A great deal of research has been conducted in ways to find lung cancer early. Several methods are currently being studied to see if they decrease the risk of dying from lung cancer.

CT Scan

The NCI-sponsored National Lung Screening Trial (NLST) showed that low-dose CT scans can be used to screen for lung cancer in people with a history of heavy smoking. Using this screening can decrease their risk of dying from lung cancer. Now researchers are looking for ways to refine CT screening to better predict whether cancer is present. 

Markers in Blood and Sputum

Scientists are trying to develop or refine tests of sputum and blood that could be used to detect lung cancer early. Two active areas of research are:

• Analyzing blood samples to learn whether finding tumor cells or molecular markers in the blood will help diagnose lung cancer early.
• Examining sputum samples for the presence of abnormal cells or molecular markers that identify individuals who may need more follow-up.

Machine Learning

Machine learning is a method that allows computers to learn how to predict certain outcomes. In lung cancer, researchers are using computer algorithms to create computer-aided programs that are better able to identify cancer in CT scans than radiologists or pathologists. For example, in one artificial intelligence study, researchers trained a computer program to diagnose two types of lung cancer with 97% accuracy, as well as detect cancer-related genetic mutations.

Treatment options for lung cancer are surgery, radiation, chemotherapy, targeted therapy, immunotherapy, and combinations of these approaches. Researchers continue to look for new treatment options for all stages of lung cancer.

Treatments for early-stage lung cancer

Early-stage lung cancer can often be treated with surgery. Researchers are developing approaches to make surgery safer and more effective.

• When lung cancer is found early, people usually have surgery to remove an entire section (lobe) of the lung that contains the tumor. However, a recent clinical trial showed that, for certain people with early-stage NSCLC, removing a piece of the affected lobe is as effective as surgery to remove the whole lobe. 
• The targeted therapy Osimertinib (Tagrisso) was approved by the FDA in 2021 to be given after surgery—that is, as adjuvant therapy—to people with early-stage NSCLC that has certain mutations in the EGFR gene.
• Two immunotherapy drugs, atezolizumab (Tecentriq) and pembrolizumab (Keytruda) have been approved by the FDA to be used as adjuvant treatments after surgery and chemotherapy, for some patients with early-stage NSCLC. 
• The immunotherapy drug nivolumab (Opdivo) is approved to be used, together with chemotherapy, to treat patients with early-stage lung cancer before surgery (called neoadjuvant). This approval, which came in 2022, was based on the results of the CheckMate 816 trial, which showed that patients who received neoadjuvant nivolumab plus chemotherapy lived longer than those who received chemotherapy alone. 
• In another trial (Keynote-671), patients with early-stage NSCLC who received pembrolizumab plus chemotherapy before surgery and pembrolizumab after surgery  had better outcomes than those who received just neoadjuvant or just adjuvant treatment.  

Treatments for advanced lung cancer

Newer therapies are available for people with advanced lung cancer. These primarily include immunotherapies and targeted therapies, which continue to show benefits as research evolves.  

Immunotherapy

Immunotherapies work with the body's immune system to help fight cancer. They are a major focus in lung cancer treatment research today. Clinical trials are ongoing to look at new combinations of immunotherapies with or without chemotherapy to treat lung cancer.

Immune checkpoint inhibitors are drugs that block an interaction between proteins on immune cells and cancer cells which, in turn, lowers the immune response to the cancer. Several immune checkpoint inhibitors have been approved for advanced lung cancer, including pembrolizumab (Keytruda). atezolizumab (Tecentriq), cemiplimab (Libtayo), durvalumab (Imfinzi), and nivolumab (Opdivo).

A key issue with immunotherapies is deciding which patients are most likely to benefit. There is some evidence that patients whose tumor cells have high levels of an immune checkpoint protein called PD-L1 may be more responsive to immune checkpoint inhibitors. Another marker for immunotherapy response is tumor mutational burden, or TMB, which refers to the amount of mutations in the DNA of the cancer cells. In some lung cancer trials, positive responses to immune checkpoint inhibitors have been linked with a high TMB. However, these markers cannot always predict a response and there is ongoing work to find better markers.

To learn more, see Immunotherapy to Treat Cancer.

Targeted Therapies

Targeted treatments identify and attack certain types of cancer cells with less harm to normal cells. In recent years, many targeted therapies have become available for advanced lung cancer and more are in development. Targeted treatments for lung cancer include the below.

Anaplastic lymphoma kinase (ALK) Inhibitors

ALK inhibitors target cancer-causing rearrangements in a protein called ALK. These drugs continue to be refined for the 5% of NSCLC patients who have an ALK gene alteration. Approved treatments include  ceritinib (Zykadia), alectinib (Alecensa), brigatinib (Alunbrig), and lorlatinib (Lorbrena).

These ALK inhibitors are improvements from previous ones in their enhanced ability to cross the blood–brain barrier. This progress is critical because, in non-small cell lung cancer patients with ALK alterations, disease progression tends to occur in the brain. 

EGFR Inhibitors

EGFR inhibitors block the activity of a protein called epidermal growth factor receptor (EGFR). Altered forms of EGFR are found at high levels in some lung cancers, causing them to grow rapidly. Osimertinib (Tagrisso) is the most effective and most widely used EGFR inhibitor. It is also used for adjuvant therapy after surgery for resectable NSCLC. Other drugs that target EGFR that are approved for treating NSCLC include afatinib (Gilotrif), dacomitinib (Vizimpro), erlotinib (Tarceva), gefitinib (Iressa). For people with Exon 20 mutations, amivantamab (Rybrevant)  is an approved targeted therapy.

ROS1 Inhibitors

The ROS1 protein is involved in cell signaling and cell growth. A small percentage of people with NSCLC have rearranged forms of the ROS1 gene. Crizotinib (Xalkori) and entrectinib (Rozlytrek) are approved as treatments for patients with these alterations. In late 2023, the FDA approved repotrectinib (Augtyro) for advanced or metastatic NSCLC with ROS1 fusions as an initial treatment and as a second-line treatment in those who previously received a ROS1-targeted drug.

BRAF Inhibitors

The B-Raf protein is involved in sending signals in cells and cell growth. Certain changes in the B-Raf gene can increase the growth and spread of NSCLC cells.

The combination of the B-Raf-targeted drug dabrafenib (Tafinlar) and trametinib (Mekinist), which targets a protein called MEK, has been approved as treatment for patients with NSCLC that has a specific mutation in the BRAF gene.

Encorafenib (Braftovi) combined with binimetinib (Mektovi) is approved for patients with metastatic NSCLC with a BRAF V600E mutation.

Other Inhibitors

Some NSCLCs have mutations in the genes NRTK-1 and NRTK-2 that can be treated with the targeted therapy larotrectinib (Vitrakvi). Those with certain mutations in the MET gene can be treated with tepotinib (Tepmetko) or capmatinib (Tabrecta). And those with alterations in the RET gene are treated with selpercatinib (Retevmo) and pralsetinib (Gavreto). A 2023 clinical trial showed that treatment with selpercatinib led to longer progression-free survival compared with people who received chemotherapy with or without pembrolizumab. Inhibitors of other targets that drive some lung cancers are being tested in clinical trials.

Researchers have trained a computer program to read slides of tissue samples to diagnose two of the most common types of lung cancer with 97% accuracy. The program also learned to detect cancer-related genetic mutations in the samples just by analyzing the images of cancer tissue.

In a process known as machine learning, the computer program scanned images of tissue slices and developed the ability to differentiate normal lung tissue from the two most common forms of lung cancer, adenocarcinomas, which make up about 40% of lung cancers, and squamous cell carcinomas, which make up about 25% to 30% of lung cancers. Even experienced pathologists can struggle to distinguish these two types of lung cancer, which arise from different types of cells and require very different treatment regimens.

To train the computer program, researchers specializing in machine learning used a deep learning method originally developed and published by Google. The program uses artificial intelligence (AI) to teach itself to get better at a task—in this case, classifying lung cancer specimens—without being told exactly how.

The program was trained using more than 1,600 histopathology slides of lung specimens made publicly available by The Cancer Genome Atlas (TCGA). The study, led by researchers at New York University's Langone Medical Center and published September 17 in Nature Medicine, represents a large improvement in the accuracy of computational methods to diagnose lung cancer; the second most accurate computational method has an accuracy rate of 83%.

Images as Data and a Public Resource

TCGA made histopathology images of tumor specimens available as a quality control measure for researchers studying the genetic sequence data collected in the project. The images “were required to make sure that the quality and identity of the tissue were correct,” said Jean C. Zenklusen, Ph.D., the director of TCGA at NCI. As an incidental benefit, Dr. Zenklusen said, the images themselves now serve as a resource for analysis.

The images made available by TCGA are large and high resolution, so the researchers at NYU divided each image into thousands of tiles, or “patches,” in a grid for the computer program to analyze individually for visual cues that could be linked to the sample’s classification. “We had about 500 patients per subtype, but thousands of patches per image, so we had nearly one million patches in the end to train the model,” said Narges Razavian, Ph.D., a machine learning and AI researcher at NYU Langone, who helped lead the study.

The accuracy with which the program learned to distinguish adenocarcinoma from squamous cell carcinoma and normal lung cells was about equal to that of experienced pathologists, but the analysis can be done much faster; the program was able to reach a conclusion in a matter of seconds rather than the minutes a pathologist would need.

The program also correctly classified 45 of 54 images that at least one of three pathologists participating in the study misclassified, suggesting that AI could offer a useful second opinion, the researchers wrote.

The program was tested on an independent set of lung cancer specimens—both frozen and freshly collected—from NYU to verify that it worked on a completely separate collection of samples.

The samples from TCGA were almost entirely tumor tissue. In this validation set, however, the samples often included other components, such as blood clots and dead tissue, “making the classification task more challenging” for the program, the researchers reported. 

In response, they reworked the program to have it focus on the parts of the tissue samples that were largely tumor (as identified by a pathologist). With that change, the method’s accuracy averaged more than 90%, which they described as “very encouraging.”

AI’s Role in Treatment and Research

Because of the computer program’s speed and accuracy, the research team suggested the tool could be used during surgery, for example, to help verify that a biopsy is of sufficient quality to make a diagnosis or to inform a surgeon that another sample is needed.

In addition to showing that AI can be used to make a quick and accurate diagnosis, the research project showed that AI could be trained to predict the presence of six of the most common genetic mutations in lung cancer adenocarcinoma, with an accuracy ranging from 64% to 86%, depending on the gene.

“That is very exciting scientifically,” Dr. Razavian said.

Currently, the only way humans can detect genetic mutations is by DNA sequencing, which can take up to 2 weeks.

“Lung cancer is usually detected late in the progression of the disease, so waiting 2 weeks to start any treatment is bad for the patient,” Dr. Razavian noted.

Many medical teams will start treatment and then adjust the medication used based on genetic test results. “What we show is that, with this program, you could start a treatment that is more likely to be the right one immediately,” Dr. Razavian said.

The program is a “black box,” in that its decisions are the result of thousands of interconnected small steps, not easy to summarize. The researchers can’t visualize exactly what the program detects in an image to predict the presence of genetic mutations, but the program can serve as “a lens that shows patterns that are hard to notice with the eye,” Dr. Razavian said.

She and her colleagues are using the program to research how genetic mutations affect the structures of cells and tissues. To approach this problem, they are using automated methods that modify the images to figure out what visual elements most influence the program’s ability to perceive mutations.

“The strengths of the study,” said Paula Jacobs, Ph.D., the associate director of NCI’s Cancer Imaging Program, “are the careful selection of the clinical problem to be addressed,” how the program was trained, and the fact that the results were verified using an independent set of lung cancer specimens.

Michael Snyder, Ph.D., chair of genetics at Stanford University, sees AI as the future of diagnosis. “I think we need to shift to using machine learning rather than rely on pathologists alone to do all the work,” he said. “Algorithms won’t replace pathologists, but they will assist them in making classifications. They will reduce the errors that pathologists would otherwise make.”

The code developed for the project is available for other researchers to use for other diagnostic applications. The NYU team has already started applying the code to learn to diagnose kidney, breast, and other cancers.

In November 2023, the Food and Drug Administration (FDA) approved repotrectinib (Augtyro) for the treatment of some advanced lung cancers that have a genetic change called a ROS1 gene fusion.

Now, the complete results of the clinical trial that led to the approval of repotrectinib have been published. 
 
In the study, nearly 80% of the participants with non-small cell lung cancer (NSCLC) who had not previously received a ROS1-targeted drug had a response, meaning that their tumors shrank, researchers reported in the New England Journal of Medicine on January 11.

Nearly 40% of the participants with NSCLC who had previously been treated with another ROS1-targeted drug, such as crizotinib (Xalkori) or entrectinib (Rozlytrek), had a response.

FDA’s approval of repotrectinib for advanced or metastatic NSCLC with ROS1 fusions includes the drug’s use as an initial treatment and as a second-line treatment in those who previously received a ROS1-targeted drug. 
 
The trial, called TRIDENT-1, evaluated repotrectinib in people with advanced solid tumors, including 127 participants who had ROS1 fusion–positive lung cancers. 

For many of these individuals, the response to repotrectinib lasted for several years. 

“Repotrectinib can lead to long-term responses for patients with ROS1 fusion–positive lung cancers, including those who have and have not received prior targeted therapy,” said Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center, who led the TRIDENT-1 study. 

Treatment with repotrectinib also shrank tumors that had spread to the brain, a common location for lung metastases, the researchers reported.  

Repotrectinib can overcome some ROS1 mutations that cause drug resistance 

Some lung tumors develop genetic mutations in ROS1 that can cause crizotinib and entrectinib to stop working. Repotrectinib was designed to be effective against tumors with these resistance mutations, including one called G2032R.

In the TRIDENT-1 trial, 10 of 17 participants (59%) whose tumors had the G2032R mutation had a response to repotrectinib. The trial was funded by Bristol Myers Squibb, the drug’s maker. 

“Although repotrectinib can overcome resistant mutations that other ROS1 inhibitors cannot overcome, the drug does not seem to have more side effects than other ROS1-targeted drugs,” said Luis Raez, M.D., who directs the Thoracic Oncology Program at Memorial Cancer Institute in Florida and was involved in the study. 

An important next step, several experts said, will be to conduct studies that can help doctors determine how best to use the different ROS1-targeted drugs in individual patients.

Expanding treatment options for advanced lung cancers with ROS1 fusions

ROS1 fusions occur when part of the gene breaks off and attaches to another gene. In lung cancer cells with the ROS1 fusion, the ROS1 protein produced as a result of these fusions is overly active, leading to uncontrolled cell growth and tumors. ROS1 fusions are present in up to 2% of people diagnosed with NSCLC. 

The fusions are typically found in people who have little or no history of smoking, but they have also been detected in heavy smokers. 

Repotrectinib blocks the activity of the ROS1 fusion protein. Although crizotinib and entrectinib can shrink some lung tumors with ROS1 fusions, these drugs are not effective against tumors with certain other ROS1 mutations that make the protein overly active. The need for new treatments has led researchers to develop the next generation of ROS1-targeted therapies.

Repotrectinib, which patients take as a capsule, is among the first approved treatments to emerge from this work. In addition to ROS1, the drug targets other proteins that fuel cancer cell growth, including ALK and several forms of NTRK proteins.

Lasting tumor responses to repotrectinib

In the TRIDENT-1 trial, 56 of 71 participants (79%) who had not previously received a ROS1-targeted drug had a response lasting at least 18 months. The median time before the disease worsened, known as progression-free survival, was nearly 36 months.  

Among those who had previously received a ROS1-targeted drug, 21 of 56 participants (38%) had a response. The median progression-free survival for this group was 9 months.

A small number of people in both groups had complete responses to treatment, meaning their cancer disappeared entirely.

Repotrectinib also appeared to be effective against lung tumors that had spread to the brain. Of the participants with brain metastases, 8 of 9 participants (89%) who had not previously received a ROS1-targeted drug had their brain tumors shrink. Brain tumors shrank in 5 of 13 participants (38%) who had previously received a ROS1-targeted drug. 

For many of these patients, the treatment responses lasted at least 1 year. 

The most common treatment-related side effect of repotrectinib was dizziness. This effect could be managed by reducing the dose of the drug or temporarily interrupting the treatment schedule, the researchers wrote. 

Other common side effects included a bad taste in the mouth (dysgeusia) and an abnormal touch sensation, such as burning or prickling, that occurs without an outside stimulus (paresthesia). Three percent of participants stopped taking repotrectinib due to treatment-related side effects. 

Limitations of the TRIDENT-1 clinical trial

A limitation of the TRIDENT-1 trial was that repotrectinib was not directly compared with other ROS1-targeted drugs in a randomized phase 3 clinical trial, Dr. Raez said. In addition, the trial included a relatively small number of participants, largely because NSCLC with ROS1 fusions is uncommon, he added.

In the absence of trials that directly compare the available ROS1-targeted drugs in patients, Dr. Drilon said oncologists should consider factors such as the durability of responses and safety when selecting treatments.

“It appears as though repotrectinib has the longest progression-free survival of the three approved ROS1-targeted therapies,” he said. And for patients who have already received a ROS1 inhibitor, repotrectinib is the only approved option right now, he added.

A new type of targeted immunotherapy drug shrank tumors in about one in three people with small cell lung cancer (SCLC), the most aggressive form of lung cancer, according to results from a clinical trial. The findings are encouraging because little progress has been made in treating advanced SCLC, experts said.

Many people with SCLC respond to initial treatment with chemotherapy and immunotherapy. But the cancer usually progresses despite additional treatment, with most of these patients dying within weeks or months.

The early-stage clinical trial tested two different doses of an experimental drug called tarlatamab in people with SCLC whose cancer had progressed after at least two previous types of treatment. Many people in the study had already received at least three different treatments.

In the trial, tumors shrank in 40% of people given 10 mg of tarlatamab every 2 weeks and in about 32% of people who received a 100 mg dose.  

Furthermore, in more than half of all patients whose tumors shrank with tarlatamab, the treatment kept the cancer at bay for at least 6 months—and in many, it did so for 9 months or longer.

This last finding was especially noteworthy, said Anish Thomas, M.D., of NCI’s Center for Cancer Research, who studies SCLC but was not involved in the trial.

“This is probably one of the most promising treatments being tested in small cell lung cancer right now,” Dr. Thomas said. The new findings are “hopeful for patients and the people who treat them, especially since this is such an aggressive disease with very few advances in treatment since the 1980s,” he continued.

Results of the trial—known as DeLLphi-301 and funded by Amgen, the company that makes tarlatamab—were presented October 20 at the annual meeting of the European Society for Medical Oncology (ESMO) in Madrid and published the same day in The New England Journal of Medicine (NEJM).

The new findings “support the use of tarlatamab in these previously treated patients,” said the trial’s senior investigator, Luis Paz-Ares, M.D., Ph.D., of Hospital Universitario 12 de Octubre in Madrid, who presented the results at the ESMO meeting.

The findings are “encouraging,” agreed Pilar Garrido, M.D., Ph.D., of Hospital Universitario Ramón y Cajal in Madrid, who spoke about the trial at the ESMO meeting but was not involved in it. However, she noted that patients need to be hospitalized to manage potentially serious side effects when they first receive the drug, which poses logistical challenges to its use.

Dr. Garrido also noted the need for more data on the effectiveness of tarlatamab against SCLC that has spread to the brain and for a biomarker that can predict which patients will respond to the drug.

According to Dr. Paz-Ares, the manufacturer of tarlatamab has already launched a large clinical trial comparing tarlatamab with standard chemotherapy in people with SCLC that has come back after one initial treatment.

Tarlatamab harnesses T cells to destroy small cell lung cancer cells

Tarlatamab is a type of immunotherapy known as a bispecific T-cell engager, or BiTE. These two-armed drugs simultaneously latch onto tumor cells and immune cells called T cells. By bringing T cells and cancer cells close together, they help the T cell recognize and destroy the cancer cell.

The arm of tarlatamab that targets small cell lung cancer cells attaches to a protein called DLL3. This protein is normally located inside cells but is often present at high levels on the surface of SCLC cells, where it can be recognized by tarlatamab.

That makes DLL3 “a very attractive target in SCLC,” Dr. Garrido said.

The trial enrolled more than 200 people with advanced, or extensive-stage, SCLC that had progressed or was no longer responding to treatment. All of the participants had previously been treated with chemotherapy, and many had also been treated with an immune checkpoint inhibitor, a different type of immunotherapy drug. All participants had received at least two prior therapies, and one-third had received three or more.

The study team analyzed the response to tarlatamab in 100 participants who received 10 mg of tarlatamab by infusion every 2 weeks and another 88 who received 100 mg every 2 weeks. An additional 34 patients on the 10-mg dose were included in the analysis of side effects.

The 40% response rate (tumor shrinkage) seen in the 10-mg group “far exceeded” the 15% response rate that has historically been seen in people treated with standard therapies for SCLC that has relapsed, Dr. Paz-Ares and his colleagues wrote in NEJM.

Furthermore, 30% of those patients who responded to the drug had responses lasting at least 9 months. That finding is “exciting,” Dr. Thomas said, because the cancer usually grows so rapidly.

The median time that people in the 10-mg group lived after starting on tarlatamab was 14.3 months, compared with 6–12 months with current treatments. Researchers are still following the trial participants to learn more about tarlatamab’s side effects and its impact on how long people live.

Based on the initial results of DeLLphi-301, the lower (10 mg) dose of tarlatamab will be used in future clinical trials, Dr. Paz-Ares said.

Common and potentially serious side effects of tarlatamab

The side effects of tarlatamab were generally “manageable,” Dr. Paz-Ares said, and only about 3% of patients in the study stopped treatment entirely because of side effects. In addition, 13% of people in the 10-mg group and 29% in the 100-mg group had to temporarily pause treatment, have their dose reduced, or both, due to side effects.

The most common side effect of tarlatamab was cytokine release syndrome, a potentially life-threatening reaction in which inflammation spreads throughout the body. Other common side effects included decreased appetite, fever, and anemia.

About one-third of the patients experienced severe side effects, including serious cases of cytokine release syndrome. Severe side effects were more frequent in those receiving the higher dose of tarlatamab.

Most cases of cytokine release syndrome were “manageable and typically treated with supportive care,” such as intravenous fluids and drugs to control fever and inflammation, Dr. Paz-Ares said. However, one person in the 10-mg group died from respiratory failure resulting from treatment.

Another potentially serious side effect of tarlatamab is ICANS (immune effector cell−associated neurotoxicity syndrome), which includes a host of neurological effects such as severe confusion, attention problems, tremor, and muscle weakness. ICANS was more common in patients in the 100-mg treatment group and led one patient in each dose group to stop treatment entirely.

Both ICANS and cytokine release syndrome are commonly seen with immunotherapies that activate T cells to kill cancer cells, including other BiTEs and CAR T-cell therapy.

Challenges, concerns, and questions remain

Dr. Thomas noted that the trial was not designed to compare tarlatamab with standard therapy for SCLC. “But there is strong historical data on how quickly the disease progresses with standard therapy.”

Another issue, he said, is that current practice calls for treating all patients with extensive-stage SCLC with chemotherapy plus an immune checkpoint inhibitor at the time of diagnosis. However, about one in four people in the trial had not been treated with an immune checkpoint inhibitor. So it would be good to know how well tarlatamab works specifically for people whose cancer has come back despite previous immunotherapy, he explained.

Possible side effects are also a concern. There were few severe cases of cytokine release syndrome in the trial and most occurred after the first or second dose of tarlatamab. Still, the potential risk of side effects with early doses “is an important consideration,” Dr. Thomas said, because patients had to be hospitalized for a couple of days as a precaution when receiving each of the first two or three infusions of tarlatamab.

In addition, people had to be in generally good physical condition to participate in the trial, and the impact of potentially serious side effects could be greater in those who are sicker, he continued.

For all these reasons, Dr. Thomas said, it will be important to know “how we can best manage side effects such that we don’t need to admit patients to the hospital, and how we can anticipate, prevent, and treat side effects.”

He also pointed out that some patients died within 6 weeks after their treatment began, before the study team could assess if the deaths were due to worsening of the cancer. And “we need to better understand whether these early deaths were due to side effects,” he said.

Finally, Dr. Garrido said, another challenge is identifying biomarkers that can predict which patients are most likely to respond to tarlatamab. The research team looked at DLL3 on tumor cells as a potential biomarker, but whether a person responded to the drug did not appear to be linked to having DLL3 in their tumors, the study team reported.  

“Despite the many challenges,” Dr. Garrido said, the results “offer renewed hope to our patients.”

For several years, the targeted drug selpercatinib (Retevmo) has been a treatment option for some people with lung cancer or thyroid cancer whose tumors contain specific changes in a gene called RET.

But there has been limited research comparing selpercatinib with other standard treatments for tumors with RET changes. Two new clinical trials have now done just that. One trial included people with lung cancer, and the other included people with medullary thyroid cancer.

In both trials, treatment with selpercatinib prolonged the amount of time people lived before their cancers got worse, called progression-free survival, compared with other treatments.

Selpercatinib is approved for treating some lung, thyroid, and other solid tumors that have RET alterations, such as mutations in the gene itself and rearrangements that fuse parts of the gene with another gene.

These mutations and fusions can result in abnormal proteins that spur cell growth and cause tumors to form. Selpercatinib, which is a pill that patients take by mouth, can block the activity of abnormal RET proteins and fusion proteins involving parts of RET.

In the lung cancer trial, LIBRETTO-431, treatment with selpercatinib more than doubled the median progression-free survival in people with advanced non-small cell lung cancer (NSCLC) containing RET fusions, compared with that in people who received chemotherapy with or without pembrolizumab (Keytruda).

And in the medullary thyroid cancer trial, LIBRETTO-531, selpercatinib was superior to two other targeted treatments based on several measures, including progression-free survival, in people with advanced medullary thyroid cancer that had RET mutations.

Results from both trials were presented on October 21 at the European Society for Medical Oncology (ESMO) Congress in Madrid and published simultaneously in the New England Journal of Medicine (NEJM).

Because of the implications of RET alterations for treatment, the findings underscore the importance of testing the tumors of people with lung cancer and medullary thyroid cancer for RET alterations at the time of diagnosis, several researchers said.

Selpercatinib superior to chemo, with or without pembrolizumab, in lung cancer

Alterations involving RET are rare, occurring in less than 1% of most cancers. About 2% of people with NSCLC have tumors with RET fusions (RET fusion–positive NSCLC).

The lung cancer trial was intended to define the most effective first-line treatment for people with advanced RET fusion–positive NSCLC. The trial was sponsored by Eli Lilly, the maker of selpercatinib.

The study’s 261 participants were randomly assigned to receive initial treatment with selpercatinib or chemotherapy, which is an initial standard treatment option. Participants in the chemotherapy group could receive pembrolizumab if their physicians recommended it. The trial was designed so at least at least 80% of participants in the chemotherapy group would get pembrolizumab.

However, it was not required because previous studies have suggested that checkpoint inhibitors such as pembrolizumab “may have limited effectiveness” for patients with RET fusion–positive NSCLC, the researchers wrote in NEJM.

At a median follow-up of about 19 months, the median progression-free survival among participants who received selpercatinib was 24.8 months, compared with 11.2 months for those in the chemotherapy group.

Tumors shrank in 84% of patients in the selpercatinib group, compared with 65% of the patients in the chemotherapy group, the researchers reported.

Based on these results, selpercatinib should be considered as a standard initial treatment for advanced RET fusion–positive NSCLC, said Herbert H. Loong, MBBS, of the Chinese University of Hong Kong, who presented the lung cancer trial’s findings at the ESMO meeting.

During a discussion of the results at the meeting, Benjamin Besse, M.D., Ph.D., of Gustave Roussy in France said that among participants who received chemotherapy, the median progression-free survival was the same—11.2 months—whether or not they received pembrolizumab.

The result suggests that “immunotherapy does not add a lot in this population,” he said.

Selpercatinib may shrink tumors in the brain

Selpercatinib was designed to cross the blood–brain barrier and to reach tumors in the brain. Previous studies have suggested that the drug may be particularly effective against tumors that have spread to the brain, as NSCLCs tend to do.

The new trial provided evidence that selpercatinib can shrink tumors in the brain in people with NSCLC. Twenty-nine participants in the trial had measurable brain metastases. During the study, these metastases shrank in 82% of those who received selpercatinib, compared with 58% of those who received chemotherapy. 

The amount of time before tumors spread to the brain was longer in the selpercatinib group than in the chemotherapy group. These findings suggest that selpercatinib may prevent or delay the formation of new tumors in the brain, noted Alexander Drilon, M.D., of Memorial Sloan Kettering Cancer Center and a researcher on the study.

As in previous trials of the drug, the most common side effects of selpercatinib included hypertension, dry mouth, and diarrhea. Doctors were able to manage most of these side effects by adjusting the dose of selpercatinib, which allowed most participants to continue to receive the therapy.

Side effects of treatment led doctors to lower the dose for 51% of the participants in the selpercatinib group, versus 29% of those in the chemotherapy group. Treatment was stopped because of side effects in 10% and 2% of the two groups, respectively.

Results confirm effectiveness in medullary thyroid cancer

In the United States, medullary thyroid cancer accounts for about 2% of thyroid cancers. About 25% of people with medullary thyroid cancer have an inherited form of the disease.

RET alterations are present in nearly all hereditary medullary thyroid cancers and in up to half of sporadic forms of the disease—that is, cancers that are not the result of an inherited mutation.

Historically, advanced medullary thyroid cancer has been much more difficult to treat than other types of thyroid cancer. 

The LIBRETTO-531 trial included 291 participants with RET-mutant medullary thyroid cancer that could not be removed by surgery or had spread to other parts of the body.

Trial participants were randomly assigned to receive initial treatment with selpercatinib or one of two other treatments, cabozantinib (Cabometyx) or vandetanib (Caprelsa). These drugs, called multi-kinase inhibitors, block the activity of several cancer-related proteins, including abnormal RET proteins.

Cabozantinib and vandetanib are not highly selective RET inhibitors, and the drugs have side effects that can cause patients to discontinue therapy. These limitations led Julien Hadoux, M.D., Ph.D., of Gustave Roussy and his colleagues to test whether selpercatinib, which is designed to target RET proteins only, would be more effective than cabozantinib or vandetanib. The trial was also sponsored by Eli Lilly.

At a median follow-up of approximately a year, the median progression-free survival was 16.8 months in the cabozantinib/vandetanib group. Because the cancer had not yet gotten worse in many patients receiving selpercatinib, the researchers couldn't yet determine a median progression-free survival for the group.

Participants in the selpercatinib group were more likely to respond to the drug—that is, to have their tumors shrink—than participants in the comparison group. The treatment response rates were 69% and 39%, respectively.

The patient responses to selpercatinib were “more frequent, more profound, and more durable” than those seen in people treated with cabozantinib or vandetanib, Dr. Hadoux said at the ESMO meeting.

In the selpercatinib group, 23 patients (12%) had a complete response, meaning there was no longer any evidence of their cancers. In the control group, 4 patients (4%) had a complete response.

More precise targeting of RET leads to fewer side effects

As in the lung cancer trial, the most common side effects of selpercatinib in the thyroid cancer trial included high blood pressure, dry mouth, and diarrhea.

Treatment side effects led doctors to lower the dose for 39% of the patients in the selpercatinib group and 77% in the cabozantinib/vandetanib group. Treatment was stopped because of side effects in about 5% and 27% of the two groups, respectively.

The greater “selectivity” of selpercatinib in targeting RET likely explains why the drug has fewer side effects than cabozantinib and vandetanib, the research team wrote.

Although some oncologists are already using selpercatinib for their patients with medullary thyroid cancer, the trial results are “practice changing,” said Laura Locati, M.D., Ph.D., of the Istituto Nazionale dei Tumori in Milan, after the presentation of the results at the ESMO meeting.

“With selpercatinib we have, for the first time, a very active treatment in terms of response rate, and prolonged response, and very few side effects compared to the standard of care,” Dr. Locati added.

What’s next for targeting RET? 

In the United States, genetic testing of tumors for RET alterations is standard practice for people with medullary thyroid cancer, noted Jaydira del Rivero, M.D., of NCI’s Center for Cancer Research, who studies endocrine cancers.

Based on the new results, Dr. del Rivero continued, selpercatinib should be considered the standard first-line therapy in patients with RET-positive medullary thyroid cancer.

The results, Dr. del Rivero added, demonstrate the movement “toward personalized approaches for treating thyroid cancers.”

The landscape of potential treatments for RET-altered cancers continues to evolve. Researchers are studying pralsetinib (Gavreto), another highly selective RET inhibitor. In the United States, pralsetinib is approved for the treatment of NSCLC with RET fusions and for RET-altered medullary thyroid cancers. The oral drug has a similar safety profile as selpercatinib and has also shown the ability to treat brain metastases, according to a recent study.

Meanwhile, next-generation RET inhibitors are being developed. A goal of this research, say those working on these medicines, is to develop treatments for cancers that have stopped responding to other therapies, including first-generation RET inhibitors. 

Highly anticipated results from a large study of people with early-stage lung cancer are generating praise, and some controversy, among oncologists who specialize in treating people with this cancer. 

The clinical trial, called ADAURA, tested giving the drug osimertinib (Tagrisso) after surgery in people with early-stage non-small cell lung cancer (NSCLC). All trial participants’ tumors had specific mutations in a gene called EGFR. Osimertinib, which is taken daily as a pill, specifically targets and kills lung cancer cells with these genetic mutations. 

In the nearly 700-patient study, people who were randomly assigned to receive osimertinib after surgery to remove their tumor(s)—known as adjuvant therapy—lived substantially longer overall than people assigned to receive a placebo after surgery. At 5 years after starting adjuvant treatment, 88% of people treated with osimertinib were still alive, compared with 78% of those treated with a placebo.

The findings “herald a new era of targeted therapy in early-stage ,” said the trial’s lead investigator, Roy Herbst, M.D., of the Yale Cancer Center, who presented the data on June 4 at the 2023 annual meeting of the American Society of Clinical Oncology (ASCO). The results were published the same day in the New England Journal of Medicine.

Many other lung cancer experts agreed. In a commentary on the ADAURA results delivered at the ASCO meeting, Ben Solomon, M.B.B.S., Ph.D., of the Peter MacCallum Cancer Center in Australia, called the findings “groundbreaking.” 

But other oncologists who specialize in treating lung cancer or conducting cancer clinical trials were less enthusiastic. Their primary criticism focused on the treatments received by participants in the placebo group, or control arm, whose cancer came back: Only about 40% received osimertinib. 

In the United States and much of Europe, osimertinib is the standard therapy in people with early-stage lung cancer that relapses. 

So the extent to which adjuvant osimertinib increased how long participants in ADAURA lived is unclear “because so many patients didn’t get the standard care,” said Bishal Gyawali, M.D., Ph.D., an oncologist at Queen’s University in Ontario, Canada.

“This is a very good drug,” Dr. Gyawali continued. But in people with early-stage lung cancer whose tumors have EGFR mutations, he said, it’s still unclear from the trial’s results if it’s “appropriate for everyone to receive immediately after surgery versus receiving the same drug at the time of relapse.”

EGFR inhibitors: From advanced- to early-stage lung cancer

Drugs that target lung cancers with EGFR mutations have been among the most successful of the targeted cancer therapy era that began more than 2 decades ago.

Osimertinib is often referred to as a third-generation EGFR inhibitor, because it was designed to address some of the shortcomings of earlier EGFR inhibitors. Key among the properties of osimertinib is an improved ability to get into the brain and, thus, shrink tumors that have spread there from the lungs—a common occurrence in NSCLC.

Osimertinib is already the standard therapy for people with metastatic NSCLC whose tumors have EGFR mutations and in those initially diagnosed with early-stage disease but whose cancer comes back, explained Charu Aggarwal, M.D., who specializes in treating lung cancer at the University of Pennsylvania Abramson Cancer Center.

And even with the dramatic improvements in the treatment of metastatic lung cancer, once the cancer has spread, it’s often fatal. Less than half of people initially diagnosed with stage IIIA NSCLC, in fact, will still be alive 5 years later.

So the ADAURA trial—which was funded by AstraZeneca, osimertinib’s manufacturer—was launched in late 2014 to see if adding osimertinib as an adjuvant therapy for early-stage NSCLC with EGFR mutations might improve outcomes. 

Specifically, the ADAURA research team wanted to know if it could prevent, or at least substantially delay, the disease from returning, and increase how long people live overall.

Improved overall survival with osimertinib

The initial results from ADAURA, published in October 2020, offered signs of possible survival improvements with adjuvant osimertinib. This treatment, they showed, dramatically improved how long people lived without any evidence of their cancer returning.

Not long after, the Food and Drug Administration (FDA) approved osimertinib as an adjuvant therapy for people with early-stage NSCLC (stages IA to IIIB) with certain EGFR mutations. That led at least some US oncologists to start routinely using osimertinib as an adjuvant therapy for these patients, Dr. Aggarwal said—at least in hospitals and cancer centers where mutation testing in tumors is a standard practice. 

Although the reasons vary, she continued, failure to routinely perform testing for EGFR mutations “has been an issue.”

But some oncologists argued that, before any wholesale changes in patient care, it was important to see if the drug also helped people live longer. This is particularly important, they argued, because osimertinib can have persistent side effects and can cost nearly half a million dollars a year.

Both are important considerations, because in ADAURA, people assigned to receive osimertinib were to take it for 3 years.

Improved overall survival with adjuvant osimertinib

In total, 682 people participated in the study. Participants were allowed to receive chemotherapy after surgery (but before starting adjuvant osimertinib or placebo), and about 60% did. Treatment with adjuvant chemotherapy was most frequent in people with stage II and IIIA disease (71% and 80%, respectively).

The large improvement in survival, Dr. Solomon noted, was seen regardless of the extent of participants’ cancer. When the analysis was limited to people with stage II to IIIA tumors, for example, the 5-year survival rate was 85% in the osimertinib group and 73% in the placebo group. 

Osimertinib’s side effects in the trial were consistent with what is typically seen with this drug, with diarrhea and rash among the most common. In the osimertinib group, 13% of people stopped taking the drug entirely because of side effects, and another 27% stopped taking it for periods but then resumed treatment.

Dr. Solomon cautioned that 3 years is a long time to be on a therapy, and that side effects, even if they seem minor, shouldn’t be discounted. 

“It’s important for clinicians not to underestimate the impact of continued toxicities on patients,” he said. Such side effects can include diarrhea, dry skin and rash, frequent coughing, and fingernail and toenail infections, among others.

But was the ADAURA placebo group an adequate comparison?

With the trial’s details published, some oncologists began to point out what they viewed as problems with the treatments given to those in the control arm—specifically, the limited number who received osimertinib once their cancer relapsed.

On Twitter, H. Jack West, M.D., a lung cancer expert at City of Hope Comprehensive Cancer Center in Los Angeles, argued that “ADAURA is unfortunately a trial of 100% access to vs <50% access to .” Instead, he wrote, the control arm should have been osimertinib “for all at relapse, as needed.”

At the ASCO meeting, Dr. Herbst noted that in the first few years of the trial, osimertinib was not yet approved for treating metastatic NSCLC in the United States and some other countries. So early on, at least, the drug wasn’t available to patients in the control arm whose cancer returned, he said. 

Later, after the initial trial results showed the improvement in disease-free survival, control arm participants could be offered the drug if their cancer relapsed after surgery.

Even with that change, however, many patients in the control arm whose cancer relapsed ended up getting earlier-generation EGFR inhibitors. And 15% received no additional treatment at all.

Importance of testing for EGFR mutations

Despite the concerns expressed about the control arm, there seems to be little disagreement that oncologists should discuss adjuvant osimertinib therapy with their patients with early-stage NSCLC that has EGFR mutations.

Dr. West wrote that he believed the overall survival improvement with adjuvant osimertinib “would hold up even if issues around conduct were not present.”

Dr. Gyawali agreed with Dr. West, while also highlighting a larger concern. “That does not mean we should not criticize the trial’s flaws,” he said. Voicing legitimate criticisms is important, he continued, so similar problems “don’t happen in future trials.”

For her part, Dr. Aggarwal said there was now little doubt about what should be happening in everyday clinical practice. “This confirms our practice to test for EGFR mutations and recommend adjuvant targeted therapy with osimertinib” for those whose tumors have the genetic changes, she said. 

Osimertinib isn’t an option, however, if patients aren’t tested for EGFR mutations. And as another study presented at the ASCO meeting showed, although testing rates appear to be increasing, they are far from 100%.

Ensuring that all patients with early-stage NSCLC are tested for EGFR mutations is essential, Dr. Herbst said. “The only way we’re going to find these mutations is if we look for them.”

Other studies are ongoing to help better guide the treatment of early-stage lung cancer and how best to use osimertinib, he explained. 

One clinical trial, called NeoADAURA, for example, is looking at the impact on patient outcomes of using osimertinib before surgery. And some researchers have already shown the potential of analyzing bits of tumor DNA floating in the blood to determine the need for adjuvant therapy or to monitor if the cancer has come back.

“We need to be able to personalize therapy,” Dr. Aggarwal said. These and other studies are pushing in that direction, she added. “We don’t have the right tools yet. But I think in the near future we’ll get there.”

When lung cancer is found early, before it has spread beyond the lungs, people usually have surgery to remove the tumor. For more than 25 years, the standard of surgical care for such patients—even those with very small tumors—has been to remove the entire large section, or lobe, of the lung that contains the tumor. This is done to reduce the chances of the cancer coming back.

But some lung surgeons have suggested that certain patients may do just as well or even better with an operation to remove only part of the affected lobe.

Now, results of a large international clinical trial show that, for certain people with early-stage non-small cell lung cancer (NSCLC), surgery to remove a piece of the affected lobe is as effective as surgery to remove the whole lobe.

In the trial, people with early-stage NSCLC who had the more limited surgery lived as long without their cancer coming back as those who had an entire lobe of the lung removed. In addition, the portion of people still living after 5 years was about 80% in both groups.

Results of the new study were reported February 9 in the New England Journal of Medicine.

The new findings signal “a tremendous change in how we approach this type of lung cancer,” said Nasser Altorki, M.D., chief of thoracic surgery at Weill Cornell Medicine and New York-Presbyterian Hospital, who led the trial.

“This groundbreaking study confirms the results of a similar large study from Japan” reported last year, said David Tom Cooke, M.D., chief of general thoracic surgery at UC Davis Health, who enrolled patients in the international study and performed surgeries on some participants.

Together, the two trials show that carefully selected patients “can benefit from having less of their lung tissue removed to give them the same chance of a cure,” Dr. Cooke said. And removing less lung tissue “might mean better lung function long term.”

Standards for lung cancer surgery have changed over time

Each lung is made up of large sections called lobes, with three lobes in the right lung and two in the left. Each lobe is further divided into several anatomical units called segments.

Surgery for lung cancer originally involved removing an entire lung. Removing a whole lobe is called a lobectomy. In sublobar surgery, sometimes called lung-sparing surgery, surgeons may remove an entire segment of a lobe, which is akin to removing a segment of an orange. Or they may remove only a wedge-shaped piece of the lung, which is like taking a bite out of the orange, Dr. Cooke explained.

In 1995, results from a key clinical trial showed that, for people with early-stage NSCLC, removing a lobe was better than removing part of a lobe. Trial participants who had only part of the affected lobe removed were three times more likely than those who had a lobectomy have their cancer come back (recur).

“Thereafter, lobectomy was the standard of surgical care for this group of patients,” explained thoracic surgeon Valerie Rusch, M.D., of Memorial Sloan Kettering Cancer Center, in an editorial accompanying the new study results. Lung-sparing surgery, Dr. Rusch noted, was used only for patients with limited lung function.

However, in recent decades, advances in imaging technology and new staging methods have enabled the detection and diagnosis of smaller, earlier-stage lung cancers, Dr. Altorki said. So, his team and others wanted to revisit the question of whether lung-sparing surgery may be a good option for some patients. 

Surgeons had a choice of lung-sparing surgery type

For the trial—which was conducted by the NCI-supported Alliance for Clinical Trials in Oncology—Dr. Altorki and his colleagues enrolled 697 people with early-stage NSCLC from June 2007 to March 2017.

To participate in the trial, people had to meet stringent criteria. They had to have a single lung tumor that was 2 cm or less in size (about the diameter of a US penny), was in the outer third of the lung, and had not spread to nearby lymph nodes or elsewhere in the body. Participants also could not have been previously treated with chemotherapy or radiation therapy for the cancer.

Half of the participants were randomly assigned to have the entire lobe containing the tumor removed, and half were assigned to have lung-sparing surgery. For patients receiving lung-sparing surgery, each surgeon could decide whether to remove a segment of the lobe or only a wedge-shaped piece.

All participants were followed for at least 5 years, and the median follow-up time was 7 years. After 5 years, 63.6% of patients who underwent lung-sparing surgery and 64.1% who underwent lobectomy had not had their cancer come back. The 5-year overall survival in the two groups was 80.3% and 78.9%, respectively.

Similar but not identical studies

In the clinical trial from Japan, 5-year overall survival in both the lung-sparing surgery and lobectomy groups was more than 90%. The higher overall survival seen in that trial may be due to subtle differences between the two studies, such as the specific types of NSCLC that patients had, Dr. Rusch wrote.

Also noteworthy, in the Japanese trial all lung-sparing surgeries were done the same way, by removing a whole segment of the lung. Some surgeons think that surgery to take out a segment of the lobe, known as segmentectomy, “is a better operation” than removing a wedge-shaped piece, Dr. Cooke said, because segmentectomy also removes the associated lymph nodes in that portion of lung. 

However, at least for patients with limited lung function, wedge surgery “is the most frequently practiced method of sublobar surgery in North America and Europe,” Dr. Altorki and his colleagues wrote. In their trial, which included sites in the United States, Canada, and Australia, about 60% of patients assigned to lung-sparing surgery underwent wedge surgery, making the trial “more representative of a ‘real-world’ setting,” they wrote.

One possible concern about the trial, Dr. Cooke said, is that it did not compare the two types of lung-sparing surgery directly. However, Dr. Altorki said, his team will soon have data to address this question.

Benefits of having less lung tissue removed

“Now that lung cancer screening for people at high risk is generally accepted, and as more people get screened, we expect that there will be more people who have these types of very early–stage tumors and who would benefit from sublobar surgery,” Dr. Altorki said.

“Although all these operations are now safe, lung-sparing surgery is associated with an even lower risk , than lobectomy,” Dr. Rusch wrote.

Perhaps most important, removing less lung tissue is believed to preserve lung function. However, neither trial found clinically meaningful differences in lung function between people who had a lobectomy and those who had lung-sparing surgery.

That could be because the studies assessed lung function using instruments that measure the amount of air entering and leaving a person’s lungs, Dr. Cooke said. Neither trial included other, more sensitive measures of lung function or used standard tests to assess people’s aerobic fitness. 

In addition, he noted, investigators did not ask patients to report how they felt after undergoing the two types of lung surgery.

Removing only a segment or a wedge offers another advantage for patients, Dr. Altorki said. People who are cured of their first non-small cell lung cancer are often at high risk of developing a second primary non-small cell lung cancer. And if a second lung cancer is found, people who initially had less lung tissue removed have more treatment options than those who had an entire lobe removed.

The era of precision lung cancer surgery

Despite these benefits, Dr. Altorki stressed, lung-sparing surgery won’t be the best option for everyone. “We need to do whatever is necessary to get a cure, or to get rid of the cancer and reduce the chance of recurrence as much as possible,” he said.

“When appropriate, lobectomy should still be performed,” Dr. Rusch wrote. “The era of ‘precision’ surgery for non-small cell lung cancer has arrived.”

Dr. Cooke compared the changing views on surgery for lung cancer to the evolution of surgical approaches for treating breast cancer. Over the years, breast surgeons have moved from doing radical mastectomies to lumpectomy or other breast-conserving surgery for some people with early-stage breast cancer.

When it comes to treating lung cancer, Dr. Cooke said, “We can’t stop here. The question now is, where does sublobar surgery fit in when we talk about precision medicine” for lung cancer? That could include treating people with immunotherapy or drugs that target specific genetic changes in a tumor before or after surgery, he said.

“This is an exciting time in the surgical care of patients with lung cancer, and it will be exciting to see where we go next,” Dr. Cooke added.