Analysts believe Cullinan Therapeutics and Taiho Oncology can overcome the safety risks as zipalertinib “sets [a] new bar” for first-line treatment of a type of lung cancer. The candidate is already under review for the the second-line setting, with a decision expected by early next year.
Taiho Oncology and Cullinan Therapeutics’ oral drug candidate zipalertinib significantly improved progression-free survival in certain patients with non-small cell lung cancer during a late-stage study.
The partners also reported some safety events, including three deaths from septic shock, but analysts say the otherwise strong survival benefit and mitigation strategies will likely outweigh the risks as zipalertinib heads toward the market.
Zipalertinib’s PFS benefit “sets a new bar” for the first-line treatment of NSCLC, analysts at William Blair told investors in a Monday note.
The partners are testing zipalertinib in the Phase 3 REZILIENT3 trial, which enrolled 280 patients with first-line advanced non-squamous NSCLC who are harboring exon 20 mutations to the EGFR gene. Participants were randomly assigned to receive zipalertinib plus chemotherapy or chemotherapy alone. REZILIENT3’s primary endpoint is PFS.
Patients who received the zipalertinib regimen had a 50% reduction in the risk of death or disease progression. Median PFS was 14.5 months compared to 8.5 months in the control group, according to a Sunday presentation at the World Conference on Lung Cancer. An interim overall survival analysis showed a 28% benefit in favor of the zipalertinib combo, though follow-up for this secondary endpoint is still ongoing.
As for safety, Taiho and Cullinan reported that adverse events grade 3 or higher—those classified as severe or medically significant—arose in 87% of patients in the zipalertinib combo arm, as opposed to 54.4% of chemotherapy controls.
Three patients died following septic shock, episodes that the companies deemed related to the study regimen. Common side effects included rashes, diarrhea and mouth inflammation.
Nevertheless, analysts believe the partners can overcome the safety risks. Taiho plans to bring these data to the FDA, Leerink Partners said in a Monday note.
“The efficacy appears robust and approvable in our view,” the firm said.
Zipalertinib is currently under regulatory review for the same type of NSCLC, but in the second-line setting. A decision is expected by Feb. 27, 2027.
Leerink projects $235 million in peak zipalertinib revenues in the second-line setting and $791 million in first-line disease.
Sunday’s readout comes after Taiho and Cullinan announced REZILIENT3’s success last month—though the partners at the time didn’t provide specific PFS data.
Ready for a challenge
Taiho and Cullinan will have plenty of competition as the proceed into the NSCLC space, including Johnson & Johnson’s Rybrevant, AstraZeneca’s Zegfrovy and Arrivent’s upcoming firmonertinib, according to Leerink.
“The efficacy profile of the REZILIENT3 regimen is very competitive with Rybrevant plus chemotherapy and should support meaningful uptake of zipalertinib in the frontline” NSCLC setting in the U.S., William Blair said.
“REZILIENT3 PFS results showed the strongest median PFS reported to date,” the analysts added, pointing to J&J’s PAPILLON trial in which Rybrevant plus chemotherapy resulted in median PFS of 11.4 months.
The firm flagged zipalertinib’s safety profile as a point of concern for investors, however. The zipalertinib combo “did meaningfully increase the rates of hematologic adverse events during the first four cycles of chemotherapy and also resulted in an imbalance in treatment-related adverse event deaths.”
Nevertheless, the group believes that “the positive trends already observed in overall survival show the side effect profile will not detract from improved outcomes for patients.” There is also potential for greater supportive care, including transfusions, when the drug is used in a U.S. healthcare setting, William Blair said.
Available orally, zipalertinib is a small molecule drug that targets activating mutations to the EGFR gene, a known cancer driver. The drug was originally developed by Cullinan but came to Taiho in 2022 when the latter acquired a Cullinan subsidiary. The companies had previously said that they plan to seek approval for zipalertinib plus chemotherapy in the first-line NSCLC setting.
