On behalf of the co-investigators, I would like to thank the committee for giving me an opportunity to share the results of early circulating tumor DNA, EGFR mutation clearance in plasmids predictor of clinical outcomes in ORA3 study. These are my disclosures. Osmoletinib is a third generation irreversible oral EGFR TTI and is preferred first-line treatment in EGFR mutant advanced non-small cell lung cancer. With the three ORA3 study, Osmoletinib demonstrated superior efficacy compared with platinum W chemotherapy in T7 and positive non-small cell lung cancer who progressed on EGFR TTI. Some patient tumor responded differently than others to Osmoletinib, so predicting clinical outcomes in non-small cell lung cancer soon after initiating treatment would be invaluable. Together we explored the association between EGFR mutation CTDNA clearance at week three and six in both Osmoletinib and chemotherapy arm of ORA3. To our knowledge, this is the first report which compares CTDNA clearance with dynamics between target therapy and chemotherapy. To briefly recap, ORA3 is a randomized phase III trial of Osmoletinib versus platinum Pemetrexate in T7 and positive non-small cell lung cancer who progressed on first-line EGFR TTI. In this exploratory analysis, EGFR mutation CTDNA analysis was conducted in plasma samples with detectable EGFR mutation using DD-PCR. We also analyzed the relation of CTDNA clearance at week three and six with PFS and over response rate. Of a total of 419 randomized patients, 291 had valid CTDNA results at baseline, of which both treatment arms of these 85 and 206 patients have undetectable and detectable CTDNA at baseline. 184 and 185 had valid CTDNA at week three and six respectively. Multivariate analysis of a progressive pre-survivor inpatient with a valid CTDNA result at baseline demonstrated undetectable CTDNA was the only progressive factor associated with longer PFS. Hazard ratio was 0.5. In support of this, in both arms, patient with undetectable EGFR mutation CTDNA at baseline had longer PFS compared with those with detectable CTDNA. Overall patient in oligomotor arm had longer PFS independent of EGFR mutation CTDNA presence at baseline compared with the chemotherapy arm. Clearance of EGFR mutation CTDNA was more frequent in the patient receiving oligomotor arm. It is more apparent at week three and the ratio was 5.0 and 3.2 for week three and six respectively. As a comparison with the CTDNA-based response just shown, this table summarizes the traditional resist-based response in patients with detectable CTDNA at baseline and valid CTDNA results at week three and six. Those receiving osmotinib had a significantly better response rate than those receiving platinum chemisorexate with an odd ratio of 3.2, which is similar to then seen with the CTDNA-based response. In both osmotinib and chemotherapy arm, patient with CTDNA clearance at three had favorable median PFS compared to patient without CTDNA clearance. In osmotinib arm, the median PFS 10.9 months versus 5.7 months. In chemotherapy arm, the median PFS was 6.2 versus 4.2 months. A similar PFS outcome was observed at week six. In conclusion, detectability of EGFR mutation CTDNA at baseline was the only statistically significant positive factor for PFS in ORA3 study. Patient with EGFR mutation CTDNA clearance at three and six had longer PFS than those without clearance across treatment arms. These data supported the potential value of early untreatment CTDNA profiling in predicting treatment benefit in EGFR mutant advanced non-small cell lung cancer. Thank you for your attention. For more information visit www.osmotinib.com

Osmoletinib

EGFR mutant

non-small cell lung cancer

CTDNA

progression-free survival