, Celgene, Ipsen, Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; research funding to their institution from AstraZeneca, BMS, Kura Oncology, MSD, and PharmaMar; other relationships with Roche; and an immediate family member has other relationships with Amgen, Ipsen, Merck Novartis, Pfizer, Sanofi, Servier, and Roche. SVL served as a consultant or advisory board member to Amgen, AstraZeneca, Bayer, BeiGene, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, and Turning Point Therapeutics; received research funding (to institution) from Alkermes, Bayer, Blueprint Medicines Corporation, BMS, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT Therapeutics, Turning Point Therapeutics; and is supported by the National Cancer Institute [grant number UM1CA186691]. GPK received research grants from Blueprint Medicines Corporation, Merck, AbbVie, Takeda, Daiichi, and Cullinan. DWB served on an advisory board for Blueprint Medicines Corporation. ASM received research funding from DoD, Mark Foundation, NIH, Novartis, and Verily; honoraria to institution for participation in advisory boards: AbbVie, BeiGene, BMS, Genentech, Inc., Janssen; travel support from: Roche; is a non-remunerated member of the Mesothelioma Applied Research Foundation Board of Directors; and is supported by the Mark Foundation for Cancer Research ASPIRE Award, the National Cancer Institute [grant number R21 CA251923], and Department of Defense Concept Award [grant number W81XWH-22-1-0021]. JJL served as a compensated consultant or advisory board member for Genentech, C4 Therapeutics, Blueprint Medicines Corporation, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, and Turning Point Therapeutics; received honorarium and travel support from Pfizer; received institutional research funding from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; and received CME funding from OncLive, MedStar Health, and Northwell Health. VSm is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AR is an employee and/or equity holder of F. Hoffmann-La Roche, Ltd and equity holder of Merck/MSD. SK is a former employee and/or equity holder of F. Hoffmann-La Roche, Ltd. AZ, MLG and ALB are employees and/or equity holders of Blueprint Medicines Corporation. JM has provided expertise for Amgen, AstraZeneca, Blueprint Medicines Corporation, BMS, Daiichi Sankyo, Hengrui, MSD, Novartis, Pierre Fabre, Roche, and Takeda; and received research funding from AstraZeneca, BMS, Pierre Fabre, and Roche. YH has declared no conflicts of interest. Data sharing The anonymized derived data from this study that underlie the results reported in this article will be made available, beginning 12 months and ending 5 years after this article’s publication, to any investigators who sign a data access agreement and provide a methodologically sound proposal to medinfo@blueprintmedicines.com. The trial protocol will also be made available, as will a data fields dictionary., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies., Methods: In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib., Results: A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5)., Conclusions: Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Background: A phase I trial was performed to evaluate the administration of carboplatin/paclitaxel in combination with ISIS-5132, a phosphorothioate antisense oligodeoxynucleotide inhibitor of c-raf-1 kinase expression, in patients with advanced non-small cell lung cancer (NSCLC)., Patients and Methods: Previously untreated patients with stage IIIB/IV NSCLC received ISIS 5132 by continuous intravenous infusion at 2.0 mg/kg/d for 14 days. Starting doses were paclitaxel 175 mg/m(2) and carboplatin targeting an area under the free platinum plasma concentration-time curve (AUC(fp)) of 5 mg . min/ml (dose level 1). The carboplatin dose was then increased to AUC(fp) 6 mg . min/ml (dose level 2) after which the paclitaxel dose was increased to 200 mg/m(2) (dose level 3). The maximum tolerated dose was established by toxicity during the first two 21-day cycles of therapy. The pharmacokinetics of all three agents was determined before and during the ISIS 5132 infusion., Results: Thirteen patients were treated with the carboplatin/paclitaxel/ISIS 5132 combination. Dose-limiting neutropenia occurred in two patients at dose level 3. Grade 3 and 4 nonhematologic toxicities were infrequent and limited to nausea and constipation. The maximum tolerated doses were carboplatin AUC(fp) 6 mg . min/ml, paclitaxel 175 mg/m(2), and ISIS 5132 2.0 mg/kg/d for 14 days. There were no objective responses and the concurrent infusion of ISIS 5132 did not alter the plasma pharmacokinetics of paclitaxel or total platinum., Conclusion: ISIS 5132 can be safely combined with standard doses of carboplatin and paclitaxel. Combining cytotoxic chemotherapeutic agents with inhibitors of aberrant signal transduction mediated by Raf proteins produced no objective responses in the dose and schedule administered in this study.