Taiho Pharmaceutical and Cullinan Therapeutics’ cancer asset is already under FDA review in a later setting, with a decision expected by February.
Taiho Pharmaceutical and Cullinan Therapeutics’ candidate zipalertinib significantly improved progression-free survival for patients with advanced non-small cell lung cancer in a late-stage trial. Already under FDA review for previously treated NSCLC, the new results tee up a potential FDA filing as a first-line treatment.
The partners said in a Wednesday night release that REZILIENT3, a global Phase 3 study for patients with NSCLC harboring epidermal growth factor receptor (EGFR) exon 20 (ex20) insertion mutations, met its primary endpoint at an interim analysis.
The companies did not share figures behind the PFS win but said its experimental EGFR inhibitor plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS when compared to chemotherapy alone.
The risk of disease progression or death is measured using a hazard ratio, with any ratio under one demonstrating that the investigational treatment is tied to a better PFS than those in the comparative arm. The closer the hazard ratio is to zero, the better the survival rate is.
An independent data committee recommended Taiho and Cullinan unblind REZILIENT3, suggesting “the magnitude of results could be significant,” according to Leerink Partners. “The total trial was powered to detect a hazard ratio of 0.60 at 90% power,” William Blair analysts wrote in a Thursday note, “strongly suggesting the interim analysis came in below 0.6 to achieve stopping criteria.”
A hazard ratio potentially below 0.6 means the zipalertinib-chemo combo could compare favorably to Dizal Pharmaceutical and AstraZeneca’s EGFR inhibitor Zegfrovy, which demonstrated a hazard ratio of 0.65—or a 35% improvement in PFS—versus chemotherapy in a Phase 3 first-line NSCLC study.
The full data will be shared at an upcoming medical conference, and the partners plan to seek regulatory approval in the first-line setting, they said in their announcement.
Zipalertinib is currently under FDA review as a monotherapy in previously treated EGFR ex20 NSCLC, with a decision expected by Feb. 27.
William Blair assumes the REZILIENT3 findings will be filed as a supplemental new drug application immediately if the approval for previously treated patients goes through, adding that the partners will likely make regulators aware of the new data to see if it can be included in the current review.
While patients with EGFR ex20 NSCLC account for a relatively small portion of the market, William Blair believes “zipa’s strong efficacy and tolerability could prove beneficial in the first-line setting.” The safety profile for the investigational arm in REZILIENT3 was manageable, the partners said.
If approved, Taiho-Cullinan’s zipalertinib-chemo combo would be the third first-line therapy to hit the market in the indication, joining Zegfrovy and Johnson & Johnson’s bispecific antibody Rybrevant plus chemotherapy, the latter of which carries certain tolerability issues, William Blair noted.
AstraZeneca recently scooped up commercial rights to Zegfrovy for up to $1.5 billion, suggesting that the drug will soon be commercialized in the U.S., the analyst said. The drug secured an accelerated approval from the FDA last year, but China-based Dizal hasn’t been able to get commercialization efforts off the ground since then.
Rybrevant and chemotherapy demonstrated a median PFS of 11.4 months in the first-line setting, while Zegfrovy showed a 10.3-month median PFS. Therefore, Leerink analysts think zipalertinib will need to show a median PFS around 11 months or more to compete. Anything below 11 months may not justify the added chemotherapy toxicity compared to Zegfrovy monotherapy, Leerink wrote.
Taiho and Cullinan came together in 2022, with the former acquiring a Cullinan subsidiary housing zipalertinib for $275 million upfront.
Cullinan now has the chance to make up to $130 million in regulatory milestones, plus a 50/50 profit share in the U.S.
