Statistical considerations
Cancer
DISEASE, CANCER
In terms of the ‘evaluable’ population, patients ‘evaluable for efficacy’ were all patients enrolled in the trial who received at least one dose of trial treatment and met the definition for the prespecified efficacy analyses criteria (RANO-HGG, RAPNO and RANO-LGG)The primary endpoint analysis was performed in the arm 1 evaluable population, which included all enrolled patients who received at least one dose of tovorafenib and had measurable disease at baseline per RANO-HGG criteria as determined by the IRC. A sample size of 60 patients in the evaluable population was considered to provide 88% power to reject the null hypothesis ORR of 21%, at the two-sided 0.05 level, assuming that the true underlying ORR of tovorafenib was 40% in this disease population. An exact binomial test was used for hypothesis testing. Responses per RAPNO and RANO-LGG criteria were evaluated in evaluable populations, which included all enrolled patients who received at least one dose of tovorafenib and had measurable disease at baseline per RAPNO and RANO-LGG criteria, respectively, as determined by the IRC.Prespecified subgroup analysis of the uniformity of the treatment effects for ORR in arm 1 was planned for subgroups defined by The ORR and CBR were calculated with 95% CIs determined using the Clopper–Pearson method. PFS and DOR were estimated by the Kaplan–Meier method and were summarized along with the corresponding two-sided 95% CI. Waterfall plots were generated for each patient’s best percentage change in sum of perpendicular diameters of measurable lesions.Safety endpoints were analyzed using descriptive statistics based on the safety population in arms 1 and 2. AEs were coded by system organ class and preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.1 and graded according to the National Cancer Institute CTCAE version 5.0.Statistical analyses were carried out using SAS version 9.4.