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.
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.
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.
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.
NCT03037385.
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.
Blueprint Medicines Corporation.
Blueprint Medicines Corporation.
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.
The comprehensive genomic profile (CGP) by next generation sequencing (NGS) ctDNA can identify a wide spectrum of GA that range from drivers with approved targeted therapies for routine use to other GA with lack of evidence for actionability. We aimed to assess the clinical utility of NGS-ctDNA based on ESCAT in a large cohort of NSCLC patients.
Advanced NSCLC patients were prospectively enrolled between 11.2015-05.2019 in the Liquid Biopsy Program in our institution. Plasma ctDNA was collected at diagnosis, under therapy or at progressive disease (PD) and analyzed by InVisionFirstTMLung. We evaluated the detection of driver GA on ctDNA and the clinical utility for accessing targeted therapies approved for routine use (EGFR mutation (m), ALK rearrangement (r), BRAFV600Em, ROS1r), according to ESCAT tiers.
Preliminary results are available for 308 patients/547 samples (n = 117 untreated; 217 at PD). 58% were females, 42% nonsmokers, with median age of 61 (24-90) and 87% had adenocarcinoma. At diagnosis, ≥1 ctDNA GA was found in 79% (91/115; 2 failed analyses): 29% (26/91) were ESCAT tier I (16 EGFRm ex19/21, 1 ALKr, 1 ROS1r, 8 BRAFV600Em), 2% ESCAT tier II (2 METa ; 1 case co-driver with EGFRm) and 31% tier III (21 KRASm with 8 cases G12C; 5 HER2m, 2EGFRm ex20). ctDNA provided clinically informative results for 33% (38/115). At PD, ≥1 ctDNA GA was found in 75% (163/217); 2 failed analyses): 65% (106/163) in ESCAT tier I (66 EGFRm ex19/21, 7 ALKr, 32 BRAFV600Em, 1 ROS1r), <1% ESCAT tier II (1 METa) and 18% tier III (16 KRASm with 10 cases G12C; 10 HER2m, 3 EGFR others). ctDNA provided clinically informative results for 60% (130/217). We detected EGFR T790M in 49% (17/35) after 1st-2nd generation TKI, C797Sm in 75% (3/4) after Osimertinib and ALK mutations in 4/7 (57%) at TKI failure, with a total of 50% (21/42) cases where ctDNA provided clinical utility.
ctDNA proved clinically informative results for 33% in untreated patients, most of them ESCAT tier I GA (22%) directing targeted therapies in routine. At time of TKI failure, ctDNA was clinically informative assessing resistance in 50% of EGFR/ALK patients.
Gustave Roussy.
Has not received any funding.
L. Mezquita: Advisory / Consultancy: Roche Diagnostics; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Tecnofarma; Honoraria (self): Roche; Honoraria (self): AstraZeneca; Travel / Accommodation / Expenses: Chugai. D. Planchard: Advisory / Consultancy: Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Travel / Accommodation / Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer; Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. F. de Kievit: Shareholder / Stockholder / Stock options: INIVATA Ltd. L. Lacroix: Advisory / Consultancy: Abbott, Astrazeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ca Bayer Healthcarer, Illumina, Genomic Health, Myriad, Novartis, Pfizer, Roche, Siemens, Thermofisher, VelaDx. J. Remon Masip: Advisory / Consultancy: Pfizer, MSD, BMS, Astrazeneca, Boehringer Ingelheim; Travel / Accommodation / Expenses: OSE Immunotherapeutics, BMS, Astrazeneca, Roche; Honoraria (self): OSE Immunotherapeutics. P. Lavaud: Travel / Accommodation / Expenses: Astellas-Pharma, AstraZeneca, Ipsen, Janssen Oncology, Mundi Pharma. A. Gazzah: Travel / Accommodation / Expenses: Boehringer Ingelheim, Novartis, Pfizer, Roche; Advisory / Consultancy: Novartis; Research grant / Funding (institution), Clinical trials at Gustave Roussy: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Research grant / Funding (institution): AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-remunerated activity/ies, Drug supply: Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. C. Morris: Shareholder / Stockholder / Stock options: INIVATA Ltd. K. Howarth: Shareholder / Stockholder / Stock options: INIVATA Ltd. E. Green: Shareholder / Stockholder / Stock options: INIVATA Ltd. C. Massard: Advisory / Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion; Research grant / Funding (institution), Clinical Trials at Gustave Roussy: AbbVie, Aduro, Agios, Amgen, Argen-x, Astex, AstraZeneca, Aveopharmaceuticals, Bayer, Beigene, Blueprint, BMS, Boehringer Ingelheim, Celgene, Chugai, Clovis, Daiichi Sankyo, Debiopharm, Eisai, Eos, Exelixis, Forma, Gamamabs, Genentech, Gortec, GSK, H3 biomed. B. Besse: Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma; Research grant / Funding (institution), Clinical Trials at Gustave Roussy: Nerviano, GSK, Pfizer, Roche-Genentech, Lilly, OSE Pharma, MSD, Celgene, Stemcentrx, Ignyta, AbbVie, Loxo Oncology, AstraZeneca, Blueprint Medicines. All other authors have declared no conflicts of interest.
Genomic rearrangements involving neurotrophic tropomyosin receptor kinase 1, 2, or 3 (NTRK1/2/3) result in constitutively active tropomyosin receptor kinase (TRK) fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the US Food and Drug Administration in 2018 for the treatment of TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. Here, we report median duration of response (DOR) data in the primary cohort and updated data in an expanded cohort of 159 patients with TRK fusion cancer treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy.
Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was February 19, 2019.
In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–not evaluable [NE]), with 17 progression events and 27 responses ongoing (range 1.6–44 months). Median progression-free survival in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). Median age was 43 years, ranging from < 1 month to 84 years; 33% < 18 years. The overall response rate was 79% (95% CI 72–85), with complete responses in 16%. Adverse events were mostly grade 1–2; 13% of patients had a grade 3–4 event related to larotrectinib. Only one patient discontinued due to an adverse event related to larotrectinib.
These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib demonstrated a favorable long-term safety profile. Screening patients for NTRK gene fusions should be considered.
NCT02122913, NCT02637687, NCT02576431.
Bayer.
Bayer.
F. Doz: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (self): Celgene; Advisory / Consultancy: Bayer; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy: Servier. L. Mascarenhas: Speaker Bureau / Expert testimony: Bayer. J. Berlin: Research grant / Funding (institution): PsiOxus; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Symphogen; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): AbbVie (pharamcyclics); Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): FivePrime; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal; Advisory / Consultancy: Seattle Genetics; Honoraria (self): Eisai; Advisory / Consultancy: Taiho; Advisory / Consultancy: Armo. All other authors have declared no conflicts of interest.
ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here.
Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Patients were treated with single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA), and standard safety evaluations.
A total of 43 patients were treated, including 17 patients with gastroesophageal adenocarcinoma (GEA), 6 with biliary cancers, 10 with colorectal cancer, and 10 other cancers. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085).
ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors.
Identifier: NCT02892123.
Zymeworks Inc.
Zymeworks Inc.
D-Y. Oh: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis; Research grant / Funding (self): Array; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Green Cross. E. Hamilton: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Casadian Therapeutics; Research grant / Funding (self): Zymewors; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Hutchinson. M. Beeram: Speaker Bureau / Expert testimony: Genentech. K-W. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (self): ALX Oncology; Research grant / Funding (self): Array BioPharma; Research grant / Funding (self): ASLAN Pharma; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Five Prime; Research grant / Funding (self): Green Cross Corp; Research grant / Funding (self): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (self): Merck MGaA; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y-K. Kang: Advisory / Consultancy: ONO; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSK BioPharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blue print; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (self): Roche; Research grant / Funding (self): Novartis. J. Chaves: Honoraria (self): PLLC. C. Vaklavas: Advisory / Consultancy: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (self): Genentech; Research grant / Funding (self): Roche; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Incyte; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pharmacyclics; Research grant / Funding (self): Tracon; Research grant / Funding (self): Innocrin; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): H3 Biomedicine. E. Elimova: Advisory / Consultancy: BMS; Honoraria (self): Zymeworks; Spouse / Financial dependant, Spouse: Merck employee in vaccine global division: Merck. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas; Advisory / Consultancy: Genomic health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): Amgen; Research grant / Funding (self): Astellas; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Bayer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Celldex; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis. A. Fortenberry: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. G. Rowse: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. T. Gray: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. R. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. F. Meric Bernstam: Research grant / Funding (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Calithera; Research grant / Funding (self): Aileron; Research grant / Funding (self): Bayer; Research grant / Funding (self): Jounce; Research grant / Funding (self): CytoMx; Research grant / Funding (self): eFFECTOR; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): PUMA Biotech; Research grant / Funding (self): Curis; Research grant / Funding (self): Millennium; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Takeda, Seattle Genetics, GlaxoSmithKline; Research grant / Funding (self), Travel / Accommodation / Expenses: Taiho, Genentech, Debiopharm Group, Pfizer; Consulting: Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, Parexel Internationa; Advisory / Consultancy: Inflection Biosciences, GRAIL, Darwin Health, Spectrum, Mersana, and Seattle Genetics. All other authors have declared no conflicts of interest.
MET exon 14 skipping (METex14), reported in 3–4% of NSCLC patients (pts), is sensitive to MET inhibition. We report interim data from Cohort A of the phase II VISION study (NCT02864992) of tepotinib, an oral potent highly selective MET inhibitor in NSCLC pts with METex14 skipping.
Pts with advanced wt EGFR/ALK NSCLC and METex14 skipping identified by liquid (L+) or tumor (T+) biopsy enrolled at 124 sites in 11 countries (35 in Asia: Japan [from Dec 2016], Republic of Korea, Taiwan [from Oct 2018]) received tepotinib 500 mg once daily until progression, intolerable toxicity or withdrawal. Primary endpoint is objective response rate (ORR) by independent review (IRC). Secondary endpoints include investigator-assessed ORR (INV), duration of response (DOR), PFS and safety (CTCAE 4.0). Pts evaluable for ORR have ≥2 post-baseline assessments or have discontinued for any reason. Predefined analysis sets include pts who are L+ or T+.
As of 14 June 2019, 1071 of 5102 prescreened pts were from Asia, 28 had been enrolled (17 Japan, 8 Korea, 3 Taiwan). At data cutoff (18 Feb 19) for efficacy and safety analyses, 87 pts had received tepotinib, treatment was ongoing in 47. In evaluable pts, ORR was 45–55% (Table). mDOR was >1 year in all groups (12.4–17.1 months) and >50% of pts were event free at 12 months (55–70%). mPFS was 9.5–12.2 months. 14 pts were from Asia (all from Japan), treatment was ongoing in 8. Of 11 evaluable pts from Japan, 6 were L+, 9 were T + (with overlap). In L+ pts, confirmed ORR (95% CI) was 66.7% (22.3, 95.7) by IRC and 83.3% (35.9, 99.6) by INV. In T+ pts, it was 33.3% (7.5, 70.1) by IRC, 55.6% (21.2, 86.3) by INV. Any/grade 3 treatment-related adverse events (TRAEs) reported by ≥ 15% of 87 treated pts were peripheral edema (48.3/8.0%), nausea (23.0/0%), diarrhea (20.7/1.1%). No TRAEs were grade 4/5. The safety profile was similar in pts from Japan. ORR: confirmed complete response/partial response. Patients evaluable for ORR have ≥2 post-baseline assessments or have discontinued for any reason. CI, confidence interval; ne, not estimable.L + T + IRC Inv n = 47 IRC n = 51 Inv n = 51 n = 48 ORR,* n (%) 24 (50.0) 26 (55.3) 23 (45.1) 28 (54.9) 95% CI 35.2, 64.8 40.1, 69.8 31.1, 59.7 40.3, 68.9 mDOR, months 95% CI 12.4 17.1 15.7 14.3 5.8, ne 7.1, ne 9.0, ne 5.7, ne 12-month event-free rate 95% CI 58% 55% 70% 59% 30, 78 28, 76 40, 87 32, 79 n = 57 n = 58 PFS events 22 24 23 22 mPFS, months 95% CI 9.5 9.5 10.8 12.2 6.7, ne 5.3, 21.1 6.9, ne 6.3, ne 12-month event-free rate 39% 42% 49% 55% 95% CI 21, 56 25, 58 31, 64 39, 69
Tepotinib has durable clinical activity and an acceptable safety profile in NSCLC pts with METex14 skipping detected by liquid or tissue biopsy.
NCT02864992.
Medical writing assistance (funded by Merck KGaA, Darmstadt, Germany) was provided by Matthew deSchoolmeester, PhD of Bioscript Science (Macclesfield, UK).
Merck KGaA.
Merck KGaA.
K. Park: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Clovis; Elli Lilly; Hanmi; ONO; Roche; Novartis. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blueprint Medicines; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Celgene, Guardant Health; Speaker Bureau / Expert testimony: MSD, Novartis, Pfizer, Roche, Takeda. R. Veillon: Research grant / Funding (institution): Takeda, AbbVie, Merck KGaA, BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Speaker Bureau / Expert testimony: DMS; Advisory / Consultancy: Pfizer, Novartis. A. Cortot: Research grant / Funding (institution): Merck KGaA; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda. J. Mazieres: Advisory / Consultancy: Roche, BMS, MSD, AstraZeneca, Pfizer, Novartis. H. Sakai: Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS, Ono, Chugai, MSD, Lilly, AstraZeneca; Research grant / Funding (institution): Merck KGaA, Regeneron, Taiho. N. Reinmuth: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer. J-Y. Han: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Novartis; Research grant / Funding (institution): ONO. M. Morise: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Chugai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: MSD; Honoraria (self), Research grant / Funding (institution): Ono; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho, Boehringer Ingelheim, Novartis, EMD, Kissei. T. Tokito: Honoraria (self): MSD, Chu-gai, Ono, Boehringer Ingelheim, Pfizer; Honoraria (self), Advisory / Consultancy: AstraZeneca. R. Bruns: Full / Part-time employment: Merck KGaA. J. Scheele: Full / Part-time employment: Merck KGaA. J. Straub: Full / Part-time employment: Merck KGaA. X. Le: Advisory / Consultancy: AstraZeneca, Lilly. P.K. Paik: Research grant / Funding (self), Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): Celgene; Advisory / Consultancy: AbbVie, BMS, Lilly, Takeda. All other authors have declared no conflicts of interest.
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.
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.
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.
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). 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.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
Not applicable
Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc.
The authors.
Boehringer Ingelheim.
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.