Breaking Ground: The Most Successful Treatment Options for RET-Positive Lung Cancer

Understanding RET-Positive Lung Cancer

Prevalence

RET-positive lung cancer is a specific subtype of non-small cell lung cancer (NSCLC) characterized by an abnormal rearrangement or fusion of the RET gene with other gene partners. This genetic alteration leads to the continuous activation of the RET kinase, which drives uncontrolled cell growth and cancer development. Although RET-positive lung cancer accounts for a relatively small percentage of NSCLC cases – approximately 2% – it translates to around 37,500 new cases globally each year. Understanding this subtype is crucial for developing targeted treatments that can effectively manage and treat the disease. Other RET alterations like RET mutations are also common in inherited and sporadic medullary thyroid cancer, and other types of cancers like ovarian, breast, pancreatic, colorectal cancers and advanced endometrial cancer.

The Role of the RET Gene in Cancer Cells

The RET gene is integral to normal cell growth and differentiation, but when it becomes altered in cancer cells, it can lead to significant problems. In RET-positive lung cancer, the fusion of the RET gene results in the production of abnormal RET proteins. These proteins are receptor tyrosine kinases that, when constitutively active, trigger downstream signaling pathways that promote tumor growth and survival. This continuous activation of the RET protein leads to the proliferation of cancer cells and contributes to the aggressive nature of RET-positive lung cancer. By targeting these abnormal proteins, researchers aim to develop therapies that can effectively halt tumor growth and improve patient outcomes.

The Evolution of RET Therapies

A historical look at treatment challenges

Before the development of targeted therapies, treatment options for RET-positive lung cancer were limited to conventional approaches such as chemotherapy and radiation. These methods, while effective to a degree, often came with significant side effects and lacked specificity in targeting the underlying genetic drivers of cancer, particularly the tumor cells. Other multi-kinase inhibitors that are able to target RET and other molecules were tested for RET cancers.

The shift to targeted therapies for precision medicine

The advent of precision medicine marked a turning point in the treatment of RET-positive lung cancer. Researchers began focusing on developing drugs that specifically inhibit the RET fusion protein, a key driver of tumor growth in RET-positive cancers. This shift led to the emergence of highly selective RET inhibitors, such as selpercatinib (Retevmo) and pralsetinib (Gavreto), which were designed to block the activity of the RET protein with minimal impact on other cellular pathways. These targeted therapies have not only demonstrated impressive clinical efficacy but have also significantly improved the quality of life for patients by reducing the toxic side effects associated with broader treatments. These targeted therapies have shown significant improvements in median progression-free survival compared to traditional treatments. Selective RET inhibitors are the preferred option to treat RET cancer patients.

Detection and Treatment

Detection of RET Fusions

Accurate detection of RET fusions is essential for diagnosing and treating RET-positive lung cancer. Several advanced technologies are employed to identify these genetic alterations in the clinic:

• Immunohistochemistry (IHC): This method detects the presence of RET proteins in tissue samples. While it can identify both known and unknown fusion locations, it is limited by the availability of specific antibodies and can produce false positives and negatives.
• Fluorescence In Situ Hybridization (FISH): Known for its high sensitivity, FISH is effective in detecting classical RET fusions. However, it is costly, time-consuming, and subject to interpretation variability.
• Next-Generation Sequencing (NGS): NGS offers high throughput and accuracy, allowing for large-scale gene screening. Despite its advantages, it may have lower sensitivity compared to RNA-based NGS.

FDA-Approved RET inhibitors for the Treatment of RET-Positive Lung Cancer

Overview of FDA-approved drugs like selpercatinib (Retevmo) and pralsetinib (Gavreto)

In recent years, selpercatinib (Retevmo) and pralsetinib (Gavreto) have revolutionized the treatment landscape for RET cancer. These drugs are highly selective inhibitors of RET that work by targeting and blocking the abnormal RET fusion protein, a primary driver of cancer growth in patients with this mutation. Selpercatinib was the first drug of its kind to receive FDA approval in 2020, followed closely by pralsetinib. Both treatments are designed for patients with metastatic RET-positive non-small cell lung cancer (NSCLC), offering a more precise and effective alternative to traditional therapies. Their oral formulation makes them convenient for patients, and they are often better tolerated than older systemic treatments.

Clinical trials have demonstrated remarkable efficacy for both selpercatinib and pralsetinib, with many patients experiencing significant tumor shrinkage and prolonged progression-free survival. For instance, in the LIBRETTO-001 trial, selpercatinib achieved an objective response rate (ORR) of 64% in previously treated RET-positive NSCLC patients, with even higher rates in treatment-naïve individuals. Similarly, the ARROW trial for pralsetinib reported ORRs of 61% in previously treated RET-positive patients. Beyond the numbers, these drugs have transformed lives, enabling many patients to regain their strength and return to daily activities. Success stories abound, with patients reporting dramatic improvements in symptoms, longer survival times, and a renewed sense of hope. These outcomes underscore the potential of targeted therapies to provide personalized and highly effective treatment options for RET-positive lung cancer patients. Similar success has been observed in clinical trials for bladder cancer, where new therapies have shown significant efficacy.

Emerging Therapies and Clinical Trials

Highlight new treatments in the pipeline

The field of RET-positive lung cancer research is advancing, with some new therapies in development. Next-generation RET inhibitors are being designed to overcome resistance that may develop with existing treatments like selpercatinib and pralsetinib. Additionally, researchers are exploring novel drug formulations to enhance drug delivery and improve efficacy. These pipeline therapies aim to expand options and provide tailored solutions for a broader range of patients. 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. The Phase 1/2 trial evaluating safety, tolerability and efficacy in patients with advanced RET-altered tumors is ongoing (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).

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. The Phase 1 clinical trial in patients with advanced RET-altered tumors is ongoing (NCT05653869) (Only China locations).

Emerging combination therapies

Combination therapies are emerging as a promising approach to enhance treatment outcomes for RET cancer patients. Studies are investigating the combinations with drugs targeting additional mutations or pathways involved in tumor growth aimed at overcoming resistance.

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

Amivantamab in combination with RET inhibitors

A Phase 1 / 2 study testing amivantamab, a bispecific antibody that targets epidermal growth factor receptor (EGFR) and MET in combination with RET inhibitors for patients who progressed on RET therapies (NCT05845671). 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. The new clinical trial lead by Dr. Tejas Patil from University of Colorado, study the effects of amivantamab, a bispecific antibody that binds to the extracellular domains of EGFR and MET in patients who progressed on TKI therapies including RET therapies.