Resistance: When RET Non-Small Cell Lung Cancer Treatments Stop Working

Updated September 2025

Understanding Drug Resistance in Cancer Therapy

Targeted cancer therapies can be very effective in eliminating cancer cells, but unfortunately some tumor cells may escape the effect of the treatment and survive. The surviving cells are able to proliferate and drive tumor growth.

RET targeted therapies have shown promise in treating RET cancer. These medications specifically target the abnormal RET proteins, slowing cancer progression and improving patient outcomes. However, despite initial success, some patients develop resistance to these cancer treatments over time.

Signs of Resistance to Cancer Treatment

Signs that a treatment may be losing its effectiveness include the return or worsening of symptoms, such as increased coughing, difficulty breathing, or new pain. Regular monitoring through scans and tests is vital to detect resistance early and adjust the treatment plan accordingly.

Resistance to Selective RET Kinase Inhibition

Targeted cancer therapies, including the FDA-approved selective RET inhibitors that specifically target or inhibit the RET molecule – selpercatinib (Retevmo) and pralsetinib (Gavreto) – have transformed the treatment of RET cancer patients. These compounds specifically target the RET protein and have shown great clinical benefit in RET fusion positive NSCLC patients, with high response rates in pretreated patients and in treatment naïve patients. They also showed a high intracranial efficacy in RET patients with brain metastases (1-3).

Previous to the development of these agents and their approval in 2020, the therapeutic options for RET fusion-positive NSCLC patients were scarce, with the standard treatment being chemotherapy drugs or immunotherapy. Some multi-kinase inhibitors that target RET were investigated for the treatment of RET cancers but the effectiveness was low and they showed some toxicity with a high number of patients requiring discontinuation of the treatment (4).

Like what happens with other selective inhibitors and despite the clinical benefit of selective RET inhibitors, within 1-3 years many RET lung cancer patients become resistant to these targeted therapies and the cancer progresses again (5). Unfortunately, there is no approved therapy to treat patients who are resistant to RET inhibitors.

RET patients can develop resistance by two main underlying mechanisms, as described here:

1. Acquired Resistance Mutations in RET Cancer Cells

RET cancer treatment resistance can happen by newly acquired mutations in the RET molecule that are developed after the treatment with selective RET targeted therapy and produce an alteration on the RET molecule that allow the cancer cell to escape the effects of targeted drugs. These mutations produce a modification of the RET molecule that avoids the therapeutic drug to bind effectively. Some of the resistant mutations described include the RET molecule solvent front mutations (RET G810 mutations) or hinge mutations. Acquired mutations confer RET acquired drug resistance, and they are found in some patients treated with selpercatinib or pralsetinib (6, 7).

How to overcome acquired cancer drug resistance?

Investigators are now developing and testing new second-generation RET inhibitors that are able to inhibit these RET resistant mutations in cancer cells, overcoming resistance. Examples of these new targeted cancer therapies and clinical trials are:

• RET inhibitor EP0031

EP0031 is a next generation specific RET inhibitor developed by Ellipses Pharma with activity against common RET fusions and mutations, including solvent front mutations that confer drug resistance of cancer cells. Earlier this year, the company presented new clinical trial data from studies in the U.S. and Europe — and the results were positive. Find more info on EP0031. Thanks to this progress, Ellipses now plans to move forward with a Phase 2 trial (NCT05443126).

• RET Inhibitor vepafestinib

The RET Inhibitor vepafestinib (TAS0953/HM06) developed by Helsinn Healthcare is a RET-specific inhibitor that is effective against RET solvent front (G810) mutations. A recent study led by Dr. Romel Somwar (MSKCC) showed great efficacy of vepafestinib in RET preclinical models, including RET cancer cell and mouse models bearing RET drug resistance mutations and superior pharmacokinetic properties in the brain (8). The brain is a common site of relapse for patients with RET NSCLC treated with targeted therapies. The phase I clinical trial is ongoing in Japan (NCT04683250). The latest results were preseted at WCLC 2025. Vepafestinib was generally well tolerated and showed promising early activity in both untreated and RET inhibitor–resistant patients, supporting further study (more info here). Global development of vepafestinib is expected in the near future.

• RET Inhibitor APS03118

The RET Inhibitor APS03118 developed by Applied Pharmaceutical Science APS03118 is a novel next-generation RET inhibitor that targets a range of RET fusions and mutations in cancer cells including drug resistance mutations. Preclinical data was recently published and showed that the compound has potent in vitro and in vivo activity against a diverse range of RET alterations.The Phase 1 clinical trial in patients with advanced RET-altered tumors is ongoing (NCT05653869) (Only China locations). Future global development is expected.

 

2. RET-Independent Mechanisms of Drug Resistance

These mechanisms of resistance are caused by an over-expression of pathways of cancer cells that are independent of RET that can also cause cancer cells to proliferation. One of the main pathways that has been characterized to produce resistance to RET inhibitors is MET amplification (9). A study led by Dr. Jessica Lin demonstrated that the majority of RET drug resistance is mediated by these RET-independent resistance mechanisms highlighting the urgent need of finding new therapies or more effective combination therapy for RET inhibitor resistance that is mediated by activation of alternative pathways (9).

How to overcome RET-independent cancer drug resistance?

Investigators are now testing combinations of drugs that target the over expressed molecules like MET along with RET inhibitors in RET cancer cells with the aim to overcome drug resistance.

Here is an example of a clinical trial that is testing combinations for RET cancer:

• MET inhibitors in combination with RET inhibitors

In many cases, patients who become resistant to targeted therapies including RET inhibitors present increased activation of EGFR or MET as a bypass signaling mechanism that allows these cancer cells to circumvent the selective pressure from the therapy.

• Amivantamab

Amivantamab, a bispecific antibody that binds to the extracellular domains of EGFR and MET in combination with RET inhibitors, is being studied for patients who progressed on TKI therapies including RET therapies (NCT05845671). The clinical trial is led by Dr. Tejas Patil from University of Colorado.

• MET ADC

The cMET-targeting antibody-drug conjugate (ADC) compound called MYTX-011, is also being studied in patients with previously treated, advanced NSCLC (NCT05652868). Results were presented at ASCO 2025. MYTX-011 was well tolerated and showed anti-tumor activity. The dose expansion study is currently ongoing as of January 2025. More info here.

• Exploring Other Mechanisms
• TROP2 overexpression

One of the latest research findings shows that RET-positive tumors can sometimes overexpress a molecule called TROP2 (among others). This is an exciting discovery because there is now a bispecific antibody that targets TROP2, currently being evaluated across different types of lung cancer, including RET. Early results look encouraging. In the Dato-DXd  Tropion Lung5 clinical trial, 8 patients with RET-positive lung cancer were treated, and 5 of them experienced more than a 30% reduction in tumor size (Info here). While the information available is still limited, these initial outcomes are promising and open the door to new potential treatment strategies for the RET community. Although the Dato-DXd Tropion Lung5 clinical trial is not currently recruiting patients (as of Sept 2025) a phase III trial of Dato-DXd compared to platinum-based chemotherapy in patients with actionable genomic alterations with disease progression on targeted therapies is warranted. More info here and here.

• MTAP Loss

Another possible mechanism of resistance that has been recently described is MTAP loss (info here), which occurs in a subset of RET-positive lung cancer patients. Two phase I/II clinical trials are available: a selective PRMT5 inhibitor, TNG462-C101 study (NCT05732831) (info here and here) and the MTRX 1719 study (Info here and here).

Importance of tumor sequencing after progression

When the cancer treatment stops working, a moment called progression, one of the most powerful tools doctors have is tumor sequencing.

By analyzing the genetic landscape of the tumor after progression, doctors can uncover the mechanisms why cancer cells became resistant (usually new mutations in the original target or alternate pathways that allow it to keep growing)

This information is invaluable. Tumor sequencing acts like a roadmap: instead of relying on trial and error, doctors can make more informed decisions about the next steps. That might mean enrolling in a clinical trial for a next-generation drug, or combining therapies to block new pathways.

Don’t Give Up Hope

Understanding and managing treatment resistance is crucial for those with RET cancer. By staying informed about current treatments and emerging options, patients can work with their healthcare team to navigate this challenging aspect of the cancer journey.

If you or a loved one is facing RET cancer, staying informed and proactive in your treatment is essential. Reach out to your healthcare providers for support and explore available resources to help manage your lung cancer journey.

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References

1. Drilon A. et al. Efficacy of Selpercatinib in RET Fusion-Positive NSCLC. N Engl J Med. 27;383(9):813-824 (2020).
2. Zhou C, Solomon B, Loong HH, 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
3. Gainor J.F. et al. Pralsetinib for RET fusion-positive NSCLC (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 22(7):959-969 (2021).
4. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653-1660. doi:10.1016/S1470-2045(16)30562-9
5. Lin JJ, Gainor JF. An early look at selective RET inhibitor resistance: new challenges and opportunities. Br J Cancer. 2021;124(11):1757-1758. doi:10.1038/s41416-021-01344-7
6. Solomon BJ, Tan L, Lin JJ, et al. RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies. J Thorac Oncol. 2020;15(4):541-549. doi:10.1016/j.jtho.2020.01.006
7. Subbiah V, Shen T, Terzyan SS, et al. Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol. 2021;32(2):261-268. doi:10.1016/j.annonc.2020.10.599
8. Miyazaki I, Odintsov I, Ishida K, et al. Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations [published correction appears in Nat Cancer. 2023 Oct;4(10):1526]. Nat Cancer. 2023;4(9):1345-1361. doi:10.1038/s43018-023-00630-y
9. Lin JJ, Liu SV, McCoach CE, 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.2020.09.015

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