Endpoint analyses
cancer, deaths, death, HGG
CANCER, DISEASE, EVALUABLE, EVENT, SECONDARY
The primary endpoint of ORR was also analyzed using the frequentist methodology (point estimates and 95% CIs) including patients from the primary and expansion cohorts. Simulations were conducted to evaluate the performance of this study design under various ORR distributions across cohorts, accounting for power, type I error, ORR estimation and probability of halting at an interim analysis. With similar treatment effects across all cohorts, this design would maintain 84–98% power and a type I error rate ≤0.04; power ranges from 55% to 90% and type I error from 0.03 to 0.14 if treatment effect varies across histologic subtypes.The efficacy evaluable population was defined as all enrolled patients, regardless of whether or not treatment was administered, and encompassed all patients enrolled in both the primary and expansion cohorts for a given histological cancer subtype. Evaluable patients included those who had progressive disease, had initiated new anti-cancer treatment, had withdrawn consent, had died, had stable disease for at least 6 weeks after the first dose day or had at least two post-baseline disease assessments (other than not evaluable).PFS, DoR and OS were analyzed for the combined primary and expansion cohorts using the Kaplan–Meier methodology, with 95% CIs for median and milestone estimates constructed using the Brookmeyer–Crowley method with a complementary log–log transformation of the survivor function; 95% CIs were used for uncertainty estimates and were investigator assessed. Patients with an unknown or missing response were treated as non-responders and were included in the denominator when calculating the percentage. Time-to-event secondary endpoints were right censored if the event was not observed during the study follow-up.The independent radiology review was done as a supportive analysis in the ATC, BTC, ASI, LGG and HGG cohorts. Primary and secondary efficacy endpoints based on independent reviewer assessment were summarized in the same way as the best response based on investigator assessment. An assessment of the concordance between the investigator-assessed response and independent reviewer-assessed response was performed. In addition, waterfall plots were generated for best confirmed response based on investigator and independent assessment.The safety population included all patients who received at least one dose of dabrafenib or trametinib. Safety data were summarized descriptively by histology and across all cohorts. Incidence of deaths and primary cause of death were summarized. An independent data monitoring committee reviewed safety and activity results from interim analyses at regular intervals and provided recommendations to the sponsor.