Dr Doroshow on RET Inhibitors in RET Fusion+ NSCLC

Deborah B. Doroshow, MD, PhD, assistant professor, medicine, the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, discusses the similarities and differences between the efficacy and safety profiles of pralsetinib (Gavreto) and selpercatinib (Retevmo) in patients with non–small cell lung cancer (NSCLC) harboring RET fusions.

In 2020, pralsetinib received FDA approval for patients with metastatic, RET fusion–positive NSCLC, based on findings from the phase 1/2 ARROW trial (NCT03037385), in which the agent led to an overall response rate (ORR) of 57% (95% CI, 46%-68%). In 2022, the FDA granted regular approval to selpercatinib for patients with locally advanced or metastatic, RET fusion–positive NSCLC, based on confirmatory follow-up data from the lung cancer arm of the phase 1/2 LIBRETTO-001 trial (NCT03157128), in which the ORR was 61% (95% CI, 55%-67%) with the agent.

Pralsetinib and selpercatinib have similar efficacy profiles in patients with NSCLC, as both agents penetrate the central nervous system and elicit high rates of durable responses, Doroshow says. Additionally, both drugs are effective in the frontline setting and after progression on platinum-based chemotherapy, Doroshow notes.

However, although selpercatinib and pralsetinib are both associated with adverse effects such as fatigue, the 2 agents can cause differential toxicities as well, Doroshow explains. For instance, pralsetinib is associated with higher levels of decreased white blood cell counts than selpercatinib. In ARROW, 34% of patients experienced any-grade leukopenia. Leukopenia was not reported in patients with lung cancer in LIBRETTO-001. Additionally, selpercatinib is associated with higher levels of liver function elevation than pralsetinib. In LIBRETTO-001, 36.7% and 35.7% of patients in the lung cancer cohort experienced increased aspartate aminotransferase and increased alanine aminotransferase, respectively, vs 41% and 30% of patients, respectively, in ARROW.

Although selpercatinib and pralsetinib generate similar efficacy outcomes in patients with RET fusion–positive NSCLC, their safety profiles are not identical or interchangeable, Doroshow emphasizes.