Oncolytics Biotech Inc T.ONC

RE:RE:RE:RE:AstraZeneca's ADC disappoints - on severe adverse events

[Noteable]

The only published randomized trial evaluating the combination of an ADC and ICI is the KATE2 trial. This study evaluated the efficacy of T-DM1 plus atezolizumab and compared it with T-DM1 (Trastuzumab emtansine ) plus placebo. The study was conducted in patients who had previously been treated for HER2-positive breast cancer and, disappointingly, the combination therapy did not result in a statistically significant improvement in PFS in the overall patient population, with a median PFS of 8.2 months in the combination arm and 6.2 months in the control arm (P = 0.33). 

However, a trend suggesting potential benefit in a specific subset of patients with positive PD-L1 expression was observed, where median PFS was 8.5 months for the combination arm and 4.1 months for the control arm (P = 0.099). This indicated that adding an ICI to HER2-targeted treatment for HER2 + breast cancer may be particularly beneficial in the PD-L1-positive subset.

In the phase III KATE2 trial, a significant increase in adverse events, including one treatment-related death, was observed in the combination arm that combined atezolizumab and T-DM1 in patients with previously treated HER2-positive metastatic breast cancer. The frequencies of clinically significant adverse events (33% vs. 19%) and most adverse reactions, particularly fever (35% vs. 16%, including several hospitalizations), increased after the introduction of atezolizumab [140]. Similarly, randomized data are now available for enfortumab vedotin, with and without pembrolizumab, in 149 patients with advanced-stage urothelial carcinoma. The introduction of pembrolizumab resulted in a higher occurrence of clinically significant (23.7% vs. 15.1%) and fatal (3.9% vs. 2.7%) adverse events, and an overall increase in the incidence of all adverse events. Notably, an increase in serious skin reactions was observed. Nevertheless, the combination received accelerated approval from the FDA in April 2023 for patients with locally advanced or metastatic urothelial carcinoma, particularly those who could not receive cisplatin-based chemotherapy. This approval was based on the efficacy of the combination. However, the lack of a randomized design in most other studies on ADC and ICI combination therapies makes it difficult to reach definitive conclusions regarding the many unanswered questions. 

These results effectively suggest that significant improvements can be made should ONCY's pelareorep be added to the ADC combination.