REZILIENT1 Trial Finds Zipalertinib Meets Primary End Point in EGFR+ NSCLC

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The phase 2b part of the REZILIENT1 trial (NCT04036682) trial evaluating zipalertinib monotherapy for the treatment of patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations who have received prior therapy has met its primary end point of overall response rate (ORR), according to a press release from Taiho Pharmaceutical Co., Ltd., Taiho Oncology, Inc., and Cullinan Therapeutics, Inc.¹

The safety profile of zipalertinib was similar to previously reported data.

Detailed findings from the phase 1/2 REZILIENT1 trial are expected to be submitted for presentation at an upcoming international medical conference. The companies plan to submit for US regulatory approval in the second half of 2025, following discussions with the FDA.

About the REZILIENT1 Trial

Zipalertinib is an orally available small molecule that works to target activating mutations in EGFR. The agent is designed as a next generation, irreversible EGFR inhibitor for the treatment of a genetically defined subset of patients with NSCLC.

In January 2022, the FDA granted breakthrough therapy designation to zipalertinib for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations and who have received prior platinum-based chemotherapy, based on data from the phase 1/2a study (NCT04036682).

The open-label, multicenter, first-in-human REZILIENT1 trial is evaluating the efficacy and safety of zipalertinib for the treatment of NSCLC harboring EGFR exon 20 insertion mutations who have received previous therapy. This trial is divided into multiple parts, including the phase 1 dose-escalation portion, the phase 2a dose-expansion portion, module A, module B, and module C.²

For the phase 2 portion of the trial, ORR served as the primary end point. Additional primary end points being explored in the trial include the rate and severity of treatment-emergent adverse events and dose-limiting toxicities, pharmacokinetics, and duration of response.

According to data from module C of the phase 2b REZILIENT1 trial presented at the ESMO Congress 2024, treatment with zipalertinib was well tolerated with a manageable safety profile in heavily pretreated patients with NSCLC harboring EGFR exon 20 insertion mutations who progressed on or after amivantamab (Rybrevant).³ In the overall population (n = 30), the ORR was 40% (95% CI, 22.7%-59.4%), including 1 (3.3%; 95% CI, 0.1%-17.2%) complete response (CR), 11 (36.7%; 95% CI, 19.9%-56.1%) partial responses (PRs), and 15 (50.0%; 95% CI, 31.3%-68.7%) patients with stable disease (SD).

Among patients given prior treatment with only amivantamab (n = 18), the ORR was 50.0% (95% CI, 26.0%-74.0%), including 1 CR (5.6%; 95% CI, 0.1%-27.3%), 8 PRs (44.4%; 95% CI, 21.5%-69.2%), and 7 with SD (38.9%; 95% CI, 17.3%-64.3%).

In the population of patients who previously received amivantamab plus other exon 20 insertion therapy, the ORR was 25.0% (95% CI, 5.5%-57.2%), including no CRs, 3 PRs (25.0%; 95% CI, 5.5%-57.2%), and 8 with SD (66.7%; 95% CI, 34.9%-90.1%).

Across all 3 respective arms of the study, the disease control rates were 90.0% (95% CI, 73.5%-97.9%), 88.9% (95% CI, 65.3%-98.6%), and 91.7% (95% CI, 61.5%-99.8%). At data cutoff, duration of response (DOR) was not estimable (NE). Median progression-free survival (PFS) was 9.7 months (90% CI, 4.1-NE).

For safety, the most common treatment-related adverse events (TRAEs) observed in the overall population included rash (38%), paronychia (36%), anemia (24%), dry skin (20%), dermatitis acneiform (16%), nausea (16%), and stomatitis (11%). The most common grade 3 or higher TRAEs were anemia (9%), rash (7%), and pneumonitis/interstitial lung disease (7%). In the overall population, 3 patients (7%) had dose reductions, with 3 patients (7%) also discontinuing treatment.

REFERENCES

1. Taiho Pharmaceutical, Taiho Oncology, and Cullinan Therapeutics announce primary endpoint met in phase 2b trial of zipalertinib in patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations who have received prior therapy. News release. Taiho Pharmaceutical Co., Ltd., Taiho Oncology, Inc., and Cullinan Therapeutics, Inc. January 28, 2025. Accessed January 29, 2025. https://tinyurl.com/mr4sd73y

2. A phase 1/​2 trial of CLN-081 in patients with non-small cell lung cancer (REZILIENT1). ClinicalTrials.gov. Updated September 19, 2024. Accessed January 29, 2025. https://clinicaltrials.gov/study/NCT04036682?tab=table

3. Passaro A, Yu HA, Nguyen D, et al. Safety and antitumor activity of zipalertinib in NSCLC patients with EGFR exon 20 insertion mutations who received prior amivantamab. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain. Abstract 1254MO.