Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials

Abstract

Background: The selective TRK inhibitor larotrectinib was approved for paediatric and adult patients with advanced TRK fusion-positive solid tumours based on a primary analysis set of 55 patients. The aim of our analysis was to explore the efficacy and long-term safety of larotrectinib in a larger population of patients with TRK fusion-positive solid tumours.

Methods: Patients were enrolled and treated in a phase 1 adult, a phase 1/2 paediatric, or a phase 2 adolescent and adult trial. Some eligibility criteria differed between these studies. For this pooled analysis, eligible patients were aged 1 month or older, with a locally advanced or metastatic non-CNS primary, TRK fusion-positive solid tumour, who had received standard therapy previously if available. This analysis set includes the 55 patients on which approval of larotrectinib was based. Larotrectinib was administered orally (capsule or liquid formulation), on a continuous 28-day schedule, to adults mostly at a dose of 100 mg twice daily, and to paediatric patients mostly at a dose of 100 mg/m2 (maximum of 100 mg) twice daily. The primary endpoint was objective response as assessed by local investigators in an intention-to-treat analysis. Contributing trials are registered with ClinicalTrials.gov, NCT02122913 (active not recruiting), NCT02637687 (recruiting), and NCT02576431 (recruiting).

Findings: Between May 1, 2014, and Feb 19, 2019, 159 patients with TRK fusion-positive cancer were enrolled and treated with larotrectinib. Ages ranged from less than 1 month to 84 years. The proportion of patients with an objective response according to investigator assessment was 121 (79%, 95% CI 72-85) of 153 evaluable patients, with 24 (16%) having complete responses. In a safety population of 260 patients treated regardless of TRK fusion status, the most common grade 3 or 4 larotrectinib-related adverse events were increased alanine aminotransferase (eight [3%] of 260 patients), anaemia (six, 2%), and decreased neutrophil count (five [2%]). The most common larotrectinib-related serious adverse events were increased alanine aminotransferase (two [<1%] of 260 patients), increased aspartate aminotransferase (two [<1%]), and nausea (two [<1%]). No treatment-related deaths occurred.

Interpretation: These data confirm that TRK fusions define a unique molecular subgroup of advanced solid tumours for which larotrectinib is highly active. Safety data indicate that long-term administration of larotrectinib is feasible.

Funding: Bayer and Loxo Oncology.

Conflict of interest statement

Declaration of interests

DSH reports grant funding, personal fees, and non-financial support from Bayer, Genmab, Loxo Oncology, and MiRNA; grant funding and personal fees from AbbVie, Adaptimmune, Amgen, Eisai, Genentech, Infinity, Kyowa, Eli Lilly, Merrimack, Pfizer, Seattle Genetics, and Takeda; grant funding from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Fate Therapeutics, Ignyta, Kite, Medimmune, Merck, Mirati, Molecular Templates, Mologen, NCI-CTEP, Novartis, Aldi-Norte, CPRIT, and Turning Point Therapeutics; personal fees from Axiom, Baxter, GLG, Group H, Guidepoint Global, Janssen, Medscape, Numab, Trieza Therapeutics, Alpha Insights, Acuta Capital, Prime Oncology, and WebMD; non-financial support from ASCO, AACR, and SITC; and other support in relation to roles as a founder and advisor for OncoResponse, and an advisor for Molecular Match and Presagia. SGD reports personal fees and travel expenses for advisory board attendance from Loxo Oncology, and travel expenses for advisory board attendance from Roche. SK reports personal fees from Loxo Oncology in relation to advisory board participation. AFF reports grant funding and personal fees from Bayer, Loxo Oncology, AbbVie, PharmaMar, Genentech, AstraZeneca, Roche, Bristol-Myers Squibb, and Merck; grant funding from Amgen and Ignyta; and personal fees from Boehringer Ingelheim. KSR reports grant funding and non-financial support from Loxo Oncology; grants, non-financial support, and travel and accommodation expenses from Roche; grant funding and non-financial support from Bayer, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Symphogen, AstraZeneca, Alligator, Merck, Bristol-Myers Squibb, and Eli Lilly; and travel and accommodation expenses from Sanofi. CMvT reports personal fees from Bayer and Novartis in relation to advisory boards. JDB reports personal fees from Bayer and research support from Bayer and Loxo Oncology; personal fees and research support from Taiho, FivePrime, and LSK Pharmaceuticals; personal fees from Celgene, Arno, AstraZeneca, Eisai, Seattle Genetics, Clovis, and Ipsen; research support from Novartis (Array), AbbVie, Immunomedics, Genentech/Roche, Eli Lilly, Incyte, Pharmacyclics, EMD Serono, Boston Biomedical, PsiOxus, Macrogenics, Symphogen, and Pfizer; participation in data and safety monitoring boards for AstraZeneca, Pancreatic Cancer Action Network, and Novocure; and a relationship with NCI (IDSC work). NF reports consulting and speaker’s bureau honoraria from Bayer. LM reports personal fees from Bayer in relation to speaker’s bureaus, institutional support for a paediatric phase 1 trial from Loxo Oncology, and travel and accommodation expenses from Thermo Fisher Scientific in relation to clinical gene sequencing; consulting fees relating to clinical trial development from Lilly Oncology and drug supply and financial support for an investigator-initiated trial from AstraZeneca, in both cases paid to his institution. ADo reports grant funding to his institution in relation to clinical trial support from Loxo Oncology, EMD Serono, Tesaro, Roche, Vertex, Regeneron, Eli Lilly, Ipsen, United Therapeutics, Mirati, Bristol-Myers Squibb, and Incuron; grant funding to his institution in relation to clinical trial support and personal fees for consultancy from AbbVie, AstraZeneca, Millenium, Takeda, and Seattle Genetics; and personal fees for consultancy from Ariad. ASP reports personal fees from Loxo Oncology, Bayer, Array Pharma, Eusa, and Roche. SB reports non-financial support from Loxo Oncology and Bayer; and personal fees in relation to advisory boards or consultancy from Bayer, Clinigen, Ipsen, Isofol, Eli Lilly, Novartis, Roche, and Sensorion. FD reports investigator fees from Loxo Oncology and Bayer; investigator fees and other support in relation to boards and travel from Bristol-Myers Squibb; investigator fees from Boehringer Ingelheim and Novartis; investigator fees and other support in relation to boards from Roche; other support in relation to boards from Tesaro; and other support in relation to consulting from Servier. RMcD reports clinical trial-related grant funding from Loxo Oncology. JDP reports personal fees from AbbVie, AstraZeneca, and Takeda in relation to advisory roles.

RJS reports financial support covering clinical trial costs from Loxo Oncology; and personal fees in relation to consultancies from Incyte, Immunogen, and Flatiron; and chairmanship of an independent data and safety monitoring board from Celsion. MT reports grant funding and personal fees from Bayer, Loxo Oncology, Ono Pharmaceutical, AstraZeneca, Pfizer, Rakuten Medical, and Bristol-Myers Squibb; grant funding from Novartis; and personal fees from Merck Serono, Eisai, Celgene, and Amgen. ML reports grant funding from Loxo Oncology to support expanded clinical testing for NTRK fusions; personal fees from Bayer, AstraZeneca, Bristol-Myers Squibb, and Takeda for ad hoc advisory boards; personal fees from Merck for a global advisory board; and grant funding from Helsinn Therapeutics for preclinical drug studies. ERR reports other support to her institution as compensation for time spent participating on advisory boards for Loxo Oncology and Bayer. SN and BHC are salaried employees of Bayer HealthCare Pharmaceuticals. TWL reports grant funding, personal fees, and non-financial support from Loxo Oncology; and grant funding, and non-financial support from Bayer; grant funding, personal fees, and non-financial support from Novartis; personal fees and non-financial support from Eli Lilly; and grant funding from Pfizer. DMH reports research grant funding from Loxo Oncology and Puma Biotechnology; research grant funding and personal fees for consulting from Bayer and AstraZeneca; personal fees for consulting from Chugai, Boehringer Ingelheim, Pfizer and Genentech/Roche; and personal fees for scientific advisory board participation from Fount Therapeutics. ADr reports honoraria for advisory boards from Loxo Oncology and Bayer; honoraria for advisory boards from Ignyta/Genentech/Roche, Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Helsinn, Beigene, BergenBio, Hengrui, Exelixis, Tyra, Verastem, MORE Health, and AbbVie; and other relationships including associated research paid to his institution from Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar, research (Foundation Medicine), royalties (Wolters Kluwer), other (Merck/Puma), and continuing medical education honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, and Oncology. CMA, RN, BG, SMF, and DW declare no competing interests.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure 1:. Trial profile

Three trials contributed patients to this analysis. The contributing trials did not have a prescreening component with central molecular testing; data on the number of patients screened for TRK fusions by local testing are consequently not available. The primary analysis set comprises those original patients included in the primary report with longer follow-up. The supplemental analysis set comprises the additional patients included in this Article. *Seven patients stopped treatment after surgery with curative intent.

Figure 2:. Waterfall plot of the maximum percentage change in tumour size according to tumour type

The waterfall plot excludes four patients who had clinical deterioration before an initial response assessment and six patients who were not evaluable due to insufficient time on therapy. GIST=gastrointestinal stromal tumour. IFS=infantile fibrosarcoma. *Maximum change in tumour size of 93% tumour growth. †Patients with brain metastases. ‡Patients with a pathological complete response.

Figure 3:. Kaplan-Meier plots of duration of response and progression-free survival

(A) Duration of response in 108 patients with confirmed responses in the combined primary and supplemental analysis sets. Two patients had complete responses pending confirmation following an earlier assessment of partial response (ie, classified overall as confirmed responses). (B) Progression-free survival in all 159 patients in the combined primary and supplemental analysis sets. Tick marks indicate censored patients.