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.

Lifestyle-Related Risk Factors

1. Smoking

Smoking is the single most significant risk factor for lung cancer, contributing to about 80% of lung cancer-related deaths. Previous radiation therapy, especially for cancers like Hodgkin lymphoma or breast cancer, also significantly increases the risk of developing lung cancer, particularly for those who smoke. The good news? Making the decision to quit smoking can dramatically lower the risk of developing this disease. It’s a life-changing step that not only benefits the lungs but also improves overall health and quality of life.

It’s not just direct smoking that poses a risk; exposure to secondhand smoke also increases the chances of developing lung cancer. Protecting yourself and your loved ones from secondhand smoke is an important way to reduce risks and create a healthier environment.

Emerging research suggests that smoking marijuana may also contribute to lung cancer risk. While studies are still ongoing, it’s another reminder of the importance of making informed choices about what we inhale into our lungs. By staying proactive and making positive changes, you can take control of your lung health and embrace a brighter, smoke-free future.

2. Secondhand Smoke

Secondhand smoke, also known as passive smoke or environmental tobacco smoke (ETS), is the smoke that comes from the burning of a cigarette, cigar, or pipe, as well as exhaled smoke from smokers. Exposure to secondhand smoke can significantly increase the risk of developing lung cancer, even for those who do not smoke. According to the National Cancer Institute, secondhand smoke is responsible for an estimated 3,000 lung cancer deaths per year in the United States.

When you breathe in secondhand smoke, you’re inhaling many of the same toxic chemicals that smokers inhale, including carcinogens like benzene and formaldehyde. These harmful substances can damage the cells in the lungs, leading to an increased risk of developing lung cancer.

The risk of lung cancer from secondhand smoke is higher for people who are exposed to it regularly, such as those who live with a smoker or work in environments where smoking is permitted. However, even occasional exposure to secondhand smoke can elevate lung cancer risk. Protecting yourself and your loved ones from secondhand smoke is critical to maintain lung health and reduce the risk of lung cancer.

3. Diet and Nutrition

Diet plays an important role in overall health, and it also can impact the risk of developing cancer. Research suggests that a diet low in fruits and vegetables may increase one’s cancer risk, as these nutrient-rich foods provide essential vitamins, minerals, and antioxidants that help protect the body from cell damage and support immune function.

Incorporating a healthy diet packed with a variety of colorful fruits and vegetables can be a simple yet powerful way to reduce cancer risk. These foods are rich in antioxidants and phytochemicals that help protect lung cells from harmful damage. By choosing a balanced diet and making fresh produce a daily priority, you’re not only supporting lung health but boosting your overall well-being.

Note the importance of obtaining nutrients from whole foods rather than relying on concentrated supplements without medical advice. Some research has shown that high-dose beta-carotene or vitamin A supplements should be avoided in smokers.

Environmental Risk Factors

1. Exposure to Radon and Carcinogens

Exposure to environmental and workplace hazards can significantly contribute to lung cancer risk. One such hazard is radon, a naturally occurring radioactive gas that can seep into homes and buildings from the ground. Radon is odorless and invisible, making it undetectable without proper testing, yet prolonged exposure is a leading cause of lung cancer in non-smokers. Ensuring your home is tested and mitigated for radon levels is a proactive step toward reducing cancer risk.

Radiation therapy, particularly when applied to the chest area, is another risk factor for lung cancer. Individuals who have undergone such treatment for cancers like Hodgkin lymphoma or breast cancer may face increased risks for developing lung cancer later on.

In addition to radon, carcinogens such as asbestos and arsenic are well-documented contributors to lung cancer. Asbestos, once widely used in construction and insulation, poses a risk when its fibers are inhaled. Arsenic exposure can occur through contaminated water or certain industrial processes. Both substances have been linked to increased lung cancer risk, which emphasizes the importance of minimizing exposure.

Occupational hazards also play a significant role. People working in industries such as mining, construction, and manufacturing may be exposed to these and other harmful carcinogens daily. Taking protective measures, including proper ventilation, personal protective equipment, and adherence to safety regulations, is essential for reducing exposure and safeguarding lung health.

By understanding and addressing these environmental and occupational risks, individuals and communities can take meaningful steps to lower lung cancer risk and create healthier living and working conditions.

2. Exposure to Asbestos

Asbestos is a group of naturally occurring minerals that were once widely used in construction, insulation, and various industrial applications due to their heat-resistant properties. However, asbestos exposure has been linked to several serious health issues, including lung cancer.

When asbestos fibers are inhaled, they can become lodged in the lung tissue, causing scarring and inflammation over time. This chronic irritation can lead to cellular changes and the development of lung cancer. According to the National Cancer Institute, asbestos exposure is responsible for an estimated 4,800 lung cancer deaths per year in the United States.

Individuals most at risk of developing lung cancer from asbestos exposure include those who have worked in industries such as construction, mining, and shipbuilding, where asbestos use was prevalent. However, anyone who has been exposed to asbestos, even in older buildings with asbestos-containing materials, can be at risk. It’s essential to minimize exposure to asbestos and to take appropriate safety measures if you suspect its presence in your environment.

3. Air Pollution

Air pollution is an increasingly recognized risk factor for lung cancer, with diesel exhaust being a significant contributor. Diesel engines emit a mixture of harmful chemicals and fine particulate matter that, when inhaled, can damage lung cells over time. This exposure is especially concerning for individuals living or working near busy highways, industrial areas, or other sources of heavy diesel traffic. Studies have linked prolonged exposure to diesel exhaust with an elevated risk of developing lung cancer.

Living in areas with high levels of general air pollution also poses risks. Pollutants from vehicles, factories, and even natural sources like wildfires can release harmful particles and gases into the air. These pollutants can penetrate deep into the lungs, causing inflammation and increasing the likelihood of cellular changes that may lead to lung cancer.

Taking steps to reduce exposure is vital for lung health. Strategies include advocating for cleaner energy initiatives, using air purifiers indoors, and staying indoors during times of poor air quality. By staying informed and proactive, individuals can help mitigate the risks associated with air pollution and contribute to cleaner, healthier environments for everyone.

Personal or Family History of Lung Cancer

Lung cancer is not considered a hereditary disease. Having a close relative with lung cancer slightly increases your risk, but this may also be due to shared environmental factors (e.g., smoking habits). While this does not guarantee you will develop the disease, it’s a reason to stay vigilant with screenings and health check-ups. If you’ve had lung cancer before, there is a higher likelihood of recurrence or developing a new cancer, especially if previous risk factors like smoking or environmental exposures persist.

Interestingly, a family history of other cancers, such as medullary thyroid cancer or papillary thyroid carcinoma, can also increase lung cancer risk. These connections are thought to be related to shared genetic mutations that predispose individuals to multiple cancer types. For example, individuals with a family history of these thyroid cancers may benefit from discussing genetic testing with their healthcare provider, especially if there’s a known mutation in the family. Men are more likely to develop thyroid cancer at an older age, particularly between the ages of 70 and 74.

By understanding your family history and genetic predispositions, you can take proactive steps to reduce risk, such as discussing personalized screening strategies or lifestyle adjustments with your doctor. Advances in genetic research are shedding light on these connections, offering new opportunities for early detection and targeted therapies that improve outcomes for individuals at higher risk.