Clinical Implications of Plasma-Based Genotyping With the Delivery of Personalized Therapy in Metastatic Non-Small Cell Lung Cancer

Abstract

Importance: The clinical implications of adding plasma-based circulating tumor DNA next-generation sequencing (NGS) to tissue NGS for targetable mutation detection in non-small cell lung cancer (NSCLC) have not been formally assessed.

Objective: To determine whether plasma NGS testing was associated with improved mutation detection and enhanced delivery of personalized therapy in a real-world clinical setting.

Design, setting, and participants: This prospective cohort study enrolled 323 patients with metastatic NSCLC who had plasma testing ordered as part of routine clinical management. Plasma NGS was performed using a 73-gene commercial platform. Patients were enrolled at the Hospital of the University of Pennsylvania from April 1, 2016, through January 2, 2018. The database was locked for follow-up and analyses on January 2, 2018, with a median follow-up of 7 months (range, 1-21 months).

Main outcomes and measures: The number of patients with targetable alterations detected with plasma and tissue NGS; the association between the allele fractions (AFs) of mutations detected in tissue and plasma; and the association of response rate with the plasma AF of the targeted mutations.

Results: Among the 323 patients with NSCLC (60.1% female; median age, 65 years [range, 33-93 years]), therapeutically targetable mutations were detected in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, or BRAF for 113 (35.0%) overall. Ninety-four patients (29.1%) had plasma testing only at the discretion of the treating physician or patient preference. Among the 94 patients with plasma testing alone, 31 (33.0%) had a therapeutically targetable mutation detected, thus obviating the need for an invasive biopsy. Among the remaining 229 patients who had concurrent plasma and tissue NGS or were unable to have tissue NGS, a therapeutically targetable mutation was detected in tissue alone for 47 patients (20.5%), whereas the addition of plasma testing increased this number to 82 (35.8%). Thirty-six of 42 patients (85.7%) who received a targeted therapy based on the plasma result achieved a complete or a partial response or stable disease. The plasma-based targeted mutation AF had no correlation with depth of Response Evaluation Criteria in Solid Tumors response (r = -0.121; P = .45).

Conclusions and relevance: Integration of plasma NGS testing into the routine management of stage IV NSCLC demonstrates a marked increase of the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Aggarwal reported consulting or advisory roles with Genentech, Inc, Bristol-Myers Squibb, Eli Lilly and Company, and Celgene Corporation and institutional research funding from Genetech/Roche, Incyte Corporation, MacroGenics, Inc, and Merck Sharp & Dohme. Dr Thompson reported a consulting or advisory role with OncoCyte Corporation. Dr Katz reported research funding from Novartis International AG. Dr Evans reported consulting or advisory roles with Genentech, Inc, and Celgene Corporation; honoraria from Genentech, Inc, and Celgene Corporation; a role on the speakers bureau for Genentech, Inc; and travel, accommodations, or expenses from Genentech, Inc, and Celgene Corporation. Dr Bauml reported consulting or advisory roles with Clovis Oncology, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Genentech, Inc, Celgene Corporation, Boehringer Ingelheim, and Guardant Health and institutional research funding from Merck Sharp & Dohme, Carevive Systems, Inc, Novartis International AG, Incyte Corporation, Bayer, and Janssen Pharmaceuticals. Dr Berman reported research funding from LingaMed, LLC. Dr Cohen reported honoraria from Bristol-Myers Squibb; a consulting or advisory role with Heat Biologics, Inc, Takeda Pharmaceutical Company Ltd, Zymeworks, Inc, and Pfizer, Inc; institutional research funding from Heat Biologics, Inc, MacroGenetics, Inc, Merck Sharp & Dohme, Takeda Pharmaceutical Company Ltd, Cleave Biosciences, and Celldex Therapeutics, Inc; and travel, accommodations, or expenses from Heat Biologics, Inc, Takeda Pharmaceutical Company Ltd, Zymeworks, Inc, Bristol-Meyers Squibb, and Pfizer, Inc. Dr Morrissette reported a consulting or advisory role with Novartis International AG; participation on the speakers bureau for Cambridge Healthtech Institute; and travel, accommodations, or expenses from Cambridge Healthtech Institute. Dr Elenitoba-Johnson reported stock or other ownership of Genomenon, Inc. Dr Langer reported honoraria from Bristol-Myers Squibb, Genentech/Roche, and Lilly/ImClone; a consulting or advisory role with Genentech/Roche, Lilly/ImClone, Merck Sharp & Dohme, Abbott Biotherapeutics, Inc, Bayer/Onyx, Clariant, Clovis Oncology, Celgene Corporation, Cancer Support Community, Bristol-Myers Squibb, Ariad Pharmaceuticals, Inc, Takeda Pharmaceutical Company Ltd, and AstraZeneca; institutional research funding from Merck Sharp & Dohme, Advantagene, Inc, Clovis Oncology, Celgene Corporation, Inovio Pharmaceuticals, Ariad Pharmaceuticals, Inc, GlaxoSmithKline, Genentech/Roche, and Stemcentrx, Inc; and other relationships with Eli Lilly and Company, Amgen, Inc, Peregrine Pharmaceuticals, Inc, and Synta Pharmaceuticals, Inc. Dr Carpenter reported honoraria from Imedex; research funding from Janssen Pharmaceuticals and Merck Sharp & Dohme; a patent, royalties, or intellectual property interest from Children’s Hospital of Philadelphia; and travel, accommodations, or expenses from VPS Hospitals in United Arab Emirates. No other disclosures were reported.

Figures

Figure 1.. Patient Enrollment and Testing Flowchart

Flowchart summarizes patient enrollment, types of next-generation sequencing (NGS) tests conducted, and mutations detected. Concurrent plasma and tissue NGS was defined as tests ordered within 24 weeks of each other and no intervening systemic therapy. A clinically relevant mutation (in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2, BRAF, and KRAS) was detected in 176 patients; a therapeutically targetable mutation (a subset of clinically relevant mutations that have targeted therapies available [eTable 2 in the Supplement]), in 113. Eighty-one patients received indicated targeted therapy. NSCLC indicates non–small cell lung cancer.

Figure 2.. Analysis of Mutation Detection by Type of Test and Disease Stage

A, Fifty-five patients had concurrent plasma and tissue next-generation sequencing (NGS) with a therapeutically targetable mutation detected. This subset included 4 patients with outside hospital testing for whom no allele fraction (AF) was reported. For the remaining 51 patients, a comparison of the AFs of therapeutically targetable mutations is shown. The horizontal black line indicates median AF for each group. For the 27 patients who had the mutation AF reported for plasma and tissue, the upper horizontal line corresponds to the median for the tissue AFs, and the lower horizontal line corresponds to the median for the plasma AFs. B, To assess the effect of disease location on detection of therapeutically targetable mutations in plasma and tissue, plasma and tissue testing results were compared for 55 patients with concurrent testing. Included are 13 with disease limited to the thoracic cavity (M1a) and 42 with extrathoracic metastases (M1b) as determined by imaging.

Figure 3.. Response of Patients to Plasma-Indicated Targeted Therapy as Measured by Response Evaluation Criteria in Solid Tumors (RECIST)

Waterfall plot shows the percentage change in target lesion diameter as determined by RECIST for patients with therapeutically targetable mutations detected by plasma. Forty-two patients with driver or resistance mutations underwent analysis, including 21 undergoing plasma next-generation sequencing at diagnosis and 21 at disease progression. Thirty-six patients (85.7%) achieved a complete response, partial response, or stable disease. An increase in size of target lesions by more than 20% indicates progressive disease, while decrease in size of target lesion of more than 30% indicates disease response.

Figure 4.. Plasma-Based Indicators of Response to Plasma Next-Generation Sequencing (NGS)–Indicated Therapy

A, Correlation between depth of response to the targeted therapy indicated by plasma, and plasma allele fraction (AF) for the therapeutically targeted mutation (r = −0.121; P = .45) in the 42 patients for whom Response Evaluation Criteria in Solid Tumors (RECIST) analysis was completed. B, Correlation between depth of response to targeted therapy and the ratio of resistance to driver mutation AF (r = 0.116; P = .67). This analysis was conducted for the 16 patients who received osimertinib mesylate to target the EGFR T790M resistance mutation detected in plasma and for whom RECIST analysis was completed.