Avid Bioservices Inc (CDMO)

[newbieee]

Facilitating the Development of Immunotherapies:
Intermediate Endpoints for Immune Checkpoint Modulators

3. "Milestone" Survival Analysis
In this approach, the proportion of survivors based on the Kaplan-Meier estimate at an interim time point is assessed in a fully powered study, and the probability of survival at the interim point is used as the basis for accelerated approval, with the confirmatory endpoint being final log-rank analysis of overall survival at a later time point in the same trial when the pre-specified number of events is reached. To support this proposal, a retrospective analysis of a phase 3 ipilimumab trial was performed (CA184-024; ipilimumab + dacarbazine vs. dacarbazine alone). This trial enrolled 502 patients with advanced but previously untreated melanoma and demonstrated an overall survival benefit for the ipilimumab combination arm (9.1 vs 11.2 months; HR = 0.716; p-value = 0.0009) (30). To assess "milestone" survival, Kaplan-Meier probability analysis was conducted for the first 300 patients randomized into the trial once those patients had reached a minimum of 2 years of follow-up. The analysis showed that the estimated 2-year overall survival rates among these 300 patients were 14.1% and 24.9% (p-value = 0.021). The timing of the analysis could have been accelerated by a year if this analysis had been incorporated in the original study design.

In addition to potentially serving as a surrogate endpoint for accelerated approval, this milestone analysis approach has several other advantages: it provides greater statistical power to detect a treatment benefit at an interim analysis, it would enable information regarding survival probabilities and long term survival information to be included in the package insert, it entails a predictable timing of analysis, and KM probability is also an OS endpoint...

http://www.elsevierbi.com/~/media/Supporting%20Documents/The%20Pink%20Sheet/75/46/FOCR_immunotherapy_issue_brief.pdf