Matthew H. Taylor

PURPOSE: Multiple reports have suggested that receiving immunotherapy infusions earlier in the day is associated with improved outcomes, including longer overall survival (OS) and lower toxicity rates. However, the definition of early varies between publications. Reports also fail to account for confounding factors (including distance to infusion center), are subject to survivor bias (analyzing postbaseline factors at baseline), and do not adjust P values for multiple comparisons when evaluating multiple potential thresholds for early versus late time of day of infusion. METHODS: We analyzed a previously reported multicenter clinical trial evaluating pembrolizumab as adjuvant therapy for participants with resectable high-risk melanoma. Standard statistical methodologies that account for potential biasses were used to evaluate the association between time of day of infusion and clinical outcomes. RESULTS: A total of 628 participants received pembrolizumab and had time of first infusion recorded. The median age was 55 years, range, 20-82. Odds of infusion before 11:00 hours increased by 32% over 12 months of therapy ( P = .013). Participants living further from their treating institution had later infusion times on average: odds of infusion before 11:00 decreased by 9% for each additional 50 miles ( P = .017). The optimal cut point for first infusion time for OS was 15:48 with hazard ratio (HR) = 1.40; changing the cut point by 30 minutes earlier to 15:18 decreased HR to 0.98, indicating lack of robustness of the threshold. No significant association was identified between proportion of early infusions and outcomes in multivariable time-dependent Cox regression models. CONCLUSION: In this multicenter trial of adjuvant pembrolizumab for participants with high-risk melanoma, analyses that account for common sources of bias found no significant association between recurrence-free or OS and time of day of infusion.

Table S1. Cell lines used for cell-based pERK assays in Figure 1A

Figure S3. Mouse plasma PK profiles for exarafenib and plixorafenib.

Table S2. X-ray crystallography data collection and refinement statistics

Figure S1. Preclinical characterization of PF-07799933 and comparison to other RAF inhibitors.

Figure S2. Crystal structures of BRAF kinase domain with PF-07799933 or encorafenib.

Figure S4. Patient PK profiles for PF-07799933.

Figure S5. Efficacy for BRAF non-V600/Class II and Class III-mutant cancer patients.

Table S4. Treatment-Emergent Adverse Events (≥3 patients) with PF-07799933 monotherapy and combination therapy

Supplementary Methods, References