A retrospective multicenter study presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting has demonstrated that rechallenge with a different first-generation RET inhibitor can be effective in patients with RET-rearranged non-small cell lung cancer (NSCLC) who previously discontinued selpercatinib (Retevmo) or pralsetinib (Gavreto) due to toxicity.
The study, conducted using data from the RET MAP registry, provides new insights into treatment sequencing for this rare patient population, where RET fusions occur in only 1% to 2% of patients with advanced NSCLC.
Efficacy Results Vary by Discontinuation Reason
Among 38 patients who discontinued first-line RET inhibitor therapy, the overall objective response rate (ORR) was 78%, with a median progression-free survival (PFS) of 12.9 months (95% CI, 9.2-30.3). The reasons for initial discontinuation were disease progression in 71% of patients and toxicity in 29%.
The most encouraging results emerged in the subset of 11 patients who received a second RET inhibitor after toxicity-related discontinuation. This group achieved an ORR of 50% and median PFS of 9.89 months (95% CI, 5.25-not applicable). Notably, all patients in this cohort received a different RET inhibitor than their initial treatment, though three patients developed toxicities upon rechallenge.
In contrast, patients who received a second RET inhibitor following disease progression (n=14) showed limited benefit, with an ORR of only 18% and median PFS of 2.14 months (95% CI, 1.61-NA).
Combination Strategies Show Modest Promise
For patients treated with a second RET inhibitor plus targeted agents designed to overcome bypass resistance (n=9), the ORR was 38% with a median PFS of 3.94 months (95% CI, 3.19-NA). Overall treatment patterns showed that 52% of patients received second RET inhibitor monotherapy, 33% received combination with targeted agents, and 15% received combination with chemotherapy.
"Rechallenge with a different RET [inhibitor] of the same class is effective after initial discontinuation due to toxicity, though toxicity may re-occur," stated Dr. Arianna Marinello, medical oncologist at Institut Gustave Roussy in Villejuif, France, and lead study author. "RET [inhibitor] rechallenge after progression demonstrates limited efficacy when used in monotherapy. However, some efficacy emerged in selected cases with combination therapies targeting bypass resistance."
Patient Characteristics and Safety Profile
The study population had a median age of 60 years at diagnosis, with 55% being female and 41% non-smokers. Most patients (92%) had adenocarcinoma histology, 66% had a KIF5B partner, and 25% presented with brain metastases. At baseline, 80% had an ECOG performance status of 0 or 1, with a median of 2 prior treatment lines.
Initial treatment distribution showed 63% of patients received selpercatinib versus 37% who received pralsetinib. Upon rechallenge, 63% maintained the same RET inhibitor while 27% switched to a different agent. Five patients (13%) experienced severe toxicity at second exposure, including three who had previously experienced toxicity with initial RET inhibition.
Addressing Unmet Medical Need
The research addresses a significant gap in treatment options for RET-rearranged NSCLC patients. While RET inhibitors have demonstrated improved outcomes for this patient population, limited data previously existed to guide treatment decisions after initial therapy failure.
The study's findings suggest that rechallenge strategies may offer meaningful clinical benefit, particularly for patients who discontinue initial therapy due to toxicity rather than disease progression. However, the researchers noted that toxicity may recur with rechallenge, requiring careful patient selection and monitoring.
