ESMO 2023: LBA4
RET fusion is found in about 1-2% of patients with non-small cell lung cancer. Retevmo, a highly selective and potent RET inhibitor that effectively crosses the blood-brain barrier, has received approval for treating advanced RET fusion-positive NSCLC. Currently, two selective RET inhibitors, Gavreto (pralsetinib) and Retevmo (selpercatinib), have obtained FDA approval. Outcomes from the Phase I/II ARROW trial, conducted across multiple global centers, have demonstrated promising results with Gavreto.
The LIBRETTO-431 trial is a Phase III, randomized, open-label study comparing Retevmo against platinum-based chemotherapy with or without pemetrexed, along with or without pembrolizumab. A total of 261 patients from 23 countries were enrolled, and their baseline characteristics were evenly distributed across the study arms. After a median follow-up of approximately 19 months, Retevmo has demonstrated superior Progression-Free Survival (PFS) compared to the control group in both the Intention to Treat (ITT) population with pembrolizumab and the overall ITT population. In the ITT-ITT-pembrolizumab population, the median PFS was 24.8 months for Retevmo, in contrast to 11.2 months for the control group. Retevmo has also shown clinically meaningful improvements in Objective Response Rate (ORR), Duration of Response (DOR), and intracranial response compared to the control. Time to central nervous system (CNS) progression was longer with Retevmo than with the control. Adverse events observed with Retevmo and the control arm were generally consistent with those reported previously. ORR was 83.7% in the Retevmo arm and 65.1% in the control arm, with DOR at 24.7 and 11.5 months, respectively.
The median time on Retevmo was approximately 70% longer than on the control (16.7 months versus 9.8 months). Treatment-emergent adverse events (TEAEs) observed with Retevmo were generally consistent with those previously reported, and most were manageable with dose modifications.
Conclusion
Retevmo has showcased remarkable effectiveness in the first-line treatment of patients with RET fusion-positive NSCLC. The pre-planned interim analysis of the study achieved its primary endpoint with great success, revealing a substantial and statistically significant improvement in median Progression-Free Survival (PFS) at 24.8 months, as opposed to 11.2 months in the chemotherapy plus pembrolizumab group. Retevmo also demonstrated superior intracranial response rates and delayed the progression of central nervous system (CNS) disease when compared to the control group.
While Gavreto displays impressive efficacy, it lags significantly behind Retevmo in terms of revenue. It’s important to recognize that the landscape for RET fusion-positive NSCLC is evolving, with the entry of key players such as Ellipses Pharma/Kelun-Biotech (EP0031) and Helsinn Healthcare (vepafestinib), both in the early stages of clinical trials for the treatment of RET fusion NSCLC. The competition between these emerging therapies and the established Retevmo and GAVRETO will undoubtedly be a focal point of interest to monitor in the coming years. This dynamic environment holds the potential to bring further advancements and options for patients with RET fusion-positive NSCLC.
