Efficacy of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy with or without amivantamab.

Abstract

8503 Background: Despite the approval of amivantamab (ami) for EGFR exon 20 insertion (ex20ins) mutant NSCLC, an unmet need remains for well-tolerated oral targeted therapies with durable clinical benefit. Zipalertinib (zipa, CLN-081, TAS6417) is a novel EGFR TKI which showed promising clinical activity and manageable safety in a phase 1/2a study in pts with ex20ins NSCLC that progressed on platinum-based chemotherapy (plt-chemo). Here we report the primary data from the pivotal phase 2b REZILIENT1 study of zipa in patients (pts) with advanced or metastatic EGFR ex20ins mutant NSCLC that progressed after prior plt-chemo with or without prior ami. Methods: Pts were enrolled in two parallel cohorts (prior plt-chemo, prior plt-chemo and ami) and treated with zipa 100 mg BID. Tumor response was assessed by blinded independent central review (BICR) per RECIST v1.1. Pts with stable, asymptomatic, or treated brain metastases (mets) were allowed. Results: As of 10 December 2024 data cut off, 176 pts (51 with prior ami and 125 with plt-chemo) were enrolled with median follow-up of 9.3 months: median age: 65 (33-85), median lines of prior therapy: 2 (1-7), prior PD1/L1: 100 (56.8%), history of brain mets: 68 (38.6%). Among all pts treated, zipa demonstrated a confirmed ORR (cORR) of 35.2%, mDoR of 8.8 months, and mPFS of 9.5 months (table 1). In pts with plt-chemo without ami, the cORR was 40.0%. Of the 51 pts with prior ami, 30 had no other ex20ins-directed therapy, while 21 had also received other ex20ins drugs (such as mobocertinib, sunvozertinib, BLU-451, or poziotinib), the cORR was 30.0% and 14.3%, respectively. Among all pts with brain mets, systemic cORR was 30.9%. The most common treatment-emergent AEs (TEAEs, all-grade) were paronychia, rash, anemia, diarrhea, dry skin, nausea, and stomatitis and the majority of the TEAEs were CTCAE grade 1 or 2. Conclusions: Zipalertinib demonstrated clinically meaningful efficacy with a manageable safety profile in pts with exon20ins NSCLC who have received prior platinum-based chemotherapy and for those who received prior amivantamab, a significant and growing unmet need. Clinical trial information: NCT04036682 . BICR assessed tumor responses per RECIST v1.1. N CR(%) PR(%) SD(%) cORR(%, 95%CI) mDOR(m, 95%CI) mPFS(m, 95%CI) Plt-chemo 125 0 50 (40.0) 55(44.0) 40.0(31.3, 49.1) 8.8(8.3, 11.4) 9.5(7.7,11.5) Prior Ami ± other ex20ins drug 51 1 (2.0) 11 (21.6) 33(64.7) 23.5(12.8, 37.5) 8.5(4.2, 14.8) 7.3(5.3,9.7) Total 176 1 (0.6) 61 (34.7) 88(50.0) 35.2(28.2, 42.8) 8.8(8.3, 11.4) 9.5(7.4, 10.0) CR=complete response, PR=partial response, SD=stable disease.