Osimertinib combined with bevacizumab and chemotherapy as 1L treatment in EGFR-mutated metastatic non-squamous non-small cell lung cancer (nsq NSCLC) with concurrent mutations.

8625 Background: Concurrent mutations in EGFR sensitive mutations (19 del/21 L858R) are associated with poor prognosis. Previous studies have shown that EGFR-TKI combined with chemotherapy or anti-angiogenic drugs confers heterogeneous degrees of benefit in this population. However, the efficacy of concurrent EGFR-TKI, anti-angiogenic agent, and chemotherapy has not been reported. Methods: This is a single-center, open-label, phase I clinical trial designed to evaluate the efficacy and safety of osimertinib combined with bevacizumab and chemotherapy as first-line treatment for EGFRm metastatic nsq NSCLC with concurrent mutations (NCT05507606). 4 induction cycles will be administered (Osimertinib, 80 mg/d, d8–21; bevacizumab, 7.5 mg/kg, d1; pemetrexed 500 mg/m², d1; and carboplatin AUC 5, d1; 3 week/cycle), after which carboplatin will be discontinued. Osimertinib combined with bevacizumab and pemetrexed will be continued as maintenance (Osimertinib, 80 mg/d, d1–21; all other remained unchanged). Bevacizumab and pemetrexed will be stopped at 2 years; osimertinib will be continued until disease progression. EGFRm include exon 19 del, L858R, T790M, G719X, L861Q, S768I, exon 20 A763–Y764 insertion, and concurrent mutations are defined as the presence of at least one destructive TP53 mutation in exons 5 to 8. The primary endpoints are safety and objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Exploratory endpoints comprise NGS comparative analysis pre-/post-treatment, 19 del/L858R subgroup analysis, ctDNA clearance, and the correlation between efficacy and prognosis. Results: 34 patients were enrolled. Males accounted for 29.41%, and the median age was 58.5 years (25-75). Patients with ECOG PS 1 and 2 comprised 97.1% and 2.9%, respectively. The EGFRm profile consisted of 19 del (50.0%), L858R (44.1%), and other mutations (5.9%, including 20 ins and L861Q). All patients have finished the 4 induction cycles. The median follow-up was 36.8 months (95% CI, 24.2–47.4). The ORR was 94.12% (95% CI, 80.32%–99.28%), the DCR was 100% (95% CI, 89.72%–100%). The median PFS and OS were 35.9 m (95% CI, 26.0–NR) with 44.1% maturity and NR with 26.5% maturity, respectively. 19 del: ORR 100%, PFS/OS NR. L858R: ORR 86.7%, mPFS 26.5m (95%CI:16.3-NR), mOS 47.8m (95%CI:22.1-NR). Others: ORR 100%, mPFS 10.8m (95%CI:7.9-NR), mOS 21.1m (95%CI:18.2-NR). Grade ≥ 3 AE occurred in 31.25% of patients during the induction phase. No deaths related to toxicity were observed. The discontinuation rate was 9.4%; no patient discontinued treatment because of AE. Conclusions: These results demonstrate that the four-drug regimen anchored by osimertinib is well tolerated and active in patients with EGFRm metastatic nsq NSCLC harboring concurrent mutations. Clinical trial information: NCT05507606 .