Efficacy and Safety of Larotrectinib in Patients With Tropomyosin Receptor Kinase Fusion-Positive Lung Cancers

Alexander Drilon, Daniel S W Tan, Ulrik N Lassen, Serge Leyvraz, Yongmei Liu, Jyoti D Patel, Lee Rosen, Benjamin Solomon, Ricarda Norenberg, Laura Dima, Nicoletta Brega, Lin Shen, Victor Moreno, Shivaani Kummar, Jessica J Lin, Alexander Drilon, Daniel S W Tan, Ulrik N Lassen, Serge Leyvraz, Yongmei Liu, Jyoti D Patel, Lee Rosen, Benjamin Solomon, Ricarda Norenberg, Laura Dima, Nicoletta Brega, Lin Shen, Victor Moreno, Shivaani Kummar, Jessica J Lin

Abstract

Purpose: Larotrectinib is a highly selective and CNS-active tropomyosin receptor kinase (TRK) inhibitor that has demonstrated efficacy across TRK fusion-positive cancers, regardless of the tumor type. The aim of this study was to assess the efficacy and safety of larotrectinib in patients with TRK fusion-positive lung cancers.

Materials and methods: Data from two global, multicenter, registrational clinical trials of patients treated with larotrectinib were analyzed: a phase II adult and young adult basket trial (NCT02576431) and a phase I adult trial (NCT02122913). The primary end point was objective response rate (ORR).

Results: By July 20, 2020, 20 patients with TRK fusion-positive lung cancer had been treated. The ORR by investigator assessment among 15 evaluable patients was 73% (95% CI, 45 to 92); one (7%) patient had a complete response, 10 (67%) had a partial response, three (20%) had stable disease, and one (7%) had progressive disease as best response. The median duration of response, progression-free survival, and overall survival were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to not estimable), respectively. Among patients with baseline CNS metastases, the ORR was 63% (95% CI, 25 to 91). Adverse events were mainly grade 1 or 2.

Conclusion: Larotrectinib is highly active with rapid and durable responses, extended survival benefit, and a favorable long-term safety profile in patients with advanced lung cancer harboring NTRK gene fusions, including those with CNS metastases. These findings support routine testing for NTRK fusions in patients with lung cancer.

Conflict of interest statement

Alexander DrilonHonoraria: Medscape, OncLive, PeerVoice, Physicians' Education Resource, Targeted Oncology, MORE Health, Research to Practice, Foundation Medicine, PeerViewConsulting or Advisory Role: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Helsinn Therapeutics, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Verastem, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Remedica, Archer, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Melendi, Repare TherapeuticsResearch Funding: Foundation MedicinePatents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology)Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology Daniel S. W. TanHonoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, PfizerConsulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, PfizerResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche Ulrik N. LassenHonoraria: Bayer, Pfizer, NovartisConsulting or Advisory Role: Bayer, PfizerResearch Funding: BMS (Inst), Roche (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Incyte (Inst), Lilly (Inst) Serge LeyvrazConsulting or Advisory Role: Bayer, ImmunocoreTravel, Accommodations, Expenses: Bayer, Immunocore Jyoti D. PatelConsulting or Advisory Role: AbbVie, AstraZeneca, Takeda Science FoundationResearch Funding: Bristol Myers Squibb (Inst) Lee RosenResearch Funding: Pfizer (Inst), Bayer (Inst), PsiOxus Therapeutics (Inst), Rgenix (Inst) Benjamin SolomonConsulting or Advisory Role: BayerResearch Funding: AstraZeneca/Merck (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/358846 Ricarda NorenbergEmployment: Bayer HealthConsulting or Advisory Role: Bayer Health (Inst) Laura DimaEmployment: Bayer Nicoletta BregaEmployment: BayerLeadership: BayerStock and Other Ownership Interests: BayerTravel, Accommodations, Expenses: BayerOther Relationship: Bayer Lin ShenConsulting or Advisory Role: MSD, Bristol Myers Squib, AstraZeneca, Daiichi Sankyo, Roche, Mingji biopharmaceutical, Harbour BioMed, MerckSpeakers' Bureau: Hutchison Whampoa, MSDResearch Funding: Yaojie Ankang (Nanjing) Technology Co, Ltd (Inst), Baiji Shenzhou (Beijing) Biotechnology Co, Ltd (Inst), Beijing Xiantong Biomedical Technology Co, Ltd (Inst), QiLu Pharmaceutical (Inst), Zaiding Pharmaceutical (Inst) Victor MorenoEmployment: STARTConsulting or Advisory Role: Merck, Bristol Myers Squibb, Bayer, Janssen Oncology, Roche, BasileaSpeakers' Bureau: BayerResearch Funding: AbbVie (Inst), ACEA Biosciences (Inst), Adaptimmune (Inst), Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), BeiGene (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Celgene (Inst), Eisai (Inst), E-therapeutics (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Menarini (Inst), Merck (Inst), Nanobiotix (Inst), Novartis (Inst), Pfizer (Inst), PharmaMar (Inst), PsiOxus Therapeutics (Inst), Puma Biotechnology (Inst), Regeneron (Inst), RigonTEC (Inst), Roche (Inst), Sanofi (Inst), Sierra Oncology (Inst), Synthon (Inst), Taiho Pharmaceutical (Inst), Takeda (Inst), Tesaro (Inst), Transgene (Inst)Expert Testimony: Medscape/Bayer, NanobiotixTravel, Accommodations, Expenses: Sanofi/RegeneronOther Relationship: Bristol Myers Squibb Shivaani KummarStock and Other Ownership Interests: PathomIQ, Arxeon TherapeuticsConsulting or Advisory Role: Seattle Genetics, Bayer, Boehringer Ingelheim, Mundipharma EDO GmbH, Harbor BioMed, SpringWorks Therapeutics, Gilead Sciences, Mirati Therapeutics, EcoR1 Capital, Cadila PharmaceuticalsResearch Funding: Bristol Myers Squibb (Inst), Dynavax Technologies (Inst), Pfizer (Inst), Loxo (Inst), Corvus Pharmaceuticals (Inst), Plexxikon (Inst), Jounce Therapeutics (Inst), ADC Therapeutics (Inst), Advenchen Laboratories (Inst), Incyte (Inst), Taiho Pharmaceutical (Inst), Bayer (Inst), Astex Pharmaceuticals (Inst), Seattle Genetics (Inst), Amgen (Inst), Genome & Company (Inst), Moderna Therapeutics (Inst), ADC Therapeutics (Inst), ORIC Pharmaceuticals (Inst), Elevation Oncology (Inst), Vincerx Pharma (Inst), Day One Therapeutics (Inst)Travel, Accommodations, Expenses: Bayer Jessica J. LinHonoraria: Pfizer, OncLiveConsulting or Advisory Role: C4 Therapeutics, Genentech, Nuvalent, Inc, Blueprint Medicines, Turning Point Therapeutics, Turning Point TherapeuticsResearch Funding: Hengrui Therapeutics (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Neon Therapeutics (Inst), Relay Therapeutics (Inst), Elevation Oncology (Inst), Bayer (Inst), Roche (Inst)Travel, Accommodations, Expenses: PfizerNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Response to larotrectinib. A waterfall plot of the maximum change in the target lesion size (investigator assessment) with larotrectinib treatment is shown for 15 evaluable patients whose lung cancers harbored a TRK fusion. aTwo patients had CNS metastases included as target lesions with a 100% and 59% reduction observed by cycle 4, respectively. Each patient number refers to the same patient across all tables and figures. CR, complete response; INV, investigator; IRC, independent review committee; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; TRK, tropomyosin receptor kinase.
FIG 2.
FIG 2.
Response to larotrectinib. A 46-year-old man diagnosed with stage IV (T4N0M1) non–small-cell lung cancer previously progressed on first-line platinum-based chemotherapy (after 9 months) and on the PD-1 inhibitor dostarlimab (after 2 months). A TPM3-NTRK1 fusion was identified on molecular profiling, and larotrectinib was initiated on trial. A brisk partial response was achieved at 1.8 months, which was subsequently confirmed; the patient discontinued treatment because of progressive disease after a durable 39 months of disease control. NTRK, neurotrophic tyrosine receptor kinase; PD-1, programmed cell death-1.
FIG 3.
FIG 3.
Larotrectinib treatment duration. A swimmer plot of the duration of larotrectinib treatment is shown for all 20 patients whose lung cancers harbored a TRK fusion. aTwo patients had CNS metastases included as target lesions with a 100% and 59% reduction observed by cycle 4, respectively. bPatient discontinued for reasons other than progression. Each patient number refers to the same patient across all tables and figures. TRK, tropomyosin receptor kinase.
FIG 4.
FIG 4.
DoR and survival. Kaplan-Meier curves of (A) DoR, (B) PFS, and (C) OS are shown for patients with TRK fusion–positive lung cancers treated with larotrectinib. At the data cutoff, the median DoR, PFS, and OS were 33.9 months (95% CI, 5.6 to 33.9), 35.4 months (95% CI, 5.3 to 35.4), and 40.7 months (95% CI, 17.2 to NE), respectively. DoR, PFS, and OS rates at 12 months are indicated with vertical dashed lines on each curve. DoR, duration of response; NE, not estimable; OS, overall survival; PFS, progression-free survival; TRK, tropomyosin receptor kinase.
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8830513/bin/po-6-e2100418-g001.jpg

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