Current Treatment Options for RET Lung Cancer

Treatment of RET non-small cell lung cancer (NSCLC)

Over the past several years, major advances in understanding RET biology have transformed the treatment landscape for patients with RET alterations. The development of selective RET inhibitors has provided patients with more effective and better-tolerated treatment options compared with many traditional approaches used in lung cancer.

Treatment decisions for RET-positive NSCLC depend on several factors, including the stage of disease, overall health, and the molecular characteristics of the tumor. For patients with metastatic (stage IV) disease, selective RET inhibitors such as selpercatinib (Retevmo) and pralsetinib (Gavreto) have become the preferred first-line treatment options when available. For patients diagnosed with earlier-stage disease, treatment approaches may include surgery, chemotherapy, and, for eligible patients, targeted therapy to reduce the risk of recurrence.

Treatment options for metastatic RET non-small cell lung cancer (NSCLC)

Metastatic stage IV RET lung cancer refers to tumors that have spread to distant sites in the body. Stage IV disease is generally unresectable. Most of the RET Non-Small Cell Lung Cancer NSCLC (70%) patients have stage IV disease at diagnosis (1,2).

First-line treatment options for RET-positive stage IV lung cancer patients are targeted therapies including the FDA-approved selective RET inhibitors that specifically target or inhibit the RET molecule: selpercatinib (Retevmo) and pralsetinib (Gavreto). The FDA approval of these agents was based on the good results reported in LIBRETTO-001 (NCT03157128) and ARROW (NCT03037385) clinical trials respectively. These RET inhibitors specifically target the RET fusion protein and showed great benefit in RET fusion positive non-small cell lung cancer patients and a high intracranial response rate in RET patients with brain metastases (3-5). 

The Phase I/II LIBRETTO-001 study of selpercatinib in 105 patients with RET fusion-positive NSCLC demonstrated an overall response rate (ORR) of 64%, with a median progression-free survival (mPFS) of 26 months in previously treated patients and 22 months in treatment-naïve patients. Median overall survival (mOS) was 47 months in previously treated patients and not reached (NR) in treatment-naïve patients. Find reference information here.

The Phase I/II ARROW study evaluated pralsetinib (400 mg once daily) in 281 patients with RET fusion-positive NSCLC. The study demonstrated an overall response rate (ORR) of 70.3%, a median duration of response (DOR) of 19.1 months, a median progression-free survival (PFS) of 13.1 months, and a median overall survival (OS) of 44.3 months. Notably, median PFS was substantially longer in patients treated in the United States (25.9 months) than in those treated in Asia (12.6 months) or Europe (12.9 months). Find reference information here.

Importantly approximately 25% of patients with RET fusion-positive NSCLC have brain metastases at baseline. Both selective RET inhibitors demonstrate substantial intracranial activity, with selpercatinib achieving an intracranial objective response rate (IC ORR) of 82% pralsetinib achieving an IC ORR of 53%.

Specific RET inhibitors showed enhanced tolerability and they are the preferred therapeutic option when compared with other cancer therapies such as multikinase inhibitors, chemotherapy, or immunotherapies based on immune checkpoint inhibitors.

Important info for the EU: Pralsetinib (Gavreto) is no longer authorized in the EU. Its marketing authorization was withdrawn in October 2024 for commercial reasons, not due to safety concerns. Currently, selpercatinib (Retevmo) is the only selective RET inhibitor authorized in the EU for RET fusion-positive NSCLC.

Treatment options for early-stage RET NSCLC

Early stage lung cancer (II-III) is generally resectable but some patients with IIIb disease have inoperable disease. For these stages, doctors look at individual features of the tumor to identify the optimal treatment option. For some patients with early-stage RET fusion positive lung cancer, treatment options may include surgical resection, chemotherapy, and, for eligible patients, adjuvant selpercatinib.

The LIBRETTO-432 clinical trial is testing Retevmo (selpercatinib) in patients with stage IB–IIIA RET fusion positive NSCLC (NCT04819100). At ASCO 2026 conference, Eli Lilly announced positive phase III LIBRETTO-432 results for selpercatinib in early-stage RET fusion-positive NSCLC. Results were also published in NEJM. The study shown that among 109 patients with stage II or IIIA disease, the event-free survival was 92% with selpercatinib and 61% with placebo. Among the 151 patients with stage IB, II, or IIIA NSCLC, the event-free survival at 2 years was 94% with selpercatinib and 70% with placebo. These results support the use of selpercatinib in the early-stage setting and highlight the need for comprehensive biomarker testing in early disease to identify actionable drivers such as RET. Eli Lilly plans to submit the results to global health authorities and the NCCN Guidelines for NSCLC were updated on June 15, 2026 to recommend RET fusion testing as part of biomarker evaluation for patients with resectable or early-stage NSCLC and selpercatinib as a treatment option for early-stage RET fusion–positive NSCLC

More reference information here and here.

Oligometastatic disease: treating a few growing spots while staying on a RET inhibitor

Some patients with RET fusion-positive NSCLC develop oligometastatic disease, meaning the cancer has spread to only a limited number of sites (commonly 1–5). In some cases, if most of the cancer remains well controlled on the specific RET inhibitor and only one or a few lesions begin to grow, doctors may recommend treating those specific lesions with a local therapy, such as stereotactic body radiation therapy (SBRT) or surgery, while continuing on the specific RET inhibitor. The goal is to control the resistant areas without abandoning an effective systemic therapy that is benefiting the patient overall. The rationale is that the growing lesions may have developed localized resistance, while the rest of the cancer remains sensitive to the RET inhibitor. Treating the resistant sites locally may allow patients to continue benefiting from selpercatinib and delay the need to switch to another systemic therapy.

Other treatment options for RET fusion positive NSCLC:

Please note: For patients with RET fusion-positive NSCLC, selective RET inhibitors are the preferred first-line treatment when available. Because these therapies specifically target the RET alteration driving the cancer, they generally provide greater benefit than chemotherapy or immunotherapy alone. RET targeted treatment strategies should be prioritized before considering chemotherapy or immunotherapy alone in patients with RET alterations.

Chemotherapy

Chemotherapy has long been a standard treatment for advanced NSCLC. However, as discussed above, patients with stage IV RET fusion-positive NSCLC should receive a selective RET inhibitor whenever possible, as these therapies provide substantially better outcomes than chemotherapy. Historically, median overall survival with standard platinum-based chemotherapy has been approximately 8–12 months. In the phase III LIBRETTO-431 trial, first-line treatment with selpercatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy with or without pembrolizumab. The median progression-free survival was 24.8 months with selpercatinib versus 11.2 months with chemotherapy.

Similarly, the phase III AcceleRET-Lung trial compared pralsetinib with standard-of-care platinum-based chemotherapy with or without immunotherapy in patients with RET fusion-positive advanced NSCLC. Pralsetinib significantly improved progression-free survival (18.7 vs. 9.0 months), objective response rate (65.5% vs. 41.6%), and median duration of response (20.6 vs. 9.7 months), further supporting the use of selective RET inhibitors as the preferred first-line treatment.

In early-stage RET fusion-positive NSCLC, platinum-based chemotherapy after surgery has traditionally been used to reduce the risk of recurrence. However, as discussed previously, the results of the Phase III LIBRETTO-432 trial, presented at ASCO 2026, demonstrated that selpercatinib significantly reduced the risk of disease recurrence, supporting its use as the new standard of care for eligible patients with resected early-stage RET fusion-positive NSCLC.

Immunotherapy

Immunotherapy is a type of cancer treatment that harnesses the body’s immune system to recognize and destroy cancer cells. Several immunotherapies, including immune checkpoint inhibitors targeting PD-1/PD-L1 or CTLA-4, have been approved for the treatment of NSCLC, either alone or in combination with chemotherapy. These therapies work by releasing the “brakes” on immune cells, enabling them to mount a stronger attack against cancer cells. Checkpoint inhibitors have demonstrated remarkable clinical benefit in many patients with NSCLC, particularly those whose tumors have high PD-L1 expression and/or a high tumor mutational burden (TMB).

However, as with many other oncogene-driven lung cancers, such as EGFR-mutant NSCLC, multiple studies have shown that RET fusion-positive lung cancers derive limited benefit from immune checkpoint inhibitors (7–9). Consistent with these findings, the phase III LIBRETTO-431 trial demonstrated that adding pembrolizumab to platinum-based chemotherapy did not improve outcomes compared with chemotherapy alone in patients with RET fusion-positive NSCLC, and both treatment approaches were inferior to first-line selpercatinib.

One possible explanation is that most RET fusion-positive lung cancers have low PD-L1 expression and a low tumor mutational burden, characteristics that are generally associated with a reduced likelihood of responding to immunotherapy. Therefore, selective RET inhibitors should be considered the preferred first-line treatment, and other targeted treatment strategies should be prioritized before considering immunotherapy alone in patients with RET alterations. Learn more about immunotherapy for RET lung cancer. 

Resistance to selective RET kinase inhibition

Currently selpercatinib (Retevmo) and pralsetinib (Gavreto) are the RET inhibitors that selectively target the RET protein and are FDA approved for the treatment of NSCLC and thyroid cancers. These treatments showed great benefit and durable responses in most patients but unfortunately within 1-3 years, many lung cancer patients with RET alterations become resistant to the therapies and the cancer progress again (10). Different mechanisms of resistance to RET inhibitors have been described, including acquired RET solvent front mutations and more frequently due to RET-independent mechanisms that involve the upregulation of alternative pathways such as MET. Finding new therapies that prevent resistance or effective treatment option for patients with RET fusion who become resistant to RET inhibitors are crucial for unmeet needs. Learn more about resistance to RET inhibition.

Learn more about lung cancer vaccines in development.

Match to a RET clinical trial
View latest RET Research

References

1. Gautschi O, Milia J, Filleron T, et al. Targeting RET in Patients With RET-Rearranged Lung Cancers: Results From the Global, Multicenter RET Registry. J Clin Oncol. 2017;35(13):1403-1410. doi:10.1200/JCO.2016.70.9352
2. Aldea M, Marinello A, Duruisseaux M, et al. RET-MAP: An International Multicenter Study on Clinicobiologic Features and Treatment Response in Patients With Lung Cancer Harboring a RET Fusion. J Thorac Oncol. 2023;18(5):576-586. doi:10.1016/j.jtho.2022.12.018
3. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
4. Subbiah V, Gainor JF, Oxnard GR, et al. Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial. Clin Cancer Res. 2021;27(15):4160-4167. doi:10.1158/1078-0432.CCR-21-0800.
5. Gainor JF, Curigliano G, Kim DW, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study [published correction appears in Lancet Oncol. 2021 Aug;22(8):e347]. Lancet Oncol. 2021;22(7):959-969. doi:10.1016/S1470-2045(21)00247-3
6. 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.
7. Offin M, Guo R, Wu SL, et al. Immunophenotype and Response to Immunotherapy of RET-Rearranged Lung Cancers. JCO Precis Oncol. 2019;3:PO.18.00386. doi:10.1200/PO.18.00386
8. Mazieres J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328. doi:10.1093/annonc/mdz167
9. Negrao MV, Skoulidis F, Montesion M, et al. Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer. J Immunother Cancer. 2021;9(8):e002891. doi:10.1136/jitc-2021-002891
10. Lin J.J. et al. Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer. Ann Oncol. 31(12):1725-1733 (2020).