Current Treatment Options for RET Lung Cancer

Lung cancer staging matters. Why? So your doctor can properly assess the spread of disease and identify the optimal treatment option. For patients with RET fusions or other RET mutations, there are targeted therapies that work to selectively block the RET molecule.

Stage IV: Targeted Therapy

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

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 difference between selective RET inhibitors and older RET multi-kinase inhibitors, is that the new compounds are able to target only RET and not other molecules, being more effective and reducing the likelihood of side effects. 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.

Stage II-III

Treatment options for early-stage RET NSCLC

Stage II-III lung cancer 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 and chemotherapy.

Different ongoing clinical trials are currently evaluating the efficacy of targeted therapy RET inhibitors in early-stage RET-positive non-small cell lung cancer.

The NAUTIKA1 study is a phase II clinical trial currently testing the selective highly selective RET inhibitor pralsetinib in patients with resectable stage II–III RET fusion positive NSCLC patients (NCT04302025). In addition to this study, the LIBRETTO-432 clinical trial is currently testing the highly selective RET inhibitor selpercatinib in patients with stage IB–IIIA RET fusion positive NSCLC (NCT04819100). For other oncogene-driven lung cancers such as EGFR or ALK lung cancer early treatment with specific inhibitors (EGFR or ALK tyrosine kinase inhibitors: ADAURA and LAURA trials for EGFR and ALINA trial for ALK ) have shown great and durable responses in EGFR or ALK lung cancer patients.

Other treatment options for RET fusion positive NSCLC

Chemotherapy

Chemotherapy works by destroying cancer cells which grow and divide quickly. Often a combination of different chemotherapy drugs is used for the treatment of NSCLC with the most common combination being the platinum-doublet chemotherapy (a combination of platinum compounds such as carboplatin or cisplatin, and a second chemotherapy agent as pemetrexed, etoposide, gemcitabine, paclitaxel, docetaxel, or vinorelbine).

Chemotherapy is a common treatment for NSCLC but as mentioned before, the treatment of stage IV RET lung cancer patients with specific RET inhibitors is encouraged. In the RET lung cancer trial, LIBRETTO-431, the treatment with the specific RET inhibitor selpercatinib led to significantly longer progression-free survival than platinum-based platinum-based chemotherapy with or without immunotherapy (pembrolizumab). The median progression-free survival of RET NSCLC patients who received selpercatinib was 24.8 months, compared with 11.2 months for those in the platinum-based chemotherapy group (6).

For early-stage RET NSCLC, chemotherapy after surgery (adjuvant chemotherapy) can help to lower the risk of the cancer coming back.

Immunotherapy

Immunotherapy is a treatment that uses a person’s immune system to destroy cancer cells. There are several types of immunotherapies including the checkpoint blockade inhibitors such as anti-PD-1/PD-L1 or anti-CTLA4 that were approved for the treatment of NSCLC (alone or in combination with chemotherapy). These drugs act by taking off the ‘brakes’ of immune cells allowing them to effectively attack and destroy cancer cells. Checkpoint blockade inhibitors have shown great responses in NSCLC patients, especially in patients who presented high levels of PD-L1 expression and/or high number of mutations (called tumor mutation burden (TMB) in their tumors.

But as happens with most of the oncogene-driven lung cancers such as EGFR mutant lung cancer, different studies have shown limited activity of these agents in RET lung cancer patients (7-9). One explanation may be that RET lung cancers are characterized by having low levels of PD-L1 expression and low TMB in the majority of patients. Other therapeutic strategies should be considered before administering immunotherapy alone for the treatment of 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.

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References

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
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
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
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.
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
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.
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
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
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
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).

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