112P - Sequencing post osimertinib with liquid biopsy to assess TKI resistance in patients with advanced EGFR-mutant NSCLC (SOLITAIRE study)

Background

Osimertinib (osi) is a 3^rd-generation EGFR TKI for treatment of advanced EGFR-mutant (EGFR+) NSCLC. However, patients (pts) eventually develop disease progression (PD) due to osi resistance. We conducted a prospective study to determine clinical utility of blood-based next-generation sequencing (bNGS) to genomically match osi-resistant (osi-R) pts to subsequent therapies and trials.

Methods

From Jul’22 to Oct’24, we recruited 100 pts with stage IV EGFR+ NSCLC who received osi in 1^st- or subsequent line at the National Cancer Centre Singapore. Upon Osi-PD, pts underwent bNGS testing (20 Guardant360; 80 FoundationACT) for actionable mutations (AMs) of osi resistance and results discussed at Molecular Tumor Board. NGS was performed on tissue biopsy (TBx) when available. We aim to determine: 1. yield of AMs with bNGS compared to standard tissue-based approach alone, 2. proportion of pts allocated to clinical trials, and 3. concordance of AMs in pts with paired tissue-liquid biopsies (TLBx).

Results

Our cohort comprised 54% females, 76% non-smokers, 89% ECOG 0-1, with median age 68 years. EGFR exon 19del/exon 21 (L858R) mutations 96%, line of osi: 1^st (71%) /2^nd (26%). Median PFS on osi was 17 months (m), TTF 24.5 m. Of 98 patients analysed, 43.9% had TBx at osi PD. Comparative yield of AMs with a TBx-only vs bNGS-based strategy was 39.8% vs 20.4% (ꭓ²=8.72, p=0.0031). In pt subset with TBx-NGS, 20/32 (62.5%) had AMs. Common AMs on bNGS included: PIK3CA (9.2%), EGFR C797S (7.1%), MET amplification (METamp+) (4.1%), and BRAF (3.1%). Histologic transformation (small cell/squamous) was seen in 7/43 (16.3%) pts with TBx. Potential biomarker-based trial options based on bNGS was recommended for 10 (10.2%) pts. Of 25 pts with AMs and evaluable TBx, 10 (40%) had concordant TLBx results. TLBx concordance for EGFR C797S/L718Q mutations was 62.5% but for METamp+ 22.2%.

Conclusions

bNGS allowed for detection of AMs for biomarker-based trial options for osi-R pts which would be missed in the absence of TBx. bNGS may be promising to screen for on-target EGFR resistance mechanisms but may under detect METamp+ and histologic transformation. TBx remains crucial for comprehensive biomarker study of osi resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

SingHealth Duke-NUS Research grant and AstraZeneca Educational grant.

Disclosure

W.L. Tan: Financial Interests, Institutional, Invited Speaker: Novartis; Financial Interests, Institutional, Other, Focus Group meeting for expert advice: Merck; Financial Interests, Institutional, Other, Reimbursement for conference meetings: MSD, AstraZeneca, Ipsen, Boehringer Ingelhem, Bristol Myers Squibb, DKSH; Financial Interests, Institutional, Funding, Educational Grant: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator, Clinical trial: Novartis, Amgen. A. Tan: Financial Interests, Personal, Advisory Board: Amgen, Pfizer, Bayer; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Guardant Health, Merck, Amgen, Takeda; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Takeda. G. Lai: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Pfizer, BMS, Roche; Other, Personal, Other, sponsorship for meeting: DKSH. P.L.S. Saw: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, Roche, BMS, Takeda; Financial Interests, Institutional, Advisory Board: Pfizer, Bayer, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca, Novartis, BeiGene. W.C. Tan: Financial Interests, Institutional, Invited Speaker: AstraZeneca, MSD, Bayer Pharmaceuticals; Financial Interests, Institutional, Invited Speaker, SingHealth Duke-NUS Academic Medicine Research Grant (Artificial Intelligence): SingHealth Duke-NUS Academic Medicine. R. Kanesvaran: Financial Interests, Institutional, Invited Speaker: Astellas, Johnson and Johnson, Ipsen, Amgen, BMS, MSD, Novartis, AstraZeneca, Sanofi, Merck; Financial Interests, Institutional, Advisory Board: Johnson and Johnson, Pfizer, Ipsen, Amgen, BMS, MSD, Bayer, AstraZeneca, Ferring; Financial Interests, Institutional, Research Grant: Sanofi, Eisai, Johnson and Johnson; Non-Financial Interests, Personal, Leadership Role, Past President: Singapore Society of Oncology, SIOG; Non-Financial Interests, Personal, Leadership Role, Vice Chairman: Singapore Cancer Society; Non-Financial Interests, Personal, Leadership Role, Medical Advisory Board Member: International Kidney Cancer Coalition. D.W. Lim: Financial Interests, Institutional, Advisory Board: MSD, Daiichi-Sankyo, Janssen, Pfizer, Amgen; Financial Interests, Institutional, Invited Speaker: Beigene, Junshi Pharma; Financial Interests, Personal, Stocks/Shares: Mesh Bio; Financial Interests, Institutional, Invited Speaker, Grant funding for investigator-sponsored study: Taiho Pharmaceuticals. D.S.W. Tan: Financial Interests, Personal, Advisory Board: Amgen, Novartis, Boehringer Ingelheim, C4 Therapeutics, AstraZeneca, GSK, Takeda, Eisai, Guardant, Merck, Pfizer, Roche, Regeneron, Genmab; Financial Interests, Institutional, Research Grant: AstraZeneca, Amgen, Pfizer, ACM Biolabs; Financial Interests, Personal, Invited Speaker: Novartis. All other authors have declared no conflicts of interest.