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Background Entrectinib is a systemic and CNS-active, potent inhibitor of TRKA/B/C and ROS1. Primary data from integrated efficacy and safety analyses (6 months' follow-up) from entrectinib clinical trials have shown that entrectinib is a promising option for patients (pts) with NTRK fusion-positive (NTRK+) solid tumors: blinded independent central review (BICR) objective response rate (ORR) was 57.4% (95% CI 43.2–70.8). We show longer follow-up data from this integrated analysis. Methods Pts with locally advanced/metastatic NTRK+ solid tumors confirmed by nucleic acid-based methods and enrolled in global (>150 sites, 15 countries) phase 1/2 entrectinib trials (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267) were included. Tumors were assessed after 4 wks (Cycle 1) then every 8 wks. Scans underwent BICR using RECIST v1.1. Primary endpoints were ORR and duration of response (DOR) by BICR. Secondary endpoints included overall survival (OS); ORR and DOR in pts with and without baseline CNS disease; intracranial (IC) ORR and DOR in pts with baseline CNS disease; safety. Results The efficacy-evaluable population comprises 54 adult pts with advanced/metastatic NTRK+ solid tumors, including pts with baseline CNS metastases. As of 30 Oct 2018 (additional 5 months' follow-up), BICR ORR was 59.3% (95% CI 45.0–72.4); complete responses n = 4 (7.4%). Median BICR DOR was 12.9 mo (95% CI 7.9–not estimable [NE]), median OS was 23.9 mo (95% CI 16.8–NE). Per baseline CNS status, BICR ORR was 58.3% (95% CI 27.7–84.8) and 59.5% (95% CI 43.3–74.4) and median DOR was NE (4.2–NE) and 12.9 mo (7.9–NE) for pts with (n = 12) and without (n = 42) CNS disease, respectively. IC ORR was 54.5% (95% CI 23.4–83.3) and median IC DOR by BICR was NE (6.7–NE). Entrectinib was well tolerated with a safety profile consistent with that previously reported; there were no new or unexpected safety findings. Conclusions In line with the primary data, these results at an additional 5 months of follow-up show that entrectinib induced clinically meaningful, durable systemic and intracranial responses in pts with NTRK+ solid tumors. Clinical trial identification ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267. Editorial acknowledgement Medical Writing support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure C. Rolfo: Speaker Bureau / Expert testimony: MSD, GuardantHealth, Mylan; Research grant / Funding (institution): Novartis, Sanofi; Non-remunerated activity/ies: Oncompass Steering scientific committee; OncoDNA: Research collaboration no renumerated for Exosomes (2017); GuarantHealth research collaboration (2019); Leadership role: IALSC, Educational Committee Member; ISLB, Vice President; Educational Chair, OLA Oncology Latin American Association; Scientific Committee Member at ESO; Membership Committee Officer, ESMO. R. Dziadziuszko: Advisory / Consultancy, Officer / Board of Directors: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Roche, AstraZeneca. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. G. Demetri: Research grant / Funding (institution): Bayer, Novartis, Pfizer, Janssen Oncology, Ignyta (now Roche) , Roche/Genentech, Loxo Oncology, AbbVie, Epizyme, Adaptimmune, GlaxoSmithKline ; Advisory / Consultancy: Novartis, Pfizer, EMD-Serono , Sanofi Oncology, Janssen Oncology, Ignyta (now Roche), Roche/Genentech, Loxo Oncology, Mirati Therapeutics, Epizyme, PharmaMar, Daiichi-Sankyo, WIRB Copernicus Group/ Arsenal Capital, ZioPharm, Polaris Pharmaceuticals, M.J. ; Licensing / Royalties: Novartis ; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: c ICON plc ; Advisory / Consultancy, Officer / Board of Directors: Blueprint Medicines; Officer / Board of Directors: Merrimack Pharmaceuticals; Shareholder / Stockholder / Stock options: G1 Therapeutics, Caris Life Sciences, Champions Oncology, Bessor Pharmaceuticals, Erasca Pharmaceuticals. B. Simmons: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche (Genentech). A. Aziez: Full / Part-time employment: Roche. X. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. S. Osborne: Full / Part-time employment: Roche. L. Paz-Ares: Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly, MSD, BMS, Roche, PharmaMar, Merck, Astra-Zeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Celgene, Amgen, Incyte, Pfizer; Officer / Board of Directors: Genomica; Research grant / Funding (institution): Astra-Zeneca, BMS, MSD; Non-remunerated activity/ies: Scientific Chair and Member of the Board of Asociación Española Contra el Cáncer (AECC; Majoir Spanish Anti-Cancer Charity); Spouse / Financial dependant: My wife (Rocio Garcia-Carbonero): - She has been EMA SAG member untill June 2017 - She has received honoraria from July 2017 onwards from Ipsen, Novartis, Pfizer, Servier, Sanofi, Roche, Amgen and Merck. [ABSTRACT FROM AUTHOR]

Background Effective targeted therapy for non-small-cell lung cancer (NSCLC) patients with human epidermal growth factor receptor 2 (HER2) mutations remains an unmet need. This study investigated the antitumor effect of an irreversible pan-HER receptor tyrosine kinase inhibitor, pyrotinib. Patients and methods Using patient-derived organoids and xenografts established from an HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma patient sample, we investigated the antitumor activity of pyrotinib. Preliminary safety and efficacy of pyrotinib in 15 HER2-mutant NSCLC patients in a phase II clinical trial are also presented. Results Pyrotinib showed significant growth inhibition of organoids relative to afatinib in vitro (P  =   0.0038). In the PDX model, pyrotinib showed a superior antitumor effect than afatinib (P  =   0.0471) and T-DM1 (P  =   0.0138). Mice treated with pyrotinib displayed significant tumor burden reduction (mean tumor volume, −52.2%). In contrast, afatinib (25.4%) and T-DM1 (10.9%) showed no obvious reduction. Moreover, pyrotinib showed a robust ability to inhibit pHER2, pERK and pAkt. In the phase II cohort of 15 patients with HER2 - mutant NSCLC, pyrotinib 400 mg resulted in a objective response rate of 53.3% and a median progression-free survival of 6.4 months. Conclusion Pyrotinib showed activity against NSCLC with HER2 exon 20 mutations in both patient-derived organoids and a PDX model. In the clinical trial, pyrotinib showed promising efficacy. Clinical trial registration NCT02535507. [ABSTRACT FROM AUTHOR]

Background NTRK1, NTRK2 and NTRK3 gene fusions (NTRK gene fusions) occur in a range of adult cancers. Larotrectinib is a potent and highly selective ATP-competitive inhibitor of TRK kinases and has demonstrated activity in patients with tumours harbouring NTRK gene fusions. Patients and methods This multi-centre, phase I dose escalation study enrolled adults with metastatic solid tumours, regardless of NTRK gene fusion status. Key inclusion criteria included evaluable and/or measurable disease, Eastern Cooperative Oncology Group performance status 0–2, and adequate organ function. Larotrectinib was administered orally once or twice daily, on a continuous 28-day schedule, in increasing dose levels according to a standard 3 + 3 dose escalation scheme. The primary end point was the safety of larotrectinib, including dose-limiting toxicity. Results Seventy patients (8 with tumours with NTRK gene fusions; 62 with tumours without a documented NTRK gene fusion) were enrolled to 6 dose cohorts. There were four dose-limiting toxicities; none led to study drug discontinuation. The maximum tolerated dose was not reached. Larotrectinib-related adverse events were predominantly grade 1; none were grade 4 or 5. The most common grade 3 larotrectinib-related adverse event was anaemia [4 (6%) of 70 patients]. A dose of 100 mg twice daily was recommended for phase II studies based on tolerability and antitumour activity. In patients with evaluable TRK fusion cancer, the objective response rate by independent review was 100% (eight of the eight patients). Eight (12%) of the 67 assessable patients overall had an objective response by investigator assessment. Median duration of response was not reached. Larotrectinib had limited activity in tumours with NTRK mutations or amplifications. Pharmacokinetic analysis showed exposure was generally proportional to administered dose. Conclusions Larotrectinib was well tolerated, demonstrated activity in all patients with tumours harbouring NTRK gene fusions, and represents a new treatment option for such patients. ClincalTrials.gov number NCT02122913. [ABSTRACT FROM AUTHOR]

BACKGROUND Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS We enrolled patients with consecutively and prospectively identified TRK fusion--positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1-2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion-positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913, NCT02637687, and NCT02576431.) [ABSTRACT FROM AUTHOR]

The article discusses research on the safety, pharmacokinetics, efficacy of rociletinib in patients with non-small cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR). The study evaluated the response rate and median progression-free survival rate of patients administered with rociletinib. The researchers examined the potential toxic effects, adverse events and anti-tumor activity of the drug.

Background Pralsetinib, an investigational agent, is a potent and selective inhibitor of oncogenic rearranged during transfection (RET) alterations and predicted resistance mutations. Up to 90% of advanced MTC is characterized by single nucleotide variants and short insertions/deletions in the RET gene. In NSCLC, 1–2% of patients (pts) harbor rearrangements resulting in RET fusions. In the first-in-human ARROW study (NCT03037385), pralsetinib showed significant clinical activity in RET-altered NSCLC and MTC and was well tolerated. Previous data show that early decline in circulating tumor DNA (ctDNA) may predict treatment outcome. We investigated the change in ctDNA levels from baseline following treatment with pralsetinib and whether early changes in ctDNA during treatment were associated with clinical responses and outcomes. Methods Blood was collected at baseline and prespecified time points during treatment. Plasma from 111 pts with locally documented RET-altered MTC and NSCLC were profiled with the Personal Genome Diagnostics PlasmaSELECT™ R64 sequencing panel. Results RET fusions were detected at baseline in 45/63 (71%) of pts with NSCLC and RET mutations in 35/48 (73%) of pts with MTC. Baseline ctDNA mutant allele fraction ?MAF; MTC? or unique fusion reads (NSCLC) correlated with the sum of target lesions ?P<0.01?. Pralsetinib led to rapid RET ctDNA decline in almost all pts and across all doses (60–600 mg QD, 100–200 mg BID). Eighty-one percent of pts with NSCLC and detectable ctDNA at baseline had undetectable RET ctDNA after 8 weeks of treatment. Clearance of RET fusions in NSCLC was observed for multiple fusion partners including CCDC6 and KIF5B. ctDNA was also undetectable after 8 weeks in 41% of pts with MTC harboring somatic RET mutations. The correlation between change in ctDNA level and clinical outcome is not yet mature, but will be reported. Conclusions Treatment with pralsetinib led to a robust and rapid decline in ctDNA in almost all patients regardless of treatment dose or tumor diagnosis and in NSCLC irrespective of fusion partner studied. Clinical trial identification NCT03037385. Editorial acknowledgement Third-party writing assistance was provided by Meredith Kalish, MD, of Ashfield Healthcare Communications, part of UDG Healthcare plc, and funded by Blueprint Medicines Corporation. Legal entity responsible for the study Blueprint Medicines Corporation. Funding Blueprint Medicines Corporation. Disclosure D.H. Lee: Honoraria (institution): AstraZeneca; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): Bristol-Myers Squibb; Honoraria (institution): CJ Healthcare; Honoraria (institution): Eli Lilly; Honoraria (institution): Janssen; Honoraria (institution): Merck; Honoraria (institution): MSD; Honoraria (institution): Mundipharma; Honoraria (institution): Novartis; Honoraria (institution): Ono; Honoraria (institution): Pfizer; Honoraria (institution): Roche; Honoraria (institution): Samyang Biopharm; Honoraria (institution): ST Cube; Advisory / Consultancy: Ministry of Food and Drug Safety, Korea; Advisory / Consultancy: Health Insurance Review and Assessment Service, Korea; Advisory / Consultancy: National Evidence-based Collaborating Agency, Korea; Advisory / Consultancy: National Cancer Control Planning Board, Korea. V. Subbiah: Advisory / Consultancy: MedImmune; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): NanoCarrier; Research grant / Funding (institution): Northwest Biotherapeutics; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Berg Pharma; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer AG; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Fujifilm; Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): D3 Oncology Solutions; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Multivir; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Loxo Oncology; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution), Takeda, Alfasigma, Sgensys, Idera, Boston Biomedical, Inhibrx, Exelixis: Remainder of organizations here due to space constraints. J.F. Gainor: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self): Incyte; Honoraria (self), Research grant / Funding (institution): ARIAD Pharmaceuticals; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Theravance; Advisory / Consultancy: Loxo; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Array BioPharma; Advisory / Consultancy: Amgen; Advisory / Consultancy: Agios; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Oncorus; Advisory / Consultancy, Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution), Moderna Therapeutics, Tesaro, Alexo Therapeutics: Remainder of organizations due to space constraints. M.H. Taylor: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai Inc; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Array Biopharma; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Loxo; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Blueprint; Honoraria (self), Advisory / Consultancy: Arqule; Honoraria (self), Advisory / Consultancy: Novartis; Research grant / Funding (institution): BioAtla. V.W. Zhu: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony: Roche-Foundation Medicine; Honoraria (self), Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (self), Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Shareholder / Stockholder / Stock options: TP Therapeutics. R.C. Doebele: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: ARIAD Pharmaceuticals; Honoraria (self), Travel / Accommodation / Expenses: Guardant Health; Honoraria (self): Takeda Pharmaceuticals; Honoraria (self): Spectrum Pharmaceuticals; Honoraria (self), Advisory / Consultancy: Trovagene; Advisory / Consultancy: OncoMed Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Licensing / Royalties, Licensing fees to institution for biologic materials: Ignyta; Advisory / Consultancy: GreenPeptide; Shareholder / Stockholder / Stock options: Rain Therapeutics; Licensing / Royalties, licensing fees for patent PCT/US2013/057495: Abbott Molecular. G. Lopes: Advisory / Consultancy: Pfizer; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): G1 Therapeutics. E. Garralda: Research grant / Funding (self), Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Menarini; Travel / Accommodation / Expenses: Glycotope; Licensing / Royalties: MSD. S.M. Gadgeel: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: ARIAD Pharmaceuticals; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AbbVie; Research grant / Funding (self), Research grant / Funding (institution): Merck; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution), Travel / Accommodation / Expenses: Takeda. C.D. Turner: Full / Part-time employment: Blueprint Medicines. M. Palmer: Full / Part-time employment: Blueprint Medicines. S. Miller: Full / Part-time employment: Blueprint Medicines. G. Curigliano: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background As new targeted therapies with CNS penetration and activity for non-small cell lung cancer (NSCLC) with ROS1 gene fusions (ROS1+) emerge, there is a need to characterize the disease course of patients (pts) receiving current treatment, especially in relation to CNS metastases (met). Methods We evaluated an anonymized cohort of ROS1+ NSCLC pts from the Flatiron Health electronic health record (EHR)-derived database of US cancer centers (2011–2018). Descriptive statistics were used for clinical and treatment pattern characterization. Kaplan-Meier curves estimated median overall survival (OS), real-world progression-free survival (rwPFS, using physician documentation in the EHR) and rwPFS in the CNS, from 1st-line treatment (1L) after diagnosis of advanced/metastatic NSCLC (aNSCLC Dx). Due to low numbers of pts in some groups, 95% CI are not reported. Results We identified 129 ROS1+ aNSCLC pts who received 1L treatment including crizotinib (n = 52, 40.3%), chemotherapy (n = 34, 26.4%), combination systemic therapy (n = 25, 19.4%), clinical study drug (n = 4, 3.1%), or no treatment (n = 14, 10.9%). For 1L crizotinib (the only approved therapy for ROS1+ NSCLC) after aNSCLC Dx median rwPFS: 8.6 m (95% CI: 6.2–12.1); OS: 19.9 m (95% CI: 15.1–NR). For pts receiving other 1L drugs median rwPFS: 5.9 m (95% CI: 4.1–7.2); OS: 18.1 m (95% CI: 12.9–34.6). There were 24 pts (18%) with CNS met at diagnosis and 20 pts (19%) at follow-up. Most pts with CNS met at or after diagnosis received surgery/radiotherapy (37/44, 84.1%). For CNS met pts who received 1L crizotinib after local treatment (6/11), median rwPFS: 8.0 m; OS: 27 m. From 1L crizotinib, pts with CNS met at follow-up only (10/21 pts with CNS mets who received 1L crizotinib), median rwPFS: 7.2 m; rwPFS-CNS: 9.1 m; OS: 15.1 m. For pts with no CNS mets anytime median rwPFS: 10.0 m; OS: 21.5 m from 1L crizotinib (34/55 pts). Conclusions In the US, ROS1+ NSCLC pts receive various 1L treatments after aNSCLC Dx. CNS was a site of metastasis in 44/129 ROS1+ NSCLC pts. Surgery/radiotherapy for CNS mets prior to systemic therapy may be associated with favorable outcomes, however conclusions on the natural history of cancers with rare mutations rely on very small patient numbers. Editorial acknowledgement Editorial support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure M.G. Krebs: Advisory / Consultancy, Officer / Board of Directors: Roche, Achilles Therapeutics, Octimet, Janssen; Research grant / Funding (institution): AstraZeneca, Bayer, BerGenBio, Blueprint, Carrick, Immutep, Incyte, Janssen, Merck, Octimet, Roche; Research grant / Funding (institution): Roche, BerGenBio; Travel / Accommodation / Expenses: AstraZeneca, BerGenBio. L. Perez: Research grant / Funding (institution), Shareholder / Stockholder / Stock options: Roche. A. Surinach: Full / Part-time employment: Genesis Research. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (institution): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. M. Martinec: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffman-La Roche Ltd. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. N.J. Meropol: Full / Part-time employment: Employed by Flatiron Health, Inc. an independent subsidiary of the Roche Group; Equity interest in Flatiron Health; Shareholder / Stockholder / Stock options: Roche. W. Wong: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. G. Crane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Entrectinib is a systemic and central nervous system (CNS)-active potent inhibitor of ROS1 and TRKA/B/C. Primary data showed that entrectinib was tolerable and achieved high objective response rates (ORR) in patients (pts) with ROS1-positive (ROS1+), ROS1 inhibitor-naive NSCLC, and in pts with NTRK fusion-positive (NTRK+) NSCLC, including pts with baseline CNS disease. We present data from an additional 5 months of follow-up. Methods Pts with locally advanced/metastatic ROS1+ or NTRK+ tumors (with or without baseline CNS disease) confirmed by nucleic acid-based methods, enrolled in global phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) were included. Disease burden was assessed per blinded independent central review (BICR) using RECIST v1.1, after cycle 1 (4 wks) then every 8 wks. Primary endpoints were ORR and duration of response (DOR) by BICR. Secondary endpoints included ORR and DOR in pts with or without baseline CNS disease, and safety. Intracranial (IC) ORR and DOR were evaluated in pts with baseline CNS disease. Results There were 53 efficacy-evaluable pts with treatment-naïve, ROS1+ NSCLC and 10 pts with NTRK+ NSCLC. As of 30 Oct 2018 (additional 5 months' follow-up), BICR ORR: ROS1+ 79.2% (95% CI 65.9–89.2) and NTRK+ 70.0% (95% CI 34.75–93.33) with complete responses in 5 (9.4%) pts and 1 (10.0%) pt, respectively. In ROS1+ NSCLC, median DOR: 24.6 mo (95% CI 12.6–34.8); in pts with and without baseline CNS disease, ORR was 73.9% (95% CI 51.6–89.8) and 83.3% (95% CI 65.3–94.4); IC ORR was 55.0% (95% CI 31.5–76.9); and median IC DOR was 12.9 mo (95% CI 5.6–not estimable). Additional efficacy for NTRK+ NSCLC pts will be presented. Entrectinib was well tolerated with a safety profile consistent with that previously reported; there were no new or unexpected safety findings. Conclusions In line with the primary data, in pts with ROS1+ and NTRK+ NSCLC after an additional 5 months of follow-up, entrectinib was well tolerated and showed clinically meaningful, durable systemic and intracranial responses. Clinical trial identification ALKA-372-001 [EudraCT 2012-000148-88] STARTRK-1 [NCT02097810] STARTRK-2 [NCT02568267]. Editorial acknowledgement Medical Writing support was provided by Laura Vergoz and Charlotte Kennerley, PhD of Gardiner-Caldwell Communications and was funded by F. Hoffmann-La Roche. Legal entity responsible for the study F. Hoffman-La Roche. Funding F. Hoffman-La Roche. Disclosure F. de Braud: Advisory / Consultancy, Officer / Board of Directors: TizianaLife Sciences, BMS, Celgene, Novartis, Servier, Pharm Research Associated, Daiichi Sankyo, Ignyta, Amgen, Pfizer, Octimet Oncology, Incyte, Teofarma, Pierre Fabre, Roche, EMD Serono ; Honoraria (self): BMS, Eli Lilly, Roche, Amgen, AstraZeneca, Gentili, Fondazione Menarini, Novartis, MSD, Ignyta, Bayer, Noema S.r.l. ACCMED, Dephaforum S.r.l. Nadirex, Roche, Biotechspert Ltd, PriME Oncology, Pfizer. S. Siena: Advisory / Consultancy: Amgen, Bayer, BMS, CheckmAb, Celgene, Daiichi-Sankyo, Incyte, Merck, Novartis, Roche-Genentech, and Seattle Genetics. F. Barlesi: Research grant / Funding (self), Travel / Accommodation / Expenses: Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda; Research grant / Funding (institution): AbbVie, ACEA, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis; Non-remunerated activity/ies: Principal Investigator for Astra-Zeneca, BMS, Merck, Pierre Fabre and Roche sponsored trials (or ISR). A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche Loxo/Bayer/Lilly Takeda/Ariad/Millenium TP Therapeutics AstraZeneca Pfizer Blueprint Medicines Helsinn Beigene BergenBio Hengrui Therapeutics Exelixis Tyra Biosciences Verastem MORE Health; Research grant / Funding (institution): Pfizer Exelixis GlaxoSmithKlein Teva Taiho PharmaMar; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Travel / Accommodation / Expenses: Merck - Food/Beverage Puma - Food/Beverage; Honoraria (self): Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice. B. Simmons: Full / Part-time employment: Roche (Genentech). X. Huang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. S. Osborne: Full / Part-time employment: Roche. R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (self): Ignyta, Loxo, Mirati; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond. [ABSTRACT FROM AUTHOR]

Background Neuregulin-1 gene (NRG1) fusions function as oncogenic drivers across various solid tumors, most notably in invasive mucinous adenocarcinoma (IMA) of the lung, and represent a rational potential target for treatment. NRG1 is a growth factor, which binds to ErbB3 or ErbB4 inducing the formation of ErbB3 or 4-containing homo- or heterodimers and activating downstream ErbB-family signaling pathways. Therefore, the ErbB-family blocker afatinib may be a potential treatment option for patients with solid tumors harboring NRG1 fusions. Methods We report a case series of all known patients with NRG1 fusion-positive solid tumors who were treated with afatinib; afatinib therapy is ongoing for some patients. Results To date, 18 patients with NRG1 fusion-positive solid tumors have been treated with afatinib (Table). These include 12 cases of non-small cell lung cancer (NSCLC; 7 of which were reported as IMA), 5 cases of gastrointestinal (GI) cancer (primarily pancreatic ductal adenocarcinoma [PDAC]) and 1 case of ovarian cancer. Various NRG1 fusion partners were identified, most commonly CD74 in patients with NSCLC (n = 7; 58%) and ATP1B1 in patients with gastrointestinal cancer (n = 3; 60%). Best response with afatinib among patients with NSCLC was partial response (PR) lasting 24 months (10 months among those specifically with IMA of the lung). Patients with PDAC experienced PR of 3 and 5.5 months' duration, and one patient has an ongoing PR after 7 months. One patient with cholangiocarcinoma had a PR lasting 8 months; another patient with ovarian cancer had stable disease (SD) of unknown duration. Conclusions Afatinib is a potential treatment option for some patients with solid tumors harboring NRG1 fusions. The efficacy and safety of afatinib will be evaluated in ongoing/planned prospective non-randomized clinical trials of targeted drugs in patients with advanced cancer with potentially actionable genomic variants (NCT02925234 and NCT02693535). Table: 63O Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  * PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Table: 63O Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  Tumor type    NRG1 fusion partner  Best response, physician assessed  Duration of response, mos  Refs  NSCLC  IMA  CD74  PR  10  1      CD74  PR  6.5  2      CD74  PD*    3      CD74  SD  3  3      SDC4  PD    3      CD74  PD    3      CD74  PR  -  4    ADC  SLC3A2  PR  12  1      SDC4  PR  12  5      -  PR  24  6      CD74  PR  14+  4, 6      SDC4  SD  4  6  GI  PDAC  ATP1B1  PR  3  7      ATP1B1  PR  5.5  8      APP  PR  7+  6, 8    Cholangiocarcinoma  ATP1B1  PR  8  5    Colorectal (KRASm +ve)  POMK  SD  4  9  Ovarian    CLU  SD  -  10  * PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Editorial acknowledgement Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo Smith Kline; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin. J. Cadranel: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AZ; Advisory / Consultancy, Non-remunerated activity/ies: BI; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Non-remunerated activity/ies: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis. B.A. Weinberg: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Caris Life Sciences; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AbbVie; Honoraria (self): Boerhinger ingelheim. S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Taiho (DSMB); Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Esanex; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Molecular Partners; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Rain Therapeutics; Research grant / Funding (institution): Threshold. K. Tolba: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Foundation One. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials : Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties, Licensing fees from patents or biological materials : Abbott Molecular; Licensing / Royalties, Licensing fees from patents or biological materials : GVKbio; Licensing / Royalties, Licensing fees from patents or biological materials: Chugai; Licensing / Royalties, Licensing fees from patents or biological materials : Genentech; Licensing / Royalties, Licensing fees from patents or biological materials: Foundation Medicine; Licensing / Royalties, Licensing fees from patents or biological materials: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): BI Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. P.K. Cheema: Honoraria (self), Advisory / Consultancy: Astrazeneca; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck. M.R. Jones: Full / Part-time employment: Qiagen. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. Solca: Full / Part-time employment: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Tahio; Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Servier. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background Inframe insertions in exon 20 of the epidermal growth factor receptor (EGFR) gene are oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike more common EGFR mutations, low frequency EGFR exon 20 insertions are resistant to clinically approved EGFR inhibitors and are associated with poor patient prognosis. There is an unmet clinical need to identify novel therapies that will be effective for patients with EGFR exon 20 insertions. Methods Cell viability of three patient-derived NSCLC cell line models harbouring EGFR exon 20 insertions, CUTO14 (A767_V769dupASV), CUTO17 (N771_H773dupNPH) and CUTO18 (S768_D770dupSVD) was assessed after treatment with a chemical compound screen targeting cancer-associated pathways. Western blotting was used to probe cell signalling following dasatinib treatment. Mutant SRC expression constructs were introduced into cell lines via lentiviral transduction and depletion of endogenous SRC levels was achieved using RNAi. Models of acquired drug resistance were developed by long-term drug exposure. Results Out of 58 screened compounds, the tyrosine kinase inhibitor dasatinib was a shared hit across all EGFR exon 20 insertion models and was superior to the EGFR inhibitor gefitinib in cell viability and apoptosis assays. Dasatinib sensitivity was rescued by expression of a gatekeeper mutant SRC that does not bind dasatinib, whilst all models were sensitive to RNAi-mediated depletion of endogenous SRC expression. Importantly, models of acquired dasatinib resistance maintain sensitivity to poziotinib, an EGFR inhibitor that can target EGFR exon 20 insertions. Similarly, dasatinib effectively inhibits cell viability of a model of acquired resistance to poziotinib, indicating two independent, targetable signalling nodes. Combined treatment with dasatinib and poziotinib prevented the emergence of drug resistance. Conclusions EGFR exon 20 insertion lung cancer models are sensitive to inhibition of parallel SRC signalling via dasatinib treatment. In a patient population with limited therapeutic options, an upfront rational combination of dasatinib with EGFR inhibitors that target EGFR exon 20 insertions has the potential to achieve durable responses. Legal entity responsible for the study Paul Huang. Funding Institute of Cancer Research, Cancer Research UK. Disclosure R. Doebele: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Genentech/Roche; Advisory / Consultancy, Travel / Accommodation / Expenses, Licensing / Royalties: Ignyta; Licensing / Royalties: Foundation Medicine; Advisory / Consultancy, Licensing / Royalties: Loxo Oncology; Advisory / Consultancy: Bayer; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: Rain Therapeutics; Honoraria (self), Advisory / Consultancy: Takeda/Millenium; Licensing / Royalties: Abbot Molecular. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]