The combination of the oral, irreversible, selective inhibitor of EGFR exon 20 insertions (EGFR exon20ins), zipalertinib (CLN-081; TAS6417), and chemotherapy will be evaluated as first-line treatment for adult patients with previously untreated locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring an EGFR exon20ins mutation, according to Taiho Oncology.1
The phase 3 REZILIENT3 trial (NCT05973773) will include about 312 patients with EGFR exon20ins mutation-positive NSCLC. The study has been launched shortly after positive phase 1/2 data of single agent zipalertinib were presented at the 2023 American Society of Clinical Oncology Annual Meeting.
About the Phase 3 REZILIENT3 Study
Trial Name: Randomized, Controlled, Open-label, Phase 3, Global Multi - Center Trial to Assess the Efficacy and Safety of Zipalertinib Plus Chemotherapy Versus Chemotherapy Alone, in Patients With Previously Untreated, Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer (NSCLC) With Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion (ex20ins) Mutations
ClinicalTrials.gov Identifier: NCT05973773
Sponsor: Taiho Oncology, Inc
Recruitment Contact: 609-250-7336, clinicaltrialinfo@taihooncology.com
Completion Date: April 21, 2027
“Patients with NSCLC who have EGFR exon 20 insertion mutations are known to have poorer outcomes than those with more common EGFR mutations,” said Volker Wacheck, MD, PhD, senior vice president, Clinical Development, Taiho Oncology, Inc, in a press release. “Advancing care for this subset of patients with NSCLC is essential to advancing care in NSCLC overall.”
In the phase 1/2 study, 73 patients with heavily pretreated EGFR exon20ins-positive NSCLC were treated with zipalertinib monotherapy at either 30, 45, 65, 100, and 150 mg administered orally, twice daily. The study population was 56% female, and patients were a median age of 64 years. Patients had received a median of 2 (range, 1-9) prior therapies, and of those prior therapies, 6% had a prior non-ex20ins EGFR tyrosine kinase inhibitor (TKI), and 41% received prior EGFR ex20ins TKIs.2
Objective responses to zipalertinib were observed at every dose level. In the overall study population, the partial response rate shown with zipalertinib was 38.4%. Stable disease was observed in 57.5%, and progressive disease (PD) was shown in 4.1%. At a median follow-up of 11 months, the median duration of response observed was 10 months (95% CI, 6 to not calculable) in the overall population.
The median progression-free survival (PFS) across all dose cohorts was 10 months (95% CI, 6-12 months).
Safety findings from the phase 1/2 study showed that treatment-emergent adverse events (TEAEs) occurred in all patients, and grade ≥3 TEAEs occurred in 53%. Treatment-related AEs (TRAEs) occurred in 99%, including grade ≥3 TRAEs in 23% of patients. The most common any-grade TRAEs observed in the study were rash (80%), paronychia (32%), diarrhea (30%), fatigue (21%), anemia (19%), dry skin (18%), and nausea (16%). Anemia was the most common grade ≥3 TRAE, having occurred in 10% of patients.
Overall, investigators of the phase 1/2 study found the antitumor activity of zipalertinib in patients with EGFR exon20ins-positive NSCLC to be promising, and the safety profile acceptable.2 The phase 3 study of zipalertinib plus chemotherapy is the next developmental step to determine whether the risk/benefit profile of zipalertinib truly makes it an alternative option for patients with EGFR exon20ins mutation-positive NSCLC.2,3
In the randomized, controlled, open-label, phase 3, global, multicenter study, investigators plan to begin with a safety lead-in assessment (part A) to determine the recommended dose of zipalertinib. Part A will include 6 to 12 patients with EGFR exon20ins mutation-positive NSCLC who will receive zipalertinib plus pemetrexed and carboplatin or cisplatin on a 21-day cycle. Treatment in part A will continue until PD or withdrawal. The recommended dose of zipalertinib will be determined by the number of dose-limiting toxicities (DLTs) observed first cycle of treatment.3
Part B of the phase 3 study will begin once part A concludes. In part B, 300 patients will be randomized according to a 1:1 ratio to receive either zipalertinib and chemotherapy or chemotherapy alone.
The primary end points to be assessed in both parts of the study are the rate and severity of TEAEs, and PFS. The primary end point of part A is to determine the rate and severity of DLTs.
Secondary end point to be explores in parts A and B include objective response rate, disease control rate, duration of response, overall survival, quality of life, pharmacokinetics, and EGFR mutation status.
Patients eligible for inclusion in the phase 3 study are those aged 18 years or older with pathologically confirmed NSCLC and documented EGFR mutation status. Patients are required to receive any prior systemic treatment for their locally advanced or metastatic nonsquamous NSCLC, have archival tissue for biopsies, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1, and a life expectancy of at least 3 months. Patients who were previously treated for brain metastases must be stable, negative pregnancy tests are required at the time of screening. All patients in the study must also agree to use contraception during the study.
“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,” said Jeffrey Jones, MD, MPH, MBA, chief medical officer, Cullinan Oncology, Inc, in the press release. “We look forward to working with our partners at Taiho to rapidly assess zipalertinib in the front line, while in parallel continuing to advance our pivotal phase 2b trial in patients who have received prior systemic treatment for locally advanced or metastatic disease.”
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. and Cullinan Oncology, Inc. August 3, 2023. Accessed August 4, 2023. https://www.taihooncology.com/us/news/2023-08-03_zipalertnib_phase3/
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. A study of zipalertinib and chemotherapy compared with chemotherapy alone in patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 Insertion. (REZILIENT3). ClinicalTrials.gov. Updated August 3, 2023. Accessed August 4, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05973773?term=NCT05973773&draw=2&rank=1
