PARP Inhibitors May Bring New Hope to Patients With Small Cell Lung Cancer

PARP inhibitors are approved by the Food and Drug Administration for the treatment of certain breast and ovarian cancers. But could they one day be given the green light to help patients with the deadliest form of lung cancer? Early study findings published in the Journal of Clinical Oncology show promising results.

Investigators at The University of Texas MD Anderson Cancer Center in Houston discovered that adding the PARP inhibitor veliparib to a standard chemotherapy regimen improved overall responses rates (ORR) in patients with relapsed small cell lung cancer (SCLC).

“Small cell lung cancer is one of the most difficult to treat cancers once it has relapsed because it is so drug resistant,” Lauren Averett Byers, M.D., associate professor of Thoracic/Head and Neck Medical Oncology, told CURE in an interview. “There are currently no approved targeted drugs for small cell lung cancer and no established biomarkers to guide treatment selection for patients, even though research from several groups has now shown that there are different subsets of small cell lung cancer that, in the lab, respond differently to specific targeted therapies.”

The phase 2 trial, which was supported by funding from the National Institutes of Health (NIH)/NCI and The LUNGevity Foundation, included 104 patients with relapsed SCLC, including some with advanced disease with brain metastasis, from seven cancer centers in the United States. Many patients had failed prior standard chemotherapy.

In the trial, patients randomly received either veliparib or placebo twice daily with the chemotherapy agent Temodar (temozolomide), which are both oral medications. This occurred between 2012 and 2015.

Although progression-free survival (PFS) was the primary endpoint, the investigators determined there was no statistically significant difference between both groups. PFS was 36 percent in the Temodar/veliparib group compared with 27 percent in the Temodar/placebo group. In addition, overall survival (OS) was similar between the two groups at 8.2 months and seven months, respectively.

However, investigators saw a significant difference in ORR, which was almost three times higher in the Temodar/veliparib group compared with the Temodar/placebo group (39 percent versus 14 percent, respectively).

“To find that the addition of the targeted PARP inhibitor therapy enhanced response rates, and to demonstrate a novel, easy to perform biomarker could potentially help us identify those patients who get benefit from adding veliparib to chemotherapy, was incredibly exciting,” Byers said.

Researchers also determined that a group of patients whose tumors expressed the protein SLFN11 — about half of patients with SCLC have this at the time their cancer is diagnosed — experienced a PFS (5.7 versus 3.6 months) and OS (12.2 versus 7.5 months) benefit.

“SLFN11’s job is to make sure that cells with lots of DNA damage don’t keep trying to replicate themselves and, rather, undergo cell death, which is why we think this makes sense as a biomarker for PARP inhibitor therapy, not just for lung cancer but potentially for other cancers where PARP inhibitors are used as well,” Byers said.

“If these results are validated in other studies, it could become the first predictive biomarker for SCLC and allow us to apply a more personalized approach to treating SCLC,” she added.

Although some toxicities were experienced, such as blood count deficiencies, treatment generally was well tolerated, Byers said.

“The main side effect was that we saw on patient’s blood work that they often had lower blood counts, especially platelets and white blood cells, which is a known side effect of these two drugs,” she said. “During the trial, we ended up decreasing the starting dose of the chemotherapy (Temodar) which helped address the low blood counts.”

Lung cancer is the leading cause of cancer death in the United States for men and women. In 2018, more than 240,000 adults will either receive a diagnosis of SCLC or non-small cell lung cancer — the more common type of the disease.

To examine this further, Byers is testing veliparib at a higher dose in combination with Temodar in the frontline setting. Through an NIH grant Byers will also be able to study whether PARP inhibitors, combined with immunotherapies, improve responses in SCLC.

“(This trial) shows the potential for translational research,” Byers said. “I hope in the next few years PARP inhibitors will become a treatment we can offer our patients routinely.”