Zipalertinib Meets Primary ORR End Point in EGFR exon 20 NSCLC

Full results from the phase 1/2 REZILIENT1 trial evaluating zipalertinib in NSCLC will be shared at a future medical conference.

Zipalertinib (CLN-081/TAS6417) monotherapy in patients with EGFR exon20 insertion mutant non–small cell lung cancer (NSCLC) who underwent prior therapy met its primary end point of overall response rate (ORR) and demonstrated a consistent safety profile in the phase 2b part of the phase 1/2 REZILIENT1 trial (NCT04036682), according to a press release from the developer, Taiho.¹

The developer currently plans to submit these data for regulatory approval in the US in the second half of 2025.

In January 2022, breakthrough therapy designation was assigned to zipalertinib for the treatment of patients with NSCLC harboring EGFR exon 20 insertion mutations who received prior platinum-based chemotherapy.²

Preliminary results from the REZILIENT1 trial were published in the Journal of Clinical Oncology in 2023.³ In June 2024, positive initial results from the phase 2b portion were announced.⁴ Full results from the trial will be submitted for presentation at an upcoming medical conference.

In the published preliminary results, lead study author Zofia Piotrowska, MD, MHS, an instructor at Harvard Medical School, and coauthors, wrote, “Zipalertinib has encouraging preliminary antitumor activity in heavily pretreated patients with EGFR exon20 insertion-mutant NSCLC, with an acceptable safety profile, including low frequency of high-grade diarrhea and rash.”³

At a data cut-off of January 12, 2024, a total of 31 patients were enrolled in the trial, and 18 were included in the data analysis of the phase 2b portion.⁴ Of the 31 patients, the median number of prior systemic anti-cancer treatments was 3.

The ORR in patients who received prior chemotherapy, amivantamab-vmjw (Rybrevant) therapy, or other exon20 insertion therapies (n = 18) was 39%, and the disease control rate (DCR) was 94%. The duration of response (DOR) and progression-free survival (PFS) were both not yet estimable (NE). Results also showed that patients who received prior chemotherapy (n = 39) had an ORR of 41%, a DCR of 97%, a DOR that was NE, and a PFS of 12 months.

According to the initially published preliminary results, 73 patients were enrolled and administered zipalertinib orally twice daily in 21-day treatment cycles and in 30, 45, 65, 100, and 150 mg dosages.

REZILIENT1 is an open-label, multi-center trial evaluating the safety, efficacy, and recommended phase 2 dose of zipalertinib in patients with NSCLC harboring EGFR exon20 insertion mutations.

Patients were 18 years or older with histologically or cytologically confirmed recurrent and/or metastatic NSCLC with EGFR exon20 insertion mutations who experienced previous platinum-based chemotherapy or previous EGFR inhibitors. They also had to have measurable disease per RECIST criteria; an ECOG performance status of 0 or 1; and adequate renal, hepatic, cardiac, and hematologic function. Exclusion criteria included spinal cord compression, history of drug-induced pneumonitis, or active infection.

Regarding safety, any-grade treatment-related adverse events (TRAEs) were observed in 99% of patients across all dose levels, and grade 3 or higher TRAEs affected 23%. The most common TRAEs of any grade were rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), and dry skin (18%). The only TRAE of grade 3 or higher to affect more than 5% of patients was anemia (10%).

Dose reductions were required in 14% of patients; 8% had to discontinue zipalertinib due to drug-related AEs. No drug-related deaths occurred.

“In an evolving treatment landscape, this is the first ever clinical data to systematically characterize the potential of an irreversible and selective EGFR exon20 insertion mutation [tyrosine kinase inhibitor] such as zipalertinib in patients who were heavily pre-treated and had received amivantamab,” Jeffrey Jones, MD, MBA, chief medical officer at Cullinan Therapeutics, stated in a press release on phase 2b findings.⁴ “With a comprehensive development plan for zipalertinib, these data further strengthen our confidence in its potential to address a significant unmet need for patients with NSCLC harboring EGFR exon20 insertion mutations.”

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 Oncology.January 28, 2025. Accessed January 28, 2025. https://shorturl.at/kmpS1
2. FDA grants breakthrough therapy designation for Cullinan Oncology’s CLN-081 in patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer. News release. Cullinan Oncology, Inc. January 4, 2022. Accessed January 29, 2025. https://tinyurl.com/3nj8jy24
3. Piotrowska Z, Tan DS, Smit EF, et al. Safety, tolerability, and antitumor activity of zipalertinib among patients with non-small-cell lung cancer harboring epidermal growth factor receptor exon 20 insertions. J Clin Oncol. 2023;41(26):4218-4225. doi:10.1200/JCO.23.00152.
4. Cullinan therapeutics announces positive initial data from pivotal phase 2b REZILIENT1 study of zipalertinib. News release. Cullinan Therapeutics, Inc. June 1, 2024. Accessed January 29, 2025. https://shorturl.at/njScb