- U. Malapelle (Napoli, Italy)
- J. Mazieres (Toulouse, France)
21O - EPAC-Lung: Pooled analysis of circulating tumor cells in advanced non-small cell lung cancer
- C. Lindsay (Manchester, United Kingdom)
- C. Lindsay (Manchester, United Kingdom)
- F. Blackhall (Manchester, United Kingdom)
- A. Carmel (Villejuif, France)
- P. Gazzaniga (Rome, Italy)
- H. Groen (Groningen, Netherlands)
- M. Krebs (Manchester, United Kingdom)
- L. Muinelo-Romay (Santiago de Compostela, Spain)
- K. Pantel (Hamburg, Germany)
- E. Rossi (Padova, Italy)
- L. Terstappen (Enschede, Netherlands)
- H. Wikman (Hamburg, Germany)
- J. Soria (Gaithersburg, CEDEX, United States of America)
- F. Farace (Villejuif, France)
- A. Renehan (Manchester, United Kingdom)
- C. Dive (Manchester, United Kingdom)
- B. Besse (Villejuif, CEDEX, France)
- S. Michiels (Villejuif, France)
Abstract
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.
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.
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centers provided data for 550 eligible patients, including 209 patients whose prognostic information was previously unpublished.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.
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.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
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.
108O - Treatment duration of brigatinib in patients enrolled in the international expanded access program (EAP)
- X. Pan (Cambridge, MA, United States of America)
- M. Lin (Cambridge, United States of America)
- X. Pan (Cambridge, MA, United States of America)
- P. Hou (Cambridge, MA, United States of America)
- S. Allen (Cambridge, MA, United States of America)
- P. Baumann (Cambridge, MA, United States of America)
- M. Hochmair (Vienna, Austria)
Abstract
Background
Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor for the treatment of advanced ALK+ non-small cell lung cancer (NSCLC). In June 2016, the international EAP was opened to enable access to brigatinib prior to commercial launch for patients with unmet medical need, including those who had exhausted available therapies or were unable to participate in a clinical study. This retrospective analysis evaluated real-world treatment duration using brigatinib EAP shipment and discontinuation data.
Methods
This analysis included data from patients with locally advanced or metastatic ALK+ NSCLC who were resistant or intolerant to at least one ALK inhibitor and had received brigatinib across multiple lines of therapy through the EAP between July 2016 and Nov 7, 2018; most patients were European. Treatment duration was recorded for patients with confirmed discontinuation, as stated on their discontinuation forms. Discontinuation was assumed for patients without confirmed discontinuation if there was a gap of > 120 days between data cutoff and last medication shipment date. Time to treatment discontinuation was estimated from Kaplan-Meier curves. Subgroup analyses were conducted based on whether patients had received prior alectinib, ceritinib, or lorlatinib.
Results
A total of 604 patients (42.4% male; median age, 58.0 years) received brigatinib, with the majority receiving brigatinib as a 3+ line agent. Across all lines of therapy, median time to brigatinib discontinuation was 10.95 months (95% CI 8.65 − 13.88). Median time to discontinuation (95% CI) was 8.72 months (7.50 − 14.93) after alectinib (N = 111), 10.33 months (8.13 − 13.62) after ceritinib (N = 249) and 7.5 months (4.47−NE) after lorlatinib (N = 37). Few patients reported discontinuation due to adverse events (N = 4, 0.7%).
Conclusions
In the real world, despite a heterogeneous patient population treated with multiple prior ALK inhibitors, time to discontinuation of brigatinib (from all lines) was almost one year. Although complete disease progression status of the patients was absent, this time-to-discontinuation analysis indicates encouraging benefit with a manageable safety profile for brigatinib.
Editorial acknowledgement
Jane Kondejewski, PhD, SNELL Medical Communicaiton, Inc.
Legal entity responsible for the study
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Funding
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
Disclosure
M.M. Lin, X. Pan, P. Hou, S. Allen, P. Baumann: Employee: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited which funded this study. M.J. Hochmair: Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Roche; Consulting, advisory roles: Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Roche.
Invited Discussant 21O and 108O
- J. Wolf (Cologne, Germany)
- J. Wolf (Cologne, Germany)
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
- F. Barlesi (Marseille, CEDEX 20, France)
- 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.
55O - Radiogenomic signatures of NSCLC brain metastases: A potential non-invasive imaging marker for ALK mutation
- S. Wadhwa (Mumbai, India)
- S. Wadhwa (Mumbai, India)
- G. Krishna.b (Mumbai, India)
- M. Malhotra (Mumbai, India)
- K. Prabhash (Mumbai, India)
- V. Noronha (Mumbai, India)
- A. Joshi (Mumbai, India)
- V. Patil (Mumbai, India)
- A. Mahajan (Mumbai, India)
Abstract
Background
NSCLC harbouring ALK rearrangement has a higher risk of developing brain metastases. Literature on MR Imaging radiogenomics (MRI-R) as predictors of ALK mutation is limited and less investigated. The aim of our study was to evaluate the semantic MRI-R parameters of NSCLC brain metastases and their correlation with ALK status.
Methods
We analyzed clinical data on 75 patients who were tested for ALK mutation and underwent MR imaging at diagnosis. Multiparametric MRI was performed in all cases. The associations between ALK mutation status and clinical features specifically age, sex, smoking, histology, TNM stage and imaging variables of brain metastasis, were analyzed using descriptive analysis (chi-square test) and univariate logistic regression analysis.
Results
There were 46 ALK positive and 29 ALK negative cases that were subjected to MRI-R analysis. ALK positive were predominantly young (83%) and non-smokers (87%) (p < 0.001). Statistically significant difference (p < 0.001) was observed in lesion morphology and its T2W border, fuzzy and infiltrative border with hypointense peripheral solid rim in ALK positive while well defined border and no solid rim in ALK negative. Predominant signal on T1W imaging was hypointense (p < 0.001) in ALK negative, whereas heterogeneity was marker of ALK positive status on T1W (p < 0.001). Lesions in ALK negative group showed central restriction on DW images (p-0.001) and peripheral restriction of the solid rim was characteristic of ALK positive (p < 0.001). ALK positive showed thick ring enhancement while patchy enhancement favoured ALK negative. Incidence of meningeal involvement was significantly higher in ALK positive and was absent in 80% of ALK negative (p-0.02). On univariate logistic regression analysis, statistically significant association was found between age, smoking history, T2W lesion morphology, T2W border, restricted diffusion, enhancement and meningeal positivity (p < 0.05).
Conclusions
ALK positive brain metastases have peculiar MR imaging features that can be non-invasive diagnostic and predictive imaging biomarkers. MR radiogenomics have potential role in individualised management of ALK positive NSCLC brain metastasis.
Legal entity responsible for the study
IEC TMH.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
110O - Plasma circulating tumor DNA analysis (ctDNA) for molecular alteration detection in advanced non-small cell lung cancer (NSCLC) patients (pts) with isolated central nervous system (CNS) metastases (mts)
- M. Aldea (Villejuif, France)
- M. Aldea (Villejuif, France)
- L. Hendriks (Maastricht, Netherlands)
- L. Mezquita (Villejuif, France)
- J. Remon-Masip (Barcelona, Spain)
- D. Planchard (Villejuif, France)
- C. Jovelet (Villejuif, France)
- J. Benitez (Barcelona, Spain)
- A. Gazzah (Villejuif, France)
- C. Naltet (Villejuif, France)
- P. Lavaud (Villejuif, France)
- L. Lacroix (Villejuif, France)
- K. Howarth (Cambridge, United Kingdom)
- C. Morris (Cambridge, United Kingdom)
- E. Green (Cambridge, United Kingdom)
- C. Nicotra (Villejuif, France)
- B. Besse (Villejuif, CEDEX, France)
Abstract
Background
In advanced NSCLC, ctDNA is an emerging tool in molecular profile testing at diagnosis and at resistance to targeted therapies. However, for CNS limited mts, ctDNA might have a reduced accuracy because of low concentrations. Aim: to assess feasibility of ctDNA in NSCLC with isolated CNS disease/progression (PD) (iCNS).
Methods
This is a retrospective analysis of consecutive advanced NSCLC pts treated at Gustave Roussy from 01.2016 to 06.2018 included in 2 prospective studies (CEC-CTC, MSN). Included: any molecular tissue alteration at baseline (EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, TP53), CNS disease and ≥1 ctDNA sample at diagnosis/PD. CtDNA was performed by next generation sequencing (NGS- InVisionSeq™-Lung). Clinical/molecular/imaging data were collected. CtDNA in iCNS group were compared to systemic PD group (with CNS PD or stable disease, S-CNS). ctDNA was defined as positive if ≥ 1 mutation in the NGS panel.
Results
422/959 screened pts had ≥1 ctDNA sample. 183/422 pts had CNS disease. 58/182 pts had ctDNA sample at time of CNS disease and 66 samples were eligible for inclusion: 21 iCNS and 45 S-CNS (≥1 sample/patient as ≥ 1 PD). In iCNS and S-CNS, pts characteristics were: median age 55 vs 59 years, female gender 94% vs 59%, adenocarcinoma histology 100% vs 93%, smoking history 35% vs 44%, median mts sites at diagnosis 1 vs 2. Prevalence of EGFR mutation at diagnosis was 76 and 61%, ALK rearrangement 18 and 10%, KRAS 6 and 5% in iCNS and in S-CNS, respectively. HER2, TP53, BRAF and MET alterations were present only in S-CNS group (12%, 10%, 5% and 2%). CtDNA was positive in 38% in iCNS vs. 98% in S-CNS groups (Fisher test, p < 0.0001) (Table).
Conclusions
In NSCLC pts with isolated CNS involvement, genomic alterations assessed by ctDNA in plasma had a low detection rate. (Table).
Legal entity responsible for the study
Gustave Roussy Institute, Villejuif, France.
Funding
Has not received any funding.
Disclosure
L. Mezquita: Consulting, advisory role: Roche Diagnostics; Lectures, educational activities: Bristol-Myers Squibb, Tecnofarma, Roche, AstraZeneca; Travel, accommodations, expenses: Chugai. D. Planchard: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. C. Morris, E. Green: Employee, shareholder: Inivata. B. Besse: Sponsored research at Gustave Roussy Cancer Center: 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; Investigator or co-investigator of trials: 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.
Invited Discussant 109O, 55O and 110O
- U. Malapelle (Napoli, Italy)
- U. Malapelle (Napoli, Italy)