Comparing becotarug plus osimertinib with a real-world osimertinib therapy cohort in platinum-refractory, advanced non–small cell lung cancer with EGFR exon 20 insertion.

8546 Background: EGFR exon 20 insertion (20ins)-positive non-small-cell lung cancer (NSCLC) is a rare subtype with limited therapeutic options and poor prognosis. Becotarug plus osimertinib showed encouraging activity and acceptable safety in a phase 1 study (NCT04448379). To assess its efficacy in EGFR 20ins-positive NSCLC, a phase 2 single-arm trial (NCT05132777) was initiated. To provide a comparator, a multicenter retrospective real-world study (NCT05513664) was served as an external control arm. Methods: Eligible patients in the phase 2 study had unresectable stage IIIB–IV NSCLC with EGFR exon 20 insertion mutations and ≥1 prior platinum-based chemotherapy; those relapsing within six months after neoadjuvant or adjuvant chemotherapy were also eligible. The external control comprised a real-world cohort treated with osimertinib, matched 1:1 on age, sex, stage, ECOG PS, brain metastases, and number of prior systemic therapies. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) in the trial arm and real-world ORR in the control arm. Secondary endpoints included disease control rate (DCR), duration of response (DoR) and progression-free survival (PFS). Safety was evaluated by incidence and severity of adverse events. Results: Of the 126 and 96 patients enrolled in the trial and control arms, respectively, 112 and 91 patients met criteria for the pre-matching cohort. After 1:1 propensity-score matching, 158 patients (79 per arm) comprised the post-matching population. Baseline characteristics were well balanced between arms, with 62.0% and 60.8% of patients, respectively, having received ≤1 prior line of systemic therapy. The IRC-assessed ORR was 46.8% (95% CI, 36.24–57.73) in the trial arm versus 7.6% (95% CI, 3.53–15.60) in the control arm. Notably, the lower bound of the trial-arm 95% CI (36.24%) exceeded the control-arm point estimate (7.6%). The absolute ORR difference was 39.2% (95% CI, 25.96–50.87; P < 0.0001), corresponding to an odds ratio of 10.72 (95% CI, 4.18–27.51). Furthermore, in a propensity score–matched analysis restricted to patients receiving osimertinib monotherapy (64 per arm), the combination therapy produced a greater ORR (42.2% 95% CI, 27.5-54.8, P < 0.0001). Higher DCR were achieved in trial arm compared to control arm (77.2% 95% CI, 66.8-85.1 vs 64.6% 95% CI, 53.6-74.2, P = 0.080). The median PFS in trial arm was significantly longer than that in control arm (6.9 vs. 4.8 months, P = 0.007). Other efficacy endpoints showed consistent trends favoring the combination therapy. The most common adverse events were EGFR-related mucocutaneous toxicities in both arms. Conclusions: This study further supports the efficacy and tolerability of becotarug plus osimertinib in patients with platinum-refractory, EGFR 20ins-positive NSCLC. Clinical trial information: NCT05513664 ; NCT05132777 .