RET fusion is present in ~2% of the NSCLC patients. RETEVMO is a highly selective and potent, brain penetrant RET inhibitor, approved for treatment of advanced RET fusion-positive NSCLC. Currently, two selective RET inhibitors, GAVRETO (pralsetinib) and RETEVMO (selpercatinib), have received FDA approval. Results from the Phase I/II ARROW trial, conducted globally across multiple centers, demonstrated promising outcomes with GAVRETO. Notably, it showed a high ORR and prolonged mPFS in both previously treated patients (61% ORR; 17.1 months mPFS) and those without prior treatment (70% ORR; 9.1 months mPFS).

LIBRETTO-431 is a Phase III, randomized, open-label trial evaluating RETEVMO versus platinum-based chemotherapy plus pemetrexed with or without pembrolizumab. A total of 261 patients were enrolled from 23 countries. Baseline characteristics were balanced across study arms. At a median follow-up of approximately 19 months, RETEVMO demonstrated superior PFS versus control in the intention to treat (ITT)-pembrolizumab and ITT populations. In the ITT- ITT-pembrolizumab population, the median PFS was 24.8 months with RETEVMO versus 11.2 months with control. Clinically meaningful improvements in ORR, DOR, and intracranial response were also observed with RETEVMO versus 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 previously reported.

Median time on RETEVMO was approximately 70% longer than the control (16.7 vs 9.8 months). Treatment emergent adverse events (TEAEs) observed with RETEVMO were generally consistent with those previously reported, and the majority were managed with dose modifications

KOL insights

“LIBRETTO 431: phase III trial of 1L selpercatinib vs chemotherapy +/- pembrolizumab in advanced RET NSCLC. Included PS 0-2 and asymptomatic brain metastases permitted. Optional crossover to selpercatinib from the control arm.” -Director of Thoracic Oncology & Developmental Therapeutics, Lombardi Comprehensive Cancer Center, US

Conclusion

RETEVMO has demonstrated remarkable efficacy in first-line treatment for patients with RET fusion-positive NSCLC. The pre-planned interim analysis of the study successfully met its primary endpoint, with a substantial and statistically significant improvement in median Progression-Free Survival of 24.8 months compared to 11.2 months in the chemotherapy plus pembrolizumab group. Notably, RETEVMO also exhibited enhanced intracranial response rates and delayed the progression of CNS disease compared to the control group. 

RETEVMO's sole rival at the moment in NSCLC is GAVRETO. A Phase III AcceleRET-Lung study is presently undergoing treatment of NSCLC as a first line of therapy. But since its confirmatory study was no longer feasible, Roche/Blueprint Medicines is in the process of withdrawing GAVRETO's expedited approval for medullary thyroid cancer. Lilly also presented findings from LIBRETTO-531 Phase III study, which evaluated RETEVMO versus multikinase inhibitors in patients with advanced or metastatic RET-mutant medullary thyroid cancer. Medullary thyroid cancer accounts for 1% to 2% of thyroid cancers in the United States. Lilly's RETEVMO beat CABOMETYX (Exelixis) and CAPRELSA (Sanofi) in RET-mutant medullary thyroid cancer segment. 

These compelling results underscore RETEVMO's role as the first-line standard of care for patients with RET fusion-positive advanced NSCLC. They emphasize the critical importance of genomic testing at the time of diagnosis to identify RET fusions, enabling informed and effective initial therapy decisions. RETEVMO's success in this study represents a significant advancement in the treatment landscape for this specific patient population, offering improved outcomes and setting a new standard for their care.

Although GAVRETO exhibits superior efficacy, it lags far behind RETEVMO in terms of revenue. Notably, the RET fusion NSCLC landscape is evolving with involvement of key players such as, Ellipses Pharma/Kelun-Biotech (EP0031) and Helsinn Healthcare (vepafestinib), both in the early clinical trial stages for the treatment of RET fusion NSCLC. The competition between these emerging drugs and the established RETEVMO and GAVRETO will be an area of keen interest to watch.

Note: The therapeutics segment is experiencing significant NSCLC clinical trial activity, which is further expected to drive Non-Small Cell Lung Caner market growth in the coming years.