The SHIVA01 trial was a randomized proof-of-concept phase II trial, testing the hypothesis of treating patients (pts) based on molecular profiles with molecularly targeted agents (MTA) in a histology agnostic manner. The trial results showed no statistically significant difference in PFS between MTA and control arm. The addition of functional information on identified mutations and their response to MTA’s may improve treatment outcomes.
The molecular profile of 20 pts treated with a MTA in the trial was analyzed in the NovellusDx Functional Annotation for Cancer Treatment (FACT), a functional mutational analysis platform, to reveal activated signaling pathways and measure the activity of these mutations in the presence of the MTA’s administered in the trial. The results of FACT were used to stratify the pts into responders and non-responders.
We uncovered the functional landscape in 12 of the 20 pts in the analyzed group. In the remaining 8 pts, no relevant mutational alterations were identified. This analysis provided experimental evidence to the oncogenic activity of the mutations and of the combination of mutations identified in the pts. Furthermore, the response of these pts' mutations to the MTA’s used was measured in-vitro, blinded to the actual clinical results. Each patient was then assigned as either a responsive or non-responsive. When the results were used to stratify the pts’ PFS data, positive patients had a median PFS of 5.8 months vs. 1.7 months in the negative group (P = 0.03 in a non-parametric test).
This analysis shows the predictive power of a new and innovative method for characterization of pts molecular profiles and their in-vitro response to MTA’s. The abundance of mutations classified as VUS and multiple mutations in different genes reveals the complexity in assigning the optimal MTA and the necessity of a functional assay. The FACT analysis accurately provided prognostic predictions of the pts treated into responsive and pts with no molecular basis for a benefit in MTA treatment. Importantly, the hypothesis driving the SHIVA01 trial proved positive by the addition of the functional interpretation of the mutational data.
Clinical trial identification
Legal entity responsible for the study
Institute Curie, Paris, France
G. Tarcic, O. Edelheit, Z. Barbash, M. Vidne, B. Miron: A full time employee of NovellusDx. All other authors have declared no conflicts of interest.