Dr Phillips on the Effect of Targeted Therapy Dose Reductions in Advanced RET+ NSCLC

“This provides a lot of reassurance for patients who may be having [adverse] effects that are cumulative, like tiredness, GI upset, [or] swelling of the legs, because it says that if I need to go down on my dose in order to stay on my therapy with a better quality of life, we’re able to maybe do that with some data saying that it’s safe, and you’re not compromising those outcomes from your cancer control perspective.”

William Phillips, MD, a hematology-oncology fellow at the University of Colorado Anschutz, discussed findings from a multicenter retrospective cohort study evaluating dose reductions of the RET inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto) and their association with real-world clinical outcomes in patients with advanced RET fusion–positive non–small cell lung cancer (NSCLC), presented during the OncLive National Fellows Forum: Lung Cancer.

The analysis, conducted at the University of Colorado and Mass General Brigham Cancer Institute, included adult patients with advanced RET-positive NSCLC who had received no prior RET inhibitor therapy and were treated with selpercatinib or pralsetinib; dose reduction was defined as a decrease to 75% or less of the FDA-approved starting dose. Among the 46 patients included, the median age was 63 years (IQR, 54-69), and 56.5% were male. Selpercatinib was more commonly used than pralsetinib at 76.1% vs 23.9%, respectively, and the RET inhibitor was given as first-line therapy in 58.7% of patients and later-line therapy in 41.3%. Because dose reduction was more frequent among patients treated in later lines (78.9% of the dose-reduction group vs 14.8% of the no-reduction group), line of therapy was adjusted for in the subsequent time-to-event analyses.

Dose reductions occurred in 19 patients (41.3%), at a median time of 8 weeks from treatment initiation, according to Phillips. Laboratory abnormalities, rather than clinical symptoms reported by patients in clinic, were the most common trigger, accounting for 58% of dose reductions; other cited reasons included myelosuppression, hepatitis, fever, fatigue, dry mouth, arthralgia, chylous effusions, and diarrhea. At a median follow-up of 38.7 months, no significant differences in progression-free survival (HR, 0.72; P = .46) or time to next systemic therapy (HR, 0.62; P = .26) were observed between patients who underwent dose reduction and those who did not. Patterns of progression, including rates of central nervous system (CNS) progression, also did not differ significantly by dose-reduction status (P = .445); 97% (n = 36 of 37) of patients with progression had undergone CNS imaging at that time.

Phillips noted that dose reductions in this real-world cohort were driven more often by findings on routine labs than by symptoms patients raised themselves, which he said may point to a hesitancy to reduce dose for chronic, subjective toxicities such as fatigue, gastrointestinal (GI) upset, and leg swelling. Because dose reduction was not linked to worse disease control in this analysis, Phillips said the data can provide reassurance that lowering the dose of a RET inhibitor to improve tolerability and quality of life does not appear to come at the cost of cancer control.