Investigators Launch Phase 3 Zipalertinib Combo Trial in EGFR+ NSCLC

Developers designed the orally available small molecule zipalertinib as an irreversible EGFR inhibitor for treating a genetically defined group of patients with NSCLC.

Developers have initiated the phase 3 REZILIENT3 trial (NCT05973773) to assess zipalertinib (CLN-081/TAS6417) plus chemotherapy as a frontline treatment option for adult patients with EGFR exon 20 insertion–mutated advanced or metastatic non–small cell lung cancer (NSCLC), according to a press release from Taiho Oncology, Inc.¹

The REZILIENT3 trial’s launch follows a previous evaluation of zipalertinib among heavily pretreated patients with NSCLC harboring EGFR exon 20 insertion mutations as part of a phase 1/2a clinical trial (NCT04036682). According to findings published in Journal of Clinical Oncology, investigators observed objective responses in 38.4% (95% CI, 27%-49%) of patients across all dose levels.² Additionally, the most common treatment-related adverse effects (TRAEs) included rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), and anemia (19%).

“Patients with NSCLC who have EGFR exon 20 insertion mutations are known to have poorer outcomes than those with more common EGFR mutations,” Volker Wacheck, MD, PhD, senior vice president of Clinical Development at Taiho Oncology, Inc., said in the press release.¹ “Advancing care for this subset of patients with NSCLC is essential to advancing care in NSCLC overall.”

Developers designed the orally available small molecule zipalertinib as an irreversible EGFR inhibitor for treating a genetically defined group of patients with NSCLC. According to a previous press release, the FDA granted breakthrough therapy designation to zipalertinib as a treatment for patients with locally advanced or metastatic EGFR-mutated NSCLC.³

Investigators of the multi-center, open-label, international, randomized phase 3 REZILIENT3 trial are enrolling patients with previously untreated advanced or metastatic nonsquamous NSCLC harboring EGFR exon 20 insertion mutations. The trial will begin with a safety lead-in portion in which patients will receive zipalertinib orally twice a day plus pemetrexed and carboplatin or paclitaxel in a 21-day cycle. In part B, approximately 300 patients will be randomly assigned to receive pemetrexed plus platinum-based chemotherapy with or without zipalertinib.

The primary end points of the REZILIENT3 trial include progression-free survival, treatment-emergent AEs, and dose-limiting toxicities. Secondary end points include objective response rate, disease control rate, duration of response, overall survival, quality of life, and pharmacokinetics.

Patients 18 years and older who have not received any prior systemic therapy for locally advanced or metastatic NSCLC with documented EGFR mutation status are eligible for enrollment on the trial. Additional inclusion criteria include having an archival tissue sample available, at least 1 measurable lesion per RECIST v1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 3 months. Those with previously treated brain metastases and stable central nervous system disease are also able to enroll on the trial.

Those who have received prior treatment with zipalertinib at any time, or thoracic radiation or major surgery within 28 days of beginning study treatment are not eligible for enrollment.

“The initiation of the phase 3 trial for zipalertinib in the first-line setting is an important step forward for this clinical research program, as it represents an opportunity for zipalertinib to help more patients with EGFR exon 20 insertion mutation NSCLC,” Jeffrey Jones, MD, MPH, MBA, chief medical officer at Cullinan Oncology, Inc., concluded.

References

1. REZILIENT3 global first-line trial of zipalertinib launched in patients with non-small cell lung cancer harboring EGFR exon 20 insertion mutations. News release. Taiho Oncology, Inc. August 3, 2023. Accessed August 4, 2023. https://shorturl.at/hiltz
2. 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. Published online June 29, 2023. doi:10.1200/JCO.23.00152
3. 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 August 4, 2023. https://shorturl.at/jkFGX