Cullinan/大鹏的zipalertinib一线III期REZILIENT3完整数据：mPFS 14.5 vs 8.5个月，但≥3级AE达87.1%

Cullinan Therapeutics and Taiho Oncology have unveiled phase 3 data for their tyrosine kinase inhibitor (TKI) that could challenge Johnson & Johnson’s Rybrevant for patients with advanced non-small cell lung cancer (NSCLC) in the front-line setting.
The addition of zipalertinib to platinum-based chemotherapy improved survival by six months in patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation-positive NSCLC. The results, presented on the Monday of the World Conference on Lung Cancer in Seoul, were part of a planned interim analysis. The partners revealed that the phase 3 study hit its primary endpoint for progression-free survival (PFS) last month, but had been holding back the detailed data.
The Rezilient3 trial enrolled 279 adults with previously untreated, locally advanced or metastatic NSCLC with the relevant mutations. In the study, a combination of zipalertinib and chemotherapy achieved a statistically significant median PFS of 14.5 months, compared to 8.5 months in patients on chemotherapy alone.
Taiho and Cullinan also observed an increased objective response rate of 65% in patients who received the combo treatment compared to 40.3% in the chemo-only cohort. The median duration of response was 14.2 months and 9.9 months, respectively.
Cullinan's Chief Medical Officer Jeffrey Jones, M.D., described the data as a “major advance” for this patient population.
“This is potentially practice-changing in extending progression-free survival beyond a year with an adverse event profile that is manageable,” Jones told Fierce ahead of the presentation.
The overall survival data from the study remains immature but has shown promise, according to the companies, with a hazard ratio for death for the zipalertinib regimen versus control of 0.72. This means that the combination treatment is helping the patients live longer, with a 28% lower risk of dying.
“This [overall survival measure] will continue to be followed along with other secondary endpoints in the trial to better characterize overall survival,” Jones said. “But based on the magnitude of the progression-free survival, these initial results should be viewed as quite encouraging.”
While 87.1% of patients on the combo treatment experienced an adverse event (AE) graded 3 or above compared to 54.4% in control arm, the companies explained in their release that these were “primarily manageable hematologic AEs.” The AEs graded 3 or above that were considered EGFR-related were “infrequent,” the partners pointed out, with the most common being rash, which was experienced by 10.7% of patients on the combo regimen.
Jones told Fierce that most of the AEs that led to discontinuation were attributable to the platinum chemotherapy and were experienced in the first four months when patients received this treatment.
NSCLC is the most common form of lung cancer, making up 80-87% of all diagnoses. EGFR mutations are prevalent in cancers such as NSCLC and are caused by a mutation of the gene that codes for the protein that sits on the cell surface and regulates how cells grow and divide. In NSCLC, mutations in EGFR occur in nearly one third of patients, Jones said, with about 4% involving an exon 20 insertion mutation in advanced disease.
Zipalertinib is a next-generation oral small molecule designed to target activating mutations in EGFR. It irreversibly inhibits EGFR mutations by binding to exon 20, a unique feature of zipalertinib, compared to AstraZeneca’s TKI Tagrisso, which blocks EGFR but does not have much clinical activity at exon 20, Jones explained.
The market for EGFR exon 20 insertion mutated NSCLC has been quite competitive over the past few years. Takeda ultimately withdrew its TKI Exkivity from the U.S. market for adult NSCLC in 2023 after the drug missed the mark in a confirmatory study. J&J capitalized on the setback and Rybrevant was approved the following year as a first-line treatment for advanced NSCLC with EGFR exon 20 insertion mutations, following a 2021 FDA approval in the second-line setting.
Although there is no head-to-head comparison, zipalertinib showed a greater mPFS of 14.5 months in the latest readout compared to J&J's bispecific Rybrevant, which was cleared on an mPFS of 11.4 months.
Taiho now plans to share the latest data with global health authorities and the FDA in hopes of carving a quick path to market, Jones explained.
The FDA already accepted zipalertinib for review in NSCLC patients with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. The FDA is expected to weigh in on zipalertinib in that later-line setting next February.
Under the terms of its 2022 deal with Taiho, Cullinan is in line to receive $30 million when zipalertinib is approved for second-line use and $100 million when it secures a first-line nod from the FDA. Taiho and Cullinan will split pretax profits from U.S. sales equally.