Going once, going twice - sold to the oncologist recycling the same drug class! In the high-stakes auction of cancer treatment options, what happens when you've already played your best card and need to bid again with something suspiciously similar? That's the question a team of researchers just tried to answer for patients with RET-rearranged lung cancer, and the results are... well, it depends on why you're rebidding.
Wait, What's RET Again?
RET is a gene that, when it gets rearranged (think: two genes that shouldn't be holding hands suddenly fusing together), can drive lung cancer in about 1-2% of non-small cell lung cancer (NSCLC) patients. It's a small club, but a consequential one. The good news? We now have drugs specifically designed to shut down this rogue gene - selpercatinib (Retevmo) and pralsetinib (Gavreto), collectively known as selective RET inhibitors, or SRIs. Selpercatinib crushed it in the LIBRETTO-431 trial, delivering a median progression-free survival of 24.8 months versus 11.2 months for chemo (Subbiah et al., NEJM 2023; DOI: 10.1056/NEJMoa2309457).
The bad news? Eventually, most tumors figure out how to dodge these drugs - through sneaky solvent front mutations or by activating backup escape routes like MET amplification (Solomon et al., Ann Oncol 2020; PMID: 33007380). And once that happens, options get thin. Real thin.
The "Can We Try That Again?" Study
Marinello and colleagues pulled data from the RET-MAP registry - a multicenter effort tracking RET-rearranged NSCLC patients across multiple institutions. Out of 411 patients treated with SRIs, 41 (about 10%) ended up getting retreated with a same-class drug. The reasons for stopping the first SRI split into two very different camps: toxicity (34%) and disease progression (66%) (Marinello et al., Clin Cancer Res 2025; DOI: 10.1158/1078-0432.CCR-25-4814).
And here's where the story forks dramatically.
The Toxicity Swap: Actually Pretty Decent
Patients who stopped their first SRI because of side effects and switched to the other one? They did surprisingly well. The objective response rate hit 67%, with a median PFS of 9.9 months and a 6-month PFS rate of 80.3%. Not bad for a "Plan B." However - and this is important for anyone ready to call this a slam dunk - side effects came back in 64% of patients, and 21% of those who started at full dose experienced grade 3 or worse toxicity. So yes, swapping works, but maybe tiptoe into the dosing rather than cannonballing in.
The Progression Rechallenge: Pump the Brakes
Now for the patients who stopped because their cancer outsmarted the drug. This is where my inner skeptic starts tapping the microphone. SRI monotherapy rechallenge after progression showed an ORR of just 23%, with a median PFS of 7 months. The 6-month PFS was 61.5%, which sounds respectable until you remember these tumors already proved they can beat this class of drugs.
Combination therapy (SRI plus another targeted agent or chemo) bumped the ORR to 39%, but the median PFS actually dropped to 4 months - suggesting these combinations might catch a few responders without fundamentally solving the resistance problem.
The bright spots? Patients with brain-only progression or oligoprogressive disease (cancer growing in just a few spots while staying controlled elsewhere) seemed to benefit more. And patients who had been on a reduced dose of their first SRI - meaning their tumors may not have faced the drug's full firepower - also appeared to do better on rechallenge. That makes biological sense, even if the numbers are too small to write home about.
The Bigger Picture
Let's be honest about what we're looking at: 41 patients, retrospective data, no control group. This isn't the kind of evidence that rewrites guidelines. But it fills a real clinical gap. When your patient with RET-rearranged NSCLC runs out of options, knowing that a toxicity-driven swap can work - and that progression-driven rechallenge mostly doesn't, except in select scenarios - is genuinely useful information.
The field is also moving. Next-generation RET inhibitors designed to overcome resistance mutations are in clinical trials, and combination strategies targeting bypass pathways like MET are being explored (Lin et al., Nat Commun 2022; DOI: 10.1038/s41467-022-28848-x). The auction isn't over. New bidders are warming up.
For now, though, this study offers a pragmatic message: switching SRIs after toxicity is a viable play. Rechallenge after progression? Save it for the right patient, and keep your expectations appropriately calibrated.
References:
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Marinello A, Rotow JK, Lomibao M, et al. Retreatment with First-Generation Selective RET Inhibitors in RET-Rearranged NSCLC Pretreated with Selpercatinib or Pralsetinib - Results from the RET-MAP Registry. Clin Cancer Res. 2025. DOI: 10.1158/1078-0432.CCR-25-4814 | PMID: 41945500
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Subbiah V, Wolf J, Konda B, et al. First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC. N Engl J Med. 2023;389(20):1839-1850. DOI: 10.1056/NEJMoa2309457 | PMID: 37870973
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Solomon BJ, Tan L, Lin JJ, et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 2020;31(12):1725-1733. DOI: 10.1016/j.annonc.2020.09.013 | PMID: 33007380
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Lin JJ, Liu SV, McCoach CE, et al. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nat Commun. 2022;13(1):1450. DOI: 10.1038/s41467-022-28848-x
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Hoe J, Kerpel-Fronius A, Gao S, et al. Treatment of non-small cell lung cancer with RET rearrangements. Cancer. 2025. DOI: 10.1002/cncr.35779
Disclaimer: The image accompanying this article is for illustrative purposes only and does not depict actual experimental results, data, or biological mechanisms.