Retreatment with First-Generation Selective RET Inhibitors in RET-Rearranged NSCLC Pretreated with Selpercatinib or
Arianna Marinello1, Julia K Rotow2, Meghanne Lomibao3
1Department of Medical Oncology, Institut Gustave Roussy, International Center for Thoracic Cancers, Villejuif, France.
Purpose:
In RET-rearranged non-small cell lung cancer (NSCLC), treatment options after first-generation selective RET inhibitors (SRI) are limited, and the value of SRI retreatment remains unclear. This study evaluates outcomes of SRI retreatment.
Experimental Design:
This multicenter retrospective study included patients with advanced RET-rearranged NSCLC who received ≥2 SRI-based therapy lines. Of 411 SRI-treated patients, 41 (10%) underwent SRI retreatment. Outcomes included objective response rate (ORR), progression-free survival (PFS), 6-month PFS, time to treatment failure, adverse events (AE).
Results:
Among 41 patients, 14 (34%) discontinued the initial SRI because of toxicity and 27 (66%) because of progression. After discontinuation for toxicity, all switched to an alternate SRI, achieving an ORR of 67%, median PFS of 9.9 months, and 6-month PFS of 80.3%. AEs reoccurred in nine patients (64%), with grade ≥3 AEs in 3 (21%) who switched at full dose. Among patients who discontinued because of progression, SRI monotherapy (n = 13) achieved an ORR of 23%, median PFS of 7 months, and 6-month PFS of 61.5%. Benefit was observed in patients with brain-only or oligoprogressive disease or dose reduction on first SRI. Combination therapy (n = 14; targeted agents, n = 11; chemotherapy, n = 3) achieved an ORR of 39%, median PFS of 4 months, and 6-month PFS of 27.3%.
Conclusions:
Same-class SRI switch after toxicity is feasible and clinically active but warrants cautious, dose-adjusted switching to mitigate toxicities. The efficacy of SRI rechallenge after progression seems limited overall. However, selected patients, such as those with brain-only or oligoprogressive disease, may derive benefit.
Insights
Switching to another selective RET inhibitor (SRI) after toxicity is effective for RET-rearranged non-small cell lung cancer (NSCLC) patients. However, retreatment after disease progression shows limited benefit, except for specific cases like brain metastases.
Area of Science:
- Oncology
- Pharmacology
Background:
- Treatment options for RET-rearranged non-small cell lung cancer (NSCLC) after initial selective RET inhibitor (SRI) therapy are limited.
- The efficacy of retreatment with SRIs in this patient population is not well-established.
Purpose of the Study:
- To evaluate the outcomes of selective RET inhibitor (SRI) retreatment in patients with advanced RET-rearranged NSCLC.
- To assess the feasibility and clinical activity of switching to an alternate SRI after toxicity and rechallenging with an SRI after progression.
Main Methods:
- A multicenter retrospective study included 411 patients with advanced RET-rearranged NSCLC who received at least two SRI-based therapy lines.
- Outcomes, including objective response rate (ORR), progression-free survival (PFS), and adverse events (AEs), were analyzed for 41 patients who underwent SRI retreatment.
Main Results:
- Switching to an alternate SRI after discontinuation due to toxicity yielded a 67% ORR and 9.9 months median PFS, with manageable recurrent toxicities.
- SRI monotherapy after progression showed a 23% ORR and 7 months median PFS.
- Combination therapy after progression resulted in a 39% ORR and 4 months median PFS, with benefit observed in patients with brain-only or oligoprogression.
Conclusions:
- Switching to the same class of SRI after toxicity is feasible and clinically active in RET-rearranged NSCLC, requiring careful dose adjustment.
- SRI rechallenge after disease progression has limited overall efficacy but may benefit selected patients with specific patterns of progression.
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