RET Inhibitor Rechallenge Demonstrates Activity in Previously Treated NSCLC

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Findings from a retrospective multicenter study demonstrated that rechallenging with an alternative first-generation RET inhibitor following prior discontinuation due to toxicity showed clinical activity in a small cohort of patients with RET-rearranged non–small cell lung cancer (NSCLC) previously treated with selpercatinib (Retevmo) or pralsetinib (Gavreto). Data were presented at the 2025 ASCO Annual Meeting.

Efficacy data from the trial revealed that among patients who were first treated with a RET inhibitor and discontinued first-line therapy (n = 38), the objective response rate (ORR) was 78%, with a median progression-free survival (PFS) of 12.9 months (95% CI, 9.2-30.3). Reasons for discontinuation included 71% who experienced disease progression and 29% who experienced toxicity.

Among patients treated with a second RET inhibitor alone after toxicity (n = 11), the ORR was 50%, with a median PFS of 9.89 months (95% CI, 5.25-not applicable [NA]). Of note, all patients in this group received a different RET inhibitor, and 3 developed toxicities at rechallenge. In patients who received a second RET inhibitor as a single agent following disease progression (n = 14), the ORR was 18%. The median PFS in this group was 2.14 months (95% CI, 1.61-NA).

Furthermore, among patients treated with a second RET inhibitor plus targeted agents for bypass resistance (n = 9), the ORR was 38%, with a median PFS of 3.94 months (95% CI, 3.19-NA). In total, 52% (n = 14) of patients received a second RET inhibitor as monotherapy, 33% (n = 9) received a second RET inhibitor plus a targeted agent, and 15% (n = 4) received a RET inhibitor plus chemotherapy.

“Rechallenge with a different RET [inhibitor] of the same class is effective after initial discontinuation due to toxicity, though toxicity may re-occur,” Arianna Marinello, MD, medical oncologist of the Cancer Medicine Department at Institut Gustave Roussy in Villejuif, France, wrote in presentation with study coinvestigators. “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.”

Patients with NSCLC in the retrospective study were selected from the RET MAP registry, were initially treated with selpercatinib or pralsetinib, and underwent a rechallenge with the same or different first-generation RET inhibitor either as a monotherapy agent or in combination therapies.

Patients treated with a RET inhibitor who underwent a rechallenge had a median age of 60 years (IQR, 49-69) at diagnosis and were mostly female (55%); most did not smoke (41%). A total of 92% of patients had adenocarcinoma histology, 66% had a KIF5B partner, 25% had brain metastases, and 80% had an ECOG performance status of 0 or 1 at baseline. Among this patient group, the median number of prior lines was 2 (IQR, 1-3), and 63% received prior selpercatinib vs 37% receiving pralsetinib.

Overall, 63% of patients maintained the same RET inhibitor upon disease progression, with 27% experiencing a change in RET inhibitor. A total of 63% of patients received non-consecutive lines of administration. Five patients (13%) experienced severe toxicity at second exposure, of which 3 experienced a toxicity with initial RET inhibition.

The study was conducted to evaluate the outcomes of patients undergoing treatment rechallenge with a first-generation RET inhibitor. Historically, the study authors noted that RET fusions occur in 1% to 2% of patients with advanced NSCLC, and RET inhibitors have shown improved outcomes for this patient group. To address limited options for those who progress following RET inhibition, rechallenge with a first-generation RET inhibitor may be attempted; however, investigators described a paucity of data supporting the practice.

Reference

Marinello A, Rotow J, Lomibao M, et al. Rechallenge with first-generation RET inhibitors in RET-rearranged NSCLC pre-treated with selpercatinib or pralsetinib: results from the RET MAP registry. J Clin Oncol. 2025;43(suppl 16):8646. doi:10.1200/JCO.2025.43.16_suppl.8646