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Matthew G Krebs
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Proffered Paper session II (ID 61)
- Event: ELCC 2019
- Type: Proffered Paper session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/11/2019, 09:00 - 10:30, Room A
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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 (ID 501)
09:00 - 10:30 | Author(s): Matthew G Krebs
- Abstract
- Presentation
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.
a9ded1e5ce5d75814730bb4caaf49419 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.
20c51b5f4e9aeb5334c90ff072e6f928 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.
fd69c5cf902969e6fb71d043085ddee6 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.
b651e8a99c4375feb982b7c2cad376e9 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).
7a6a3ffa2dadc03a6151ee2c4d6fa383 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.
934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study
F. Hoffmann-La Roche.
213f68309caaa4ccc14d5f99789640ad Funding
Ignyta, Inc., a wholly owned subsidiary of F. Hoffmann-La Roche Ltd.
682889d0a1d3b50267a69346a750433d 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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21O - EPAC-Lung: Pooled analysis of circulating tumor cells in advanced non-small cell lung cancer (ID 434)
09:00 - 10:30 | Author(s): Matthew G Krebs
- Abstract
- Presentation
Background
We assessed the clinical validity of circulating tumor cell (CTC) quantification for prognostication of patients with advanced non-small cell lung cancer (NSCLC) by undertaking a European pooled analysis of individual patient data. This is the largest study of its kind and the first to examine between-centre heterogeneity of CTC identification in NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Methods
Nine European NSCLC CTC centers were asked to provide reported/unreported anonymised data for patients with advanced NSCLC who participated in CellSearch CTC studies from January 2003 - March 2017. We used Cox regression models, stratified by centre, to establish the association between CTC count and survival. We assessed the added value of CTCs to prognostic clinico-pathological models using likelihood ratio (LR) statistics and c-indices.
20c51b5f4e9aeb5334c90ff072e6f928 Results
Seven out of nine eligible centers provided data for 550 eligible patients, including 209 patients whose prognostic information was previously unpublished. CTC counts of ≥ 2 and ≥5 per 7·5 mL were associated with reduced progression-free survival (≥2 CTCs: HR 1.72, p < 0·001; ≥5 CTCs: HR 2.21, p < 0·001) and overall survival (≥2 CTCs: HR 2·18, p < 0·001; ≥5 CTCs: HR 2·75, p < 0·001), respectively. Survival prediction was significantly improved by addition of baseline CTC count to LR clinico-pathological models (log-transformed CTCs p < 0·0001; ≥2 CTCs p < 0·0001; ≥5 CTCs p < 0·0001), while more moderate improvements were observed with the use of c-index models. There was minor evidence of between-center heterogeneity in the effect on PFS, but not OS.No difference in CTC profile was observed between key NSCLC molecular subsets such as EGFR, ALK, and KRAS.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
These data confirm CTCs as an independent prognostic indicator of progression-free survival and overall survival in advanced NSCLC. CTC count improves prognostication when added to full clinico-pathological predictive models. ≥2 CTCs is an appropriate cutoff to move towards establishing clinical utility.
b651e8a99c4375feb982b7c2cad376e9 Legal entity responsible for the study
The authors.
213f68309caaa4ccc14d5f99789640ad Funding
Has not received any funding.
682889d0a1d3b50267a69346a750433d Disclosure
C.R. Lindsay: Institutional funding for an ongoing phase II trial for which I am PI; Supported by Roche as part of an ESMO translational fellowship awarded in 2014-2016. F.H. Blackhall: Grants: AstraZeneca, Novartis, Pfizer, Amgen, BMS; Consultancy fees: Cell Medica, MSD; Speaker bureau: BI; Advisory board work: Regeneron, Medivation, AbbVie, Takeda, Roche, Ibsen. M.G. Krebs: Advisory board: J&J. L. Terstappen: Inventor on a number of US patents related to CellSearch, rights of which assigned to Johnson&Johnson, CellSearch kits obtained from Johnson&Johnson through a collaborative agreement with the MCBP. J-C. Soria: Consultancy fees: AZ, Astex, Clovis, GSK, GamaMabs, Lilly, MSD, Mission Therapeutics, Merus, Pfizer, PharmaMar, Pierre Fabre, Roche/Genentech, Sanofi, Servier, Symphogen, Takeda; Full time employee: MedImmune; Shareholder: AZ, Gritstone. All other authors have declared no conflicts of interest.
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