1262P - Combined molecular analysis of circulating tumour DNA and tumour tissue to identify osimertinib resistance

Background

Resistance to first-line osimertinib in patients with EGFR mutation (EGFRm) positive advanced NSCLC is inevitable. Identifying resistance mechanisms may guide subsequent (targeted) therapy for these patients. As resistance can be heterogeneous within patients, we hypothesized that a complete resistance mechanism analysis requires next-generation sequencing (NGS) of both plasma as well as tumor biopsies in patients experiencing disease progression (PD) while on first line osimertinib treatment.

Methods

Upon experiencing PD on osimertinib, patients underwent both liquid biopsy and tumor biopsy for resistance mechanism analysis. Plasma sequencing utilized AVENIO ctDNA expanded panel, tumor biopsies utilized DNA and RNA NGS following local standards. Successful sequencing was defined by the identification of the EGFRm. Results were discussed in a Molecular Tumor Board (MTB) to formulate a treatment advice.

Results

Between February 2020 and January 2024, 150 patients were enrolled. The EGFRm was detected in 81% (122/150) of plasma samples and in 94% (141/150) of tumor biopsies. In 79% (118/150) of the patients, the EGFRm was detected in plasma as well as in the tumor biopsy. In 88 of these 118 patients, a total of 136 resistance mechanisms covered by both modalities were detected: 45 in tumor, 37 in plasma only, and 54 in both (concordance rate: 40%). Twenty-seven of these 88 patients harbored EGFR, MET and/or ERBB2 amplification in both tumor and plasma, 14 in the tumor alone. Mean EGFRm variant allele frequency in plasma differed significantly between these groups (31.8 vs 8.2%, p < 0.05).

Across all 150 patients, single-modality analysis of resistance mechanisms covered by both modalities would have identified 75% of resistance mechanisms with tumor biopsy alone, 59% with plasma sequencing alone.

The MTB advised chemotherapy for 58 patients and targeted therapy for 54, adherence rate was 77%.

Conclusions

Combining plasma sequencing and tumor biopsy analysis uncovers additional resistance mechanisms compared to a single modality approach, highlighting the importance of combining both modalities for a complete assessment of resistance mechanisms and associated treatment options.

Clinical trial identification

NCT04737382.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AstraZeneca.

Disclosure

S. Badrising: Financial Interests, Institutional, Speaker, Consultant, Advisor: Janssen, Pfizer. G. Ruiter: Financial Interests, Institutional, Local PI: AstraZeneca, Daiichi Sankyo, Cullinan Oncology, Boehringer Ingelheim, Merus, Bayer, Bristol Myers Squibb, Pierre Fabre, Navire BridgeBio, Ikena Oncology, Scorpion Therapeutics, Taiho Oncology, Revolution Medicine. W.S.M.E. Theelen: Financial Interests, Institutional, Research Grant, From AstraZeneca, MSD and Sanofi/Regeron for investigor-initiated studies.: Netherlands Cancer Institute. B.V. Veggel: Financial Interests, Personal and Institutional, Other, outside the submitted work: advisory board, invited speaker and/or PI: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Board, outside the submitted work: advisory board, invited speaker and/or PI: Bristol Myers Squibb, Novartis, Lilly, Roche. S. Hashemi: Financial Interests, Institutional, Other, Research grant/advisory role: AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Janssen, GSK, MSD, Novartis, Roche, Takeda. A.J. Van Der Wekken: Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche, Takeda; Financial Interests, Institutional, Advisory Board: AstraZeneca, Boehringer-Ingelheim, Janssen, Lilly, Novartis, Pfizer, Roche, Takeda; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Boehringer-Ingelheim, Janssen, Lilly, Novartis, Pfizer, Roche, Takeda. L.E. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, AnHeart ; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, Educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, Sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: Medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: Gilead; Financial Interests, Institutional, Local PI: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Other, vice chair scientific committee: Dutch Thoracic Group. M.S. Paats: Financial Interests, Institutional, Advisory Board: Chiesi, Eli Lilly, Janssen, Merck, Pfizer; Financial Interests, Institutional, Other, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Chiesi, Eli Lilly, Roche. D. Van Den Broek: Non-Financial Interests, Institutional, Non financial benefits, Outside the submitted work: Delfi Diagnostics. K. Monkhorst: Financial Interests, Institutional, Advisory Board: AbbVie, AstraZeneca, BMS, Bayer, Boehringer Ingelheim, Lilly, MSD, Merck, Pfizer, Roche; Financial Interests, Institutional, Coordinating PI: AstraZeneca; Non-Financial Interests, Institutional, Product Samples: Roche SS. E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. A.J. De Langen: Financial Interests, Institutional, Other, Research grant: BMS, MSD, Boehringer, AstraZeneca; Non-Financial Interests, Institutional, Other, Non-financial support: Merck Serono; Non-Financial Interests, Institutional, Other, Research grant: Roche. All other authors have declared no conflicts of interest.