1171P - A phase II theranostic study with osimertinib in patients with EGFR-mutated non-small cell lung cancer (NSCLC) progressing on EGFR tyrosine kinase inhibitors (TKI) and undetectable EGFR T790M (THEROS)

Background

Personalized sequences of targeted agents instructed by the detection of resistance mechanisms by rebiopsy or liquid biopsy enable impressive survival outcomes in patients with advanced NSCLC harboring therapeutically tractable oncogenic drivers. Overcoming EGFR T790M-associated TKI resistance with osimertinib is a prime example of this approach. Limitations of current biomarkers may deny patients this treatment option. We hypothesized that early detection of metabolic response by FDG-PET identifies additional patients benefitting from sequenced osimertinib.

Methods

Patients with EGFR-mutated NSCLC progressing on 1^st/2^nd generation EGFR TKI with EGFR T790M undetectable by liquid biopsy and – if feasible – tumor biopsy were eligible. Metabolically active tumor lesions were confirmed by FDG-PET/CT. Patients received one cycle (28 d) of osimertinib 80 mg/d. Patients with objective metabolic response (PERCIST) in a second FDG-PET performed after at least 14 days of osimertinib remained on study treatment. Patients without metabolic response went off study. Using an optimal Simon’s two-stage design the rate of metabolic responses (PERCIST) was the primary study endpoint. Secondary endpoints included clinical benefit rate (CBR) at 4 months in metabolic responders, time to treatment failure (TTF), safety and survival endpoints.

Results

From May 2019 to June 2021, 16 patients (38% female, median age 70 [50-82] years; 14 patients evaluable) progressing on 1^st/2^nd generation EGFR TKI were enrolled at two sites. There were 5 early metabolic responses (31% of ITT, 36% of evaluable). CBR at 4 months in responders was 100%. With 4 patients still on treatment, median TTF and progression-free survival have not been reached. No new safety signals were obtained.

Conclusions

Early metabolic response identifies patients with durable clinical benefit from sequenced osimertinib despite undetectable EGFR T790M. This describes a new approach to response-based personalization of treatment trajectories in NSCLC with therapeutically tractable driver oncogenes.

Clinical trial identification

NCT03810066.

Editorial acknowledgement

Legal entity responsible for the study

University Hospital Essen.

Funding

AstraZeneca.

Disclosure

M. Wiesweg: Financial Interests, Personal, Advisory Board: Amgen, Boehringer Ingelheim, Novartis, Roche, Takeda, Pfizer, GSK; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb, Takeda. S. Michels: Financial Interests, Institutional, Research Grant: Novartis, Pfizer, Janssen. M. Metzenmacher: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, MSD, Novartis, Pfizer, Roche, Takeda. A. Drzezga: Financial Interests, Personal, Stocks/Shares: Siemens Healthineers, Lantheus Holding; Financial Interests, Personal, Advisory Board: Siemens Healthineers, GE Healthcare, Biogen, Novo Nordisk, Invicro, Radiation Protection Committee; Financial Interests, Institutional, Research Grant: Siemens Healthineers, Life Molecular Imaging, GE Healthcare, AVID Radiopharmaceuticals, SOFIE, Eisai. H. Schildhaus: Financial Interests, Personal, Advisory Board: MSD, BMS, Roche Pharma, Novartis Oncology, AstraZeneca, Eisai, Takeda, ZytoVision, Zytomed Systems, Molecular Health; Financial Interests, Institutional, Research Grant: Novartis Oncology; Financial Interests, Personal, Full or part-time Employment: Targos Molecular Pathology, Inc. J. Wolf: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Financial Interests, Institutional, Research Grant: BMS, Janssen Pharmaceutical, Novartis, Pfizer. K. Herrmann: Financial Interests, Personal, Stocks/Shares: Sofie Biosciences, Aktis Oncology, Theranostics; Financial Interests, Personal, Advisory Board: Sofie Biosciences, Theranostics, Pharma15, Janssen, Novartis/Adacap, AstraZeneca, Bayer, Curium, AktisOncology, SiemensHealthineers, GE Healthcare, BostonScientific, Amgen, Y-mAbs. M.H.H. Schuler: Financial Interests, Personal, Invited Speaker: Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Roche; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca; Non-Financial Interests, Principal Investigator, Member, Study Steering Board: Janssen. All other authors have declared no conflicts of interest.