1740P - Track and treat in NSCLC (TATIN) - ctDNA guided treatment of early resistance to second-line osimertinib treatment in patients with EGFR mutation positive (EGFRm) NSCLC

Background

Osimertinib resistance is currently determined by radiological progression. At this time point, patients often deteriorate and might not be able to receive subsequent treatment. Therefore, there is a need for early resistance identification to improve patient outcome.

Methods

In this multicenter prospective study, patients with EGFRm NSCLC that developed T790m resistance on 1^st/2^nd generation EGFR TKI were treated with osimertinib. At baseline and every 8 weeks, patients were radiologically evaluated with CT and blood was drawn for next generation sequencing of circulating tumor DNA (ctDNA) using the Avenio ctDNA expanded panel. Patients were treated with osimertinib until radiological progression (RECISTv1.1). The aim of this study was to identify % of patients in which resistance could be detected using ctDNA analysis prior to progressive disease (PD).

Results

From 7-2019 to 7-2020, 25 patients were enrolled and 23 were evaluable. The primary EGFR driver was detected in 19/23 (83%) and in 17/23 (74%) EGFR T790M was found. At April 1^st 2021, 18 patients had radiological PD, 1 patient clinical PD and 4 patients had no PD. The interval between elevation of the primary EGFR driver variant allele frequency (VAF) and PD was 0 weeks (median; range 0.0-34.1) for all 19 patients with PD, and 8.9 weeks (median; range 7.3-34.1) for the patients with detectable ctDNA and elevation before PD. In 5 patients, elevation of EGFR VAF was detected at PD. Despite earlier detection, in 5 patients no elevation was detected at PD. In the remaining 3 patients ctDNA was never detected. Co-alterations leading possibly to osimertinib resistance were detected in 11/19 (58%) patients prior to PD (BRAFV600E 2; ERBB2m 1; METm 2; EGFRC797Sm 2; PIK3CAm 1; ERBB2amp 2; METamp 7).

Conclusions

Detection of the oncogenic driver and monitoring evolution of resistance prior to PD is possible in a selected group of patients with detectable ctDNA at the start of osimertinib treatment. Sequential ctDNA analysis may guide initiation of additional therapy targeting resistance mechanisms. Future results in a large cohort will provide evidence whether ctDNA guided treatment on osimertinib progression has clinical utility.

Clinical trial identification

NCT04148066.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Roche.

Disclosure

D. van den Broek: Financial Interests, Institutional, Advisory Role: Roche. K. Monkhorst: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Benecke; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: BMS; Financial Interests, Institutional, Advisory Role: Roche; Financial Interests, Institutional, Advisory Role: MSD; Financial Interests, Institutional, Advisory Role: AbbVie; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Diaceutics; Financial Interests, Institutional, Advisory Role: Lilly; Financial Interests, Institutional, Advisory Role: Bayer; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim; Non-Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Takeda; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Invited Speaker: PGDx; Financial Interests, Institutional, Invited Speaker: Delfi. S. Burgers: Financial Interests, Institutional, Advisory Board: Roche; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim. E.F.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Board: Bayer; Financial Interests, Institutional, Advisory Board: Celgene; Financial Interests, Institutional, Advisory Board: DSI; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Takeda; Financial Interests, Institutional, Advisory Board: Regeneron; Financial Interests, Institutional, Advisory Board: Roche Genentech; Financial Interests, Institutional, Advisory Board: Roche Diagnotics; Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Bristol Myers Squibb; Financial Interests, Institutional, Sponsor/Funding: Merck; Financial Interests, Institutional, Sponsor/Funding: MSD; Financial Interests, Institutional, Sponsor/Funding: Roche Genentech; Financial Interests, Institutional, Sponsor/Funding: Novartis; Financial Interests, Institutional, Sponsor/Funding: PharmaMar; Financial Interests, Institutional, Sponsor/Funding: Takeda; Financial Interests, Institutional, Sponsor/Funding: Bayer; Financial Interests, Institutional, Sponsor/Funding: Clovis; Financial Interests, Institutional, Sponsor/Funding: Eli Lilly. A.J. de Langen: Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: MSD Oncology; Financial Interests, Institutional, Advisory Role: Roche; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Advisory Role: Lilly; Financial Interests, Institutional, Advisory Role: Blueprint Medicines; Financial Interests, Institutional, Sponsor/Funding: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Bristol Myers Squibb; Financial Interests, Institutional, Sponsor/Funding: Merck Serono; Financial Interests, Institutional, Sponsor/Funding: MSD Oncology; Financial Interests, Institutional, Sponsor/Funding: Roche; Financial Interests, Institutional, Sponsor/Funding: Merus. All other authors have declared no conflicts of interest.