Taiho Oncology chief medical officer (CMO) Dr Harold Keer recently discussed with Srivani Venna the outcomes from the Phase III REZILIENT3 trial of zipalertinib and chemotherapy in previously untreated, advanced non-small cell lung cancer (NSCLC).
In the interview, Dr Keer discusses the trial’s statistically significant improvement in progression-free survival (PFS) and the overall survival (OS) data, which remain immature. He also addresses treatment-related adverse events (AEs), rates of dose reductions and discontinuations, and what the treatment could mean for patients’ quality of life.
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Dr Keer also tells Clinical Trials Arena that the study examines how consistently the PFS benefit was observed across patient subgroups, while highlighting the patient-reported outcome data.
Srivani Venna (SV): What were the hazard ratio, confidence interval, and level of statistical significance for the PFS benefit, and how was PFS measured in the trial?
Dr Harold Keer (HK): REZILIENT3 met its primary endpoint, demonstrating a statistically significant improvement in PFS with zipalertinib plus chemotherapy compared with chemotherapy alone. The hazard ratio was 0.50 (95% CI: 0.34–0.73; P=0.00015), indicating a 50% reduction in the likelihood of progressing in the treatment arm. This translated into a median PFS of 14.5 months with the combination versus 8.5 months with chemotherapy alone, representing a six-month improvement. PFS, the trial’s primary endpoint, was assessed by blinded independent central review, or BICR.
SV: At the interim analysis, what were the key OS findings, including the number of deaths recorded, the median follow-up duration, and whether the survival benefit was consistent across major patient subgroups?
HK: The survival analysis was triggered by the positive PFS readout in the interim analysis, hence it is immature. At the data cutoff, 24 deaths had occurred among 140 patients receiving zipalertinib plus chemotherapy and 31 among 139 patients receiving chemotherapy alone. With a median follow-up of 10.9 months, the OS hazard ratio was 0.72 (95% CI: 0.42–1.23; P=0.11082), with median OS not estimable in either arm. The study allows patients in the chemotherapy arm to cross over and receive zipalertinib at the time of progression, and 64.2% have done so. This has the potential to decrease any observed difference between the treatment arms. Given the immaturity of the OS data, it is too early to draw conclusions about an OS benefit or its consistency across patient subgroups. The study is ongoing to further characterise OS with subsequent analyses driven by the number of progression or survival events.
SV: How did AEs affect treatment delivery in practice, specifically the rates of dose reductions, treatment discontinuations, hospitalisations, and treatment-related deaths in each study arm?
HK: AEs in the combination arm were increased compared to chemotherapy alone; however, the majority of these were myelosuppression, worse in the first four cycles of treatment and managed with dose reduction or discontinuation. For zipalertinib, 43.6% of patients had an AE leading to dose reduction and 17.1% had an AE leading to discontinuation. Corresponding rates for pemetrexed in the combination arm were 48.6% and 31.4%, and for platinum chemotherapy 32.9% and 15.7%. In the chemotherapy-alone arm, dose reductions occurred in 21.3% for pemetrexed and 15.4% for platinum, with discontinuation rates of 11.8% and 5.1%, respectively. There were three treatment-related deaths (2.1%) in the combination arm and none in the chemotherapy arm. Hospitalisation rates were not reported in the WCLC presentation.
SV: Given the higher rate of grade 3 or greater AEs, what was the combination’s actual impact on patients’ quality of life and symptom burden?
HK: Grade 3 or higher AEs were higher in the zipalertinib and chemotherapy arm compared to the chemotherapy alone arm. This was also associated with a higher overall response rate, a shorter time to response, and a longer duration of response. We cannot yet comment on how these different observations translate into quality of life and symptom burden. The REZILIENT3 study is collecting patient-reported outcome (PRO) data and plans to report on that at a later date. At the time of the analysis for the WCLC presentation, these data were ongoing and not reported at WCLC.
SV: How consistent was the PFS benefit across predefined subgroups such as age, sex, disease stage, and geographic region, and were any notable differences observed?
HK: PFS consistently favoured zipalertinib plus chemotherapy across all of the subgroups presented, with some variability in the magnitude of observed effect. Specifically, in patients with baseline brain metastases, the HR was 0.38 compared to 0.62 in those without. There may be regional differences, with a PFS HR of 0.4 for rest-of-world (ROW) vs 0.82 in Asia. Lesser variations were seen in males vs. females (0.39 vs 0.63) and those < 65 vs over 65 (0.38 vs 0.78). Disease stage was not included among the subgroup analyses presented at WCLC. These subgroup analyses should be interpreted cautiously given the smaller patient numbers within individual groups; the overall trial result remains the most robust assessment of treatment effect.
