Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting ALK and ROS1 Fusion and Resistance Mutations in Patients With Non-Small-Cell Lung Cancer

Affiliations

PMID: 32923908
PMCID: PMC7448797 (available on 2021-04-02)
DOI: 10.1200/PO.19.00281

Abstract

Purpose: Liquid biopsy specimen genomic profiling is integrated in non-small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK /ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes.

Patients and methods: Patients with advanced ALK/ROS1-positive NSCLC were prospectively enrolled in the study by researchers at eight French institutions. Plasma samples were analyzed using InVisionFirst-Lung and correlated with clinical outcomes.

Results: Of the 128 patients included in the study, 101 were positive for ALK and 27 for ROS1 alterations. Blood samples (N = 405) were collected from 29 patients naïve for treatment with tyrosine kinase inhibitors (TKI) or from 375 patients under treatment, including 105 samples collected at disease progression (PD). Sensitivity was 67% (n = 18 of 27) for ALK/ROS1 fusion detection. Higher detection was observed for ALK fusions at TKI failure (n = 33 of 74; 46%) versus in patients with therapeutic response (n = 12 of 109; 11%). ALK-resistance mutations were detected in 22% patients (n = 16 of 74) overall; 43% of the total ALK-resistance mutations identified occurred after next-generation TKI therapy. ALK G1202R was the most common mutation detected (n = 7 of 16). Heterogeneity of resistance was observed. ROS1 G2032R resistance was detected in 30% (n = 3 of 10). The absence of circulating tumor DNA mutations at TKI failure was associated with prolonged median overall survival (105.7 months). Complex ALK-resistance mutations correlated with poor overall survival (median, 26.9 months v NR for single mutation; P = .003) and progression-free survival to subsequent therapy (median 1.7 v 6.3 months; P = .003).

Conclusion: Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Laura MezquitaConsulting or Advisory Role: Roche, Roche Diagnostics, Takeda Speakers’ Bureau: Roche, Bristol-Myers Squibb, Tecnofarma Travel, Accommodations, Expenses: Roche, Bristol-Myers SquibbAurélie SwalduzHonoraria: Roche, Bristol-Myers Squibb, Takeda, AZD Consulting or Advisory Role: Eli Lilly, Pfizer, Bristol-Myers Squibb Travel, Accommodations, Expenses: Takeda, Pfizer, Boehringer Ingelheim, RocheKaren HowarthEmployment: Inivata Stock and Other Ownership Interests: Inivata Research Funding: Inivata Patents, Royalties, Other Intellectual Property: Patent pendingDavid PlanchardHonoraria: Prime Oncology, Peer CME Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche, Pfizer, MSD Oncology, Celgene, MedImmune, BeiGene Research Funding: AstraZeneca/MedImmune (Inst),, Bristol-Myers Squibb (Inst),, Boehringer Ingelheim (Inst), Eli Lilly (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Sanofi/Aventis (Inst), Taiho Pharmaceutical (Inst), Daiichi Sankyo (Inst), AbbVie (Inst)Gonzalo RecondoConsulting or Advisory Role: Roche, Amgen, Pfizer Travel, Accommodations, Expenses: AstraZeneca, PfizerFrank De KievitEmployment: Inivata Travel, Accommodations, Expenses: InivataVincent PlagnolEmployment: Inivata, Genomics Stock and Other Ownership Interests: Inivata, Genomics Patents, Royalties, Other Intellectual Property: Inivata patentsEtienne RouleauHonoraria: AstraZeneca (Inst), Roche (Inst), Bristol-Myers Squibb (Inst), AstraZeneca Research Funding: AstraZeneca (Inst) Travel, Accommodations, Expenses: AstraZeneca, Bristol-Myers SquibbPierre FournelConsulting or Advisory Role: Bristol-Myers Squibb, Amgen, MSD Oncology, Eli Lilly, AstraZeneca, Pfizer, AbbVie, Takeda, Roche, AstraZeneca, Amgen, Eli Lilly, Pfizer, Bristol-Myers-Squibb, MSD Oncology Research Funding: Bristol-Myers Squibb (Inst), AstraZeneca (Inst), Amgen (Inst), Pfizer (Inst), Pfizer/EMD Serono (Inst), Ipsen (Inst) Travel, Accommodations, Expenses: Novartis, Roche, Eli Lilly, Pfizer, Boehringer Ingelheim, AstraZeneca, Amgen, Bristol-Myers Squibb, MSD OncologyCaroline CaramellaHonoraria: Bristol-Myers Squibb Honoraria: MSD Oncology, PfizerClaire TissotConsulting or Advisory Role: Roche, Bristol-Myers Squibb, AstraZeneca, MSD OncologyJulien AdamConsulting or Advisory Role: Roche, Bristol-Myers Squibb, AstraZeneca, Merck Sharp & Dohme Research Funding: Pierre Fabre (Inst), Merck Sharp & Dohme (Inst)Samuel WoodhouseEmployment: Inivata Patents, Royalties, Other Intellectual Property: Patents related to fusion technology used by Inivata and in this articleEdouard AuclinHonoraria: Sanofi Genzyme, MundipharmaJordi RemonConsulting or Advisory Role: Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD Oncology, AstraZeneca, Roche, Inivata, OSE ImmunotherapeuticsClive MorrisEmployment: Inivata Leadership: Inivata Stock and Other Ownership Interests: InivataEmma GreenEmployment: Inivata Stock and Other Ownership Interests: InivataChristophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm Group, Roche, Ipsen, Janssen, Eli Lilly, MSD Oncology, Novartis, Pfizer, Sanofi, Orion, Tahio, Blueprint Medicines, Innate Pharma, PharmaMarMaurice PérolConsulting or Advisory Role: Eli Lilly, Roche, Pfizer, AstraZeneca, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Amgen, Takeda, Chugai Pharma Research Funding: AstraZeneca (Inst), Roche (Inst), Takeda (Inst) Travel, Accommodations, Expenses: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, PfizerBenjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Eli Lilly (Inst), Onxeo (Inst), Bristol-Myers Squibb (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Biogen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Ignyta (Inst), Ipsen (Inst), Merck (Inst), MSD Oncology (Inst), Nektar (Inst), PharmaMar (Inst), Sanofi (Inst), Spectrum Pharmaceuticals (Inst), Takeda (Inst), Tiziana Therapeutics (Inst)Pierre SaintignyHonoraria: HTG Molecular Diagnostics, Inivata, ArcherDx, Bristol-Myers Squibb, Roche Molecular Diagnostics, Roche, AstraZeneca, Novartis, Bristol-Myers Squibb Foundation, Illumina No other potential conflicts of interest were reported.