Bayer - Industry Satellite Symposium Industry Satellite symposium

Emerging data on TRK inhibition in TRK fusion lung cancer

Lecture Time
16:35 - 16:50
Speakers
  • A. Drilon (New York, NY, United States of America)
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
Fri, 12.04.2019
Time
16:30 - 17:30
Authors
  • A. Drilon (New York, NY, United States of America)
Bayer - Industry Satellite Symposium Industry Satellite symposium

Ask the experts: Patient cases from TRK inhibitor clinical trials

Lecture Time
17:05 - 17:15
Speakers
  • L. Bubendorf (Basel, Switzerland)
  • A. Drilon (New York, NY, United States of America)
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
Fri, 12.04.2019
Time
16:30 - 17:30
Authors
  • L. Bubendorf (Basel, Switzerland)
  • A. Drilon (New York, NY, United States of America)
Bayer - Industry Satellite Symposium Industry Satellite symposium

Q&A and close

Lecture Time
17:15 - 17:30
Speakers
  • L. Bubendorf (Basel, Switzerland)
  • A. Drilon (New York, NY, United States of America)
Location
Room C, Geneva Palexpo, Geneva, Switzerland
Date
Fri, 12.04.2019
Time
16:30 - 17:30
Authors
  • L. Bubendorf (Basel, Switzerland)
  • A. Drilon (New York, NY, United States of America)
Mini Oral session I Mini Oral session

111O - Activity of larotrectinib in TRK fusion lung cancer

Presentation Number
111O
Lecture Time
08:00 - 08:05
Speakers
  • A. Drilon (New York, NY, United States of America)
Session Name
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
Thu, 11.04.2019
Time
08:00 - 08:50
Authors
  • A. Drilon (New York, NY, United States of America)
  • S. Kummar (Stanford, CA, United States of America)
  • V. Moreno (Madrid, Spain)
  • J. Patel (Chicago, IL, United States of America)
  • U. Lassen (Copenhagen, Denmark)
  • L. Rosen (Los Angeles, CA, United States of America)
  • B. Childs (Whippany, NJ, United States of America)
  • S. Nanda (Whippany, NJ, United States of America)
  • M. Cox (San Francisco, CA, United States of America)
  • N. Ku (San Francisco, CA, United States of America)
  • A. Farago (Boston, MA, United States of America)

Abstract

Background

Tropomyosin receptor kinases (TRK) fusions involving NTRK1, NTRK2 and NTRK3 genes occur in a diverse range of tumor types including lung cancer. Larotrectinib, the first FDA-approved selective TRK inhibitor, has demonstrated an overall response rate of 75% by independent central review across a broad range of tumor types (Drilon et al., NEJM 378:731-9, 2018). Here we report on the subset of lung cancer patients that have been treated with larotrectinib.

Methods

NSCLC patients with TRK fusion cancer detected by molecular profiling from two clinical trials (NCT02122913 and NCT02576431) were eligible. Larotrectinib (100 mg BID) was administered on a continuous 28-day schedule until withdrawal, unacceptable toxicity or disease progression. Efficacy was investigator assessed using RECIST version 1.1.

Results

As of July 30, 2018 eleven patients with metastatic lung adenocarcinoma were enrolled. Median age was 52 years (range 25 – 76). Eight patients had fusions involving NTRK1 and diverse fusion partners; EPS15 (n = 2), TPM3 (n = 2), IRF2BP2 (n = 2), TPR (n = 1), SQSTM1 (n = 1). Three patients had fusions involving NTRK3; fusion partners SQSTM1 (n = 2) and ETV6. Ten patients had prior systemic therapy (5 patients had 3 or more prior therapies) with best response on last prior therapy being 1 partial response and 4 stable disease. Seven patients were evaluable for response to larotrectinib. One patient had a complete response, 4 patients had a partial response, and 2 patients had stable disease (ORR 71%). The median time to response was 1.8 months. The duration of response ranged from 7.4+ months to 17.6+ months; the median duration of response was not reached. Two patients discontinued treatment due to disease progression and 1 withdrew consent. Four patients were on treatment less than 1 month and were non-evaluable for efficacy. Larotrectinib was well tolerated, with treatment related adverse events being predominantly grade 1 and grade 2.

Conclusions

Larotrectinib is highly active in lung cancer patients harboring NTRK gene fusions. These results strongly support the inclusion of NTRK gene fusions as part of routine molecular testing for patients with lung cancer.

Clinical trial identification

NCT02122913, NCT02576431.

Legal entity responsible for the study

Loxo Oncology Inc. Bayer AG.

Funding

Loxo Oncology Inc. Bayer AG.

Disclosure

A. Drilon: Honoraria: Ignyta, Loxo, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech, Roche, Takeda, ARIAD, Millenium, Helsinn, Beigene, BerGenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences; Research: Foundation Medicine. V. Moreno: Educational grant: Medscape/Bayer. U. Lassen: Honorarium: Bayer. L. Rosen: Research funding: Loxo Oncology. B.H. Childs, S. Nanda: Employee: Bayer Healthcare Pharmaceuticals. M.C. Cox, N.C. Ku: Employee: Loxo Oncology. A.F. Farago: Consulting: Bayer; Consulting, research funding: Loxo, AstraZeneca, Genentech, Pharmamar, AbbVie & Stemcentrx; Research funding: Ignyta, Merck, BMS. All other authors have declared no conflicts of interest.

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Proffered Paper session II Proffered Paper session

109O - Entrectinib in locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC): Integrated analysis of ALKA-372-001, STARTRK-1 and STARTRK-2

Presentation Number
109O
Lecture Time
09:39 - 09:51
Speakers
  • F. Barlesi (Marseille, CEDEX 20, France)
Location
Room A, Geneva Palexpo, Geneva, Switzerland
Date
Thu, 11.04.2019
Time
09:00 - 10:30
Authors
  • F. Barlesi (Marseille, CEDEX 20, France)
  • A. Drilon (New York, NY, United States of America)
  • F. De Braud (Milano, Italy)
  • B. Cho (Seoul, Korea, Republic of)
  • M. Ahn (Seoul, Korea, Republic of)
  • S. Siena (Milano, Italy)
  • M. Krebs (Manchester, United Kingdom)
  • C. Lin (Taipei, Taiwan)
  • T. John (Heidelberg, VIC, Australia)
  • D. Tan (Singapore, Singapore)
  • T. Seto (FUKUOKA, Fukuoka, Japan)
  • R. Dziadziuszko (Gdansk, Poland)
  • H. Arkenau (London, United Kingdom)
  • C. Rolfo (Baltimore, MD, United States of America)
  • J. Wolf (Cologne, Germany)
  • C. Ye (South San Francisco, United States of America)
  • T. Riehl (South San Francisco, United States of America)
  • S. Eng (South San Francisco, United States of America)
  • R. Doebele (Aurora, United States of America)

Abstract

Background

Entrectinib is a potent ROS1 inhibitor (as well as TRKA/B/C), designed to effectively penetrate the central nervous system (CNS); brain metastases are common in patients (pts) with advanced ROS1 fusion-positive NSCLC. Entrectinib achieves therapeutic levels in the CNS with antitumour activity in multiple intracranial tumour models. We present updated integrated safety and efficacy data from three Phase 1/2 entrectinib studies (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]) in pts with locally advanced/metastatic ROS1 fusion-positive NSCLC.

Methods

The analysis included pts with ROS1 inhibitor-naïve NSCLC harbouring a ROS1 fusion identified via nucleic acid-based diagnostic platforms. The ROS1 safety-evaluable population included pts who received ≥1 dose of entrectinib; the integrated efficacy analysis included pts with at least 6 months of follow-up. Tumour assessments were done at wk 4 and then every 8 wks by blinded independent central review (BICR), using RECIST v1.1. Primary endpoints by BICR: overall response rate (ORR), duration of response (DOR). Key secondary endpoints: progression-free survival (PFS), safety. Additional endpoints: intracranial ORR (complete/partial response), DOR in pts with intracranial response, PFS in pts with or without baseline CNS disease.

Results

In the ROS1 safety-evaluable population (n = 134), at least one treatment-related AE (TRAE) of any grade was seen in 93% of pts. Pts with at least one TRAE by highest grade were: grade 1/2, 59%; grade 3, 31%; grade 4, 4%. There were no grade 5 TRAEs. TRAEs led to dose reduction or discontinuation in 34% and 5% of pts, respectively. Efficacy outcomes are summarised in the table.

Conclusions

Entrectinib is highly active in pts with ROS1 fusion-positive NSCLC, including pts with CNS disease. Entrectinib is well tolerated with a manageable safety profile.

Clinical trial identification

ALKA-372-001 = EudraCT 2012-000148-88 – start date: 2015, trials ongoing STARTRK-1= NCT02097810 – start date: 2014, active, not recruiting (last update 2018) STARTRK-2 = NCT02568267 – start date: 2015, recruiting (last update 2018).

Editorial acknowledgement

Medical writing and editorial support provided by Charlotte Kennerley PhD of Gardiner-Caldwell Communications, Ashfield Healthcare Communications and was sponsored by Roche in accordance with Good Publication Practice guidelines.

Legal entity responsible for the study

F. Hoffmann-La Roche.

Funding

Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.

Disclosure

F. Barlesi: Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, Takeda. A. Drilon: Advisory boards: Bayer, Ignyta, Loxo Oncology, Pfizer, Roche/Genentech, TP Therapeutics; Research funding: Loxo Oncology. F. De Braud: Advisory boards: Novartis, Roche/Genetech, Merk Serono, Bristol-Myers Squibb, GlaxoSmithKline, BMS, Celgene, Servier, Ignyta, Pfizer, MSD, Philogen, AstraZeneca, Boehringer Ingelheim, Sanofi Aventis, Giscad, Italfarmaco, Eli Lilly, Amgen, Nadirex. S. Siena: Advisory boards: Amgen, Bayer, BMS, CheckmAb, Celgene, Incyte, Merck, Novartis, Roche and Seattle Genetics. M.G. Krebs: Honoraria for Advisory boards: Roche, Janssen, Octimet, Achilles therapeutics; Travel grants: AstraZeneca. C.C. Lin: Honoraria: AstraZeneca, BeiGene, Daiichi Sankyo, Novartis, Roche; Advisory boards: Blueprint, Boehringer Ingelheim, Novartis. T. John: Advisory boards: BMS, AstraZeneca, Boehringer, Takeda, Pfizer, Novartis, Merck, Ignyta, Roche. D.S.W. Tan: Grants and honoraria for Advisory boards: Novartis, Bayer, Boehringer Ingelheim, Merck, AstraZeneca, BMS, Roche, Pfizer and grants from GSK, Novartis, AstraZeneca. T. Seto: Honoraria/research: Astellas, AZ, Bayer, BMS, Chugai, Daiichi Sankyo, Eisai, EliLilly, Kissei, Kyowa HakkoKirin, MerckSerono, Mochida, MSD, Nippon, Novartis, BI, NipponKayakuOno, Pfizer, Roche, Sanofi, ShowaYakuhinKako, Taiho, Takeda, YakultHonsha, Verastem. R. Dziadziuszko: Honoraria, consulting fees: Roche, Pfizer, Boehringer Ingelheim, Clovis Oncology, Novartis, AstraZeneca, Tesaro. H-T. Arkenau: Employee: HCA; Advisory boards: Beigene, Guardant Health, Bicycle. C. Rolfo: Honoraria, Advisory boards: Mylan, Novartis, MSD, GuardantHealth, AstraZeneca. J. Wolf: Corporate sponsored research: BMS, MSD, Novartis, Pfizer; Advisory boards: AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Ignyta, Lilly MSD, Novartis, Pfizer, Roche. C. Ye, T. Riehl, S. Eng: Employee: Genentech. R.C. Doebele: Research: Ignyta; Advisory boards; Roche, Ignyta, Takeda, AstraZeneca, Bayer; Stock ownership: Rain Therapeutics; Patent or biological material licensing fees: Ignyta, Abbott Molecular, Rain Therapeutics. All other authors have declared no conflicts of interest.

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