Final results of afatinib plus chemotherapy with genomic profiling in osimertinib-refractory EGFR-mutant NSCLC: NEJ025B.

8596 Background: Osimertinib is commonly used as a first-line treatment for EGFR-mutated advanced NSCLC. However, the optimal treatment following osimertinib failure remains unclear. This study evaluated afatinib plus chemotherapy for EGFR-mutated NSCLC resistant to osimertinib. Initial findings were presented at ASCO2023, and this report provides final data, including blood NGS analysis. Methods: Patients (pts) with EGFR mutations (Del19 or L858R) after osimertinib failure were treated with afatinib (20 mg daily) combined with carboplatin (AUC5 mg/mL/min) and pemetrexed (500 mg/m² every 3 weeks), followed by maintenance therapy with afatinib plus pemetrexed until progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (6M-PFSR). Secondary endpoints included PFS, OS, ORR, DOR, and safety. Blood samples were collected before and during treatment, and at progression, to evaluate biomarkers using CAPP-SEQ. Results: Between June 7, 2020, and January 19, 2022, 36 pts were enrolled. One pt met exclusion criteria, leaving 35 pts for efficacy analysis. The mean age was 70 years; 60% were women, and 54.3% were nonsmokers. The median observation period was 29.1 months (cutoff date: January 18, 2024). The primary endpoint, 6M-PFSR, was 57.1% (95% CI, 39.3–71.5), exceeding the threshold of 35%. Notably, 28.6% of pts achieved long-term PFS of ≥1 year. ORR was 51.4%, DCR was 88.6%, median PFS was 8.2 months, median DOR was 5.6 months, and median OS was 22.5 months. By mutation type, ORRs were similar for Del19 and L858R (46.7% and 55.0%, respectively), but median PFS was longer for Del19 than for L858R (9.6 vs. 5.2 months). Pts who had responded to prior osimertinib (CR/PR, n=29) had longer median PFS than non-responders (SD/PD/NE, n=6) (8.5 vs. 5.8 months). Adverse events (AEs) from TKI and chemotherapy were common but manageable. The most frequent AEs were diarrhea (52.8%), anorexia (47.2%), fatigue (36.1%), and paronychia (36.1%). Interstitial pneumonia occurred in 3 pts (8.3%), with one treatment-related death. In plasma NGS analysis, clearance of EGFR mutations during treatment was a key predictive factor. Pts without EGFR mutation clearance had shorter PFS and OS compared to those with clearance (PFS: 5.7 vs. 12.0 months; OS: 15.7 vs. 34.4 months). Efficacy was observed even in pts with p53 mutations, a known resistance factor. MET gene amplification was detected in 4 pts upon resistance. Conclusions: Afatinib combined with platinum-based chemotherapy demonstrated satisfactory efficacy and manageable toxicity in pts with tumors refractory to osimertinib. EGFR mutation clearance during treatment was predictive of therapeutic outcomes. This regimen may be a promising second-line option after osimertinib failure. Clinical trial information: 021200005 .