Targeting Innovation in Small Cell Lung Cancer

After consulting multiple doctors about her ongoing cough and congestion, LeeAnn Devore asked one of her physicians if she might have lung cancer.

“He said the symptoms weren’t right,” says Devore, 66, of Magnolia, Texas. Three X-rays in five months confirmed that she had pneumonia in her right lung, yet she wasn’t responding to traditional treatments. Finally, in November 2016, one doctor decided to do a biopsy of her lung tissue, and the results were positive for small cell lung cancer (SCLC). The 4-centimeter mass had been hidden in X-rays by the pneumonia.

“I was devastated,” says Devore, who had retired two years earlier. “The diagnosis scared me because lung cancer grows so quickly, and my mother died of lung cancer.”

The standard first-line treatment for patients with SCLC is chemotherapy, which is usually effective for a few months, and then the cancer recurs. But Devore’s oncologist at The University of Texas MD Anderson Cancer Center in Houston asked if she was interested in joining a clinical trial that could boost her odds of survival by adding veliparib, a PARP inhibitor, to her chemotherapy regimen. Veliparib is a targeted therapy: It blocks the PARP proteins in cancer cells that are responsible for repairing damaged DNA.

“Breaks in DNA are common in cancers that are trying to divide rapidly, and chemotherapy causes additional breaks in the cancer DNA,” says Lauren Averett Byers, M.D., an associate professor of thoracic head and neck medical oncology at MD Anderson. “If you add a PARP inhibitor that prevents the cancer cells from repairing damaged DNA, this can increase the likelihood that those cells will die.”

It turns out that many cases of SCLC already have abnormalities in DNA repair ability, rendering them especially sensitive to PARP inhibitors.

Devore’s response was phenomenal. After six rounds of chemotherapy plus veliparib, she stopped the chemotherapy because the cancer shrank so significantly. The disease was in remission for nearly a year. Although Devore discontinued the PARP inhibitor when the cancer spread to bones in her back and a membrane surrounding her brain, radiation and chemotherapy treatments have further extended her life.

Patients such as Devore are benefiting from a proliferation of new research in the field of SCLC, a disease that accounts for 10 to 15 percent of lung cancer diagnoses and has a median survival rate of less than one year. In August — after two decades with no new drug approvals for this type of lung cancer — the Food and Drug Administration (FDA) approved Opdivo (nivolumab), an immunotherapy, to treat patients with SCLC that has progressed after at least two types of therapy. Several other immunotherapies have also shown promising results in clinical trials, as has lurbinectedin, a synthetic version of a marine-based compound.

EXTENDING LIFE WITH IMMUNOTHERAPY

“It’s really exciting to see some new options coming onto the scene,” says Anna Farago, M.D., Ph.D., a lung cancer specialist at Massachusetts General Hospital and an instructor at Harvard Medical School, both in Boston. “The bottom line is that the overall survival of patients with small cell lung cancer has not significantly improved for the past 30 years. Now the hope is that with these newer approaches, we will see substantial improvements in how long and how well patients are living.”

Patients often experience their first symptoms, such as cough, shortness of breath, chest discomfort, weight loss and infections like bronchitis, after the disease has spread outside the lungs, known as extensive stage SCLC. Smoking is by far the leading risk factor of the disease, followed by radon and asbestos exposure.

Unlike non-small cell lung cancer, which accounts for 80 to 85 percent of lung cancers, SCLC can rarely be treated by surgery because the disease has often spread to areas such as the other lung or other parts of the body at the time of diagnosis, says Neal Ready, M.D., Ph.D., a professor at Duke University School of Medicine in Durham, North Carolina. Although patients respond well to initial chemotherapy treatment, the benefit is typically short-lived in extensive stage SCLC because the cancer quickly becomes resistant to the drugs.

If SCLC is caught before it has metastasized — known as limited stage disease — up to 25 percent of patients can be cured with a combination of chemotherapy and radiation, says Charles Rudin, M.D., Ph.D., chief of the thoracic oncology service at Memorial Sloan Kettering Cancer Center in New York City.

With the emergence of targeted therapies, researchers are discovering new strategies to tackle the disease by stimulating the immune system to recognize and attack cancer cells. Opdivo, for example, blocks the PD-1 protein, which prevents the immune system’s T cells from attacking cancer cells. The FDA’s approval of the drug was based on a study that compared patients who received Opdivo alone with others who received a combination of Opdivo and another immunotherapy, Yervoy (ipilimumab), which blocks the activity of a protein known as CTLA-4.

The results showed that 11 percent of the participants who took Opdivo alone experienced marked tumor shrinkage that lasted for more than one year; so did approximately 19 percent of those who took the combination. The participants were also tested for a biomarker called PD-L1 to determine if this protein was associated with a higher response to the drug, but no link was found. “To be able to give patients a drug that is well tolerated and less toxic than chemotherapy is a significant breakthrough,” Ready says. “Oncologists are almost always unhappy about using the currently indicated second-line chemotherapy because it causes a lot of nausea and fatigue, and it may not have much benefit, so these new treatments are meeting a major area of need.”

Although his patients usually experience fewer side effects from immunotherapies than chemotherapies, Ready says, stimulating the immune system can lead to rashes, diarrhea, joint pain, fatigue and inflammation in the adrenal glands or thyroid and, in rare cases, the lungs or bowels.

SALERNO began to build a wood plank wall in his office before his small cell lung cancer diagnosis. He stopped when he got sick and thought he wouldn't finish. But the new treatment he received has enabled him to finish the project. - PHOTO BY JOLIE RODRIGUEZ

SALERNO began to build a wood plank wall in his office before his small cell lung cancer diagnosis. He stopped when he got sick and thought he wouldn't finish. But the new treatment he received has enabled him to finish the project. - PHOTO BY JOLIE RODRIGUEZ

Robert Salerno, who received a diagnosis of SCLC in September 2017, was grateful when his oncologist recommended that he try Opdivo after his cancer recurred following six rounds of chemotherapy. During treatment, Salerno had been hospitalized three times due to the possibility of infections. “My white blood cells, platelets and red blood cells sank to an all-time low when I was on chemotherapy,” says Salerno, 74. “I needed to be in the hospital to bring my numbers back to safe levels.”

THE SEARCH FOR BIOMARKERS

He started receiving a combination of Opdivo and Yervoy in July 2018 and has experienced just mild side effects, such as fatigue and shortness of breath. A CT scan in September revealed that his tumors had shrunk by over 25 percent. “When I was first diagnosed, I was hoping to live at least six months,” says Salerno, who lives in Castle Rock, Colorado. “But it’s been more than a year now, and I’ve had the chance to go on vacation in Florida and continue with house projects. I hope this new therapy gives me more time.”

Clinical trials are showing great promise for treatment of the disease. In September, researchers on the Impower133 trial reported a survival benefit from Tecentriq (atezolizumab) in patients with extensive stage SCLC in the first-line setting — a benefit seen for the first time in 20-plus years.

The drug added two months to patients’ lives when given along with standard of care chemotherapy, which is a combination of carboplatin and etoposide, compared with those who received chemotherapy plus placebo. Similarly, patients in the Tecentriq group also lived longer without disease progression than the placebo group (5.2 months versus 4.3 months, respectively).

Keytruda (pembrolizumab) is another promising immunotherapy, and results of a recent phase 2 clinical trial showed the drug to be especially effective in patients with the PD-L1 biomarker. Their overall response rate was 35.7 percent, compared with 6 percent among those without the biomarker.

Finding biomarkers to identify which patients will benefit from different treatments has been difficult in SCLC, but a recent study conducted by Byers suggests that there may be a marker to determine who is more likely to respond to PARP inhibitors such as veliparib. In the retrospective study, Byers’ team found that patients who had high levels of the SLFN11 gene benefited most. “When a cell has DNA damage, the SLFN11 gene forces it to die rather than continue living,” Byers says. “Half of all small cell tumors have high levels of this biomarker, and the overall survival of patients in this category who took a PARP inhibitor was five months longer than (for) those who had lower levels of the gene.”

IN THE PIPELINE

Researchers are also exploring whether measuring tumor mutational burden (TMB) might be another way to predict who will respond to immune checkpoint inhibitors. “Now we have methods of sequencing tumor DNA to identify the number of mutated genes, and people with higher TMB may have a higher response to combinations like Opdivo and Yervoy,” Ready says.

If lurbinectedin continues to produce positive results, patients may have a second-line treatment option in addition to PARP inhibitors and immunotherapies. The drug inhibits the activated transcription process, making it difficult for the cancer to produce proteins and other factors involved in tumor growth.

When researchers studying lurbinectedin recently presented results at the American Society of Clinical Oncology Annual Meeting, the phase 2 clinical trial findings impressed Suresh Ramalingam, M.D., deputy director of the Winship Cancer Institute of Emory University in Atlanta, Georgia. “What caught my attention is that the researchers treated patients who had progressed on other therapies, and after they received lurbinectedin, their median survival was a year,” he says. “This is remarkable, given that the benefit of standard chemotherapy lasts only for a few months.” The phase 3 clinical trial for the drug has been completed, and the results will be released within the next year. “Overall, the side effect profile seems comparable to other treatments in this setting,” he says.

A monoclonal antibody drug, Rova-T (rovalpituzumab tesirine), which focuses on the protein DLL3 in cancer cells, is also being studied. “Scientists have created a protein that recognizes the DLL3 and delivers a potent chemotherapy to the cancer cell,” Ready says.

RADIATION ADVANTAGES

Findings showed that the drug produced a response rate of 14.3 percent among patients with SCLC that expressed DLL3 and who had received at least two prior lines of chemotherapy. Several clinical trials are comparing Rova-T with standard chemotherapy options in SCLC.

Pharmacological options are vital in the field of SCLC, but radiation also plays an important role. For people with limited stage SCLC who have had a good response to initial chemotherapy and lung radiation treatment, prophylactic (preventive) radiation to the brain may be offered because there is a high risk that the cancer will spread to the brain. “The brain can be a sanctuary site for small cell lung cancer because the chemotherapy doesn’t penetrate as well to the brain as other tissues,” Rudin says. “A lowdose of radiation can reduce the risk of recurrence and increase survival.”

For people with extensive stage disease, the benefits of prophylactic radiation are less clear, he says. In one Japanese study, a group of these patients experienced no survival benefits from prophylactic radiation. “Radiation can have adverse side effects like fatigue and short-term memory loss,” Rudin adds.

DOUG CLARKE, who is a firefighter with the Rocky Hill Fire Department in Connecticut, hopes his clinical trial participation will help save others. - PHOTO BY SARAH CRUZ

DOUG CLARKE, who is a firefighter with the Rocky Hill Fire Department in Connecticut, hopes his clinical trial participation will help save others. - PHOTO BY SARAH CRUZ

Doug Clarke underwent prophylactic cranial irradiation after finishing chemotherapy and radiation treatment for SCLC in his right lung and nearby lymph nodes. The 54-year-old was surprised by the diagnosis, which he received in July 2016, because he had never smoked and was in the best shape of his life. Clarke, who lives in Rocky Hill, Connecticut, had recently joined a team of volunteer firefighters to climb 700 flights of stairs in the American Lung Association’s annual Fight for Air Climb.

Nine months after he started treatment, the cancer had spread to his adrenal gland, multiple lymph nodes and skin. Clarke started a combination of Opdivo and Yervoy, and the immunotherapies were effective for nearly one year. When the cancer started growing again, Clarke joined a clinical trial for another investigational immunotherapy drug that blocks the protein Tim-3.

For Clarke, the opportunity to participate in clinical trials brings hope that he can participate in next year’s Fight for Air Climb, just as he has the last two years as a survivor. “I’m going to continue using my cancer to speak out, raise money and move closer to a cure,” he says. “I may not be able to find a cure for myself, but the results from these clinical trials might help someone else down the line.”