PARP inhibitor shows benefit for small cell lung cancer patients
In a randomized, Phase II trial led by researchers at MD Anderson, adding the PARP inhibitor veliparib to a standard chemotherapy agent improved overall response rates (ORR) in patients with small cell lung cancer (SCLC). Researchers also identified a select group of patients — those whose tumors expressed SLFN11 — who also saw a progression-free survival (PFS) and overall survival (OS) benefit, suggesting a promising biomarker for the PARP-inhibitor sensitivity in SCLC.
According to the American Cancer Society, more than 234,000 people will be diagnosed with lung cancer and 154,050 will die from the disease in 2018, making it the leading cause of cancer death. SCLC primarily is associated with smoking and accounts for about 10 to 15 percent of all lung cancers. While recent advances in immunotherapy and targeted agents have begun to offer hope for those with non-small cell lung cancer (NSCLC), patients with SCLC have not experienced the same degree of benefit.
“Currently, the survival for most small cell lung cancer patients is less than a year — it’s the sixth leading cause of cancer death in the U.S., independent of non-small cell lung cancer,” says Byers, the study’s corresponding author. “We currently have no approved targeted therapies, no biomarkers. Patients desperately need new treatment options. However, I think we are on the cusp of changing the outlook for our patients.”
PARP as a therapeutic target in SCLC was discovered by Byers during her fellowship at MD Anderson while working in the lab of John Heymach, M.D., Ph.D., chair of Thoracic/Head and Neck Medical Oncology, who also is an author on this study. In 2012, Byers and Heymach published a milestone paper reporting the target, which generated great clinical interest. This clinical trial is the first randomized study published as a result of that first study.
PARP inhibitors block a DNA repair pathway; the class of inhibitors currently is approved for the treatment of BRCA-mutated metastatic breast and ovarian cancers.
“As important as discovering PARP’s target, our study has found a biomarker determining which small cell lung cancer patients will benefit from the therapy,” Byers says. “Currently, there are no biomarkers for the management of this disease. To be able to select patients for the appropriate treatment would significantly change the care we are able to offer.”
For the Phase II study, Byers and her colleagues enrolled 104 patients with relapsed SCLC from seven centers across the country. Between 2012 and 2015, patients were randomized to receive either veliparib or placebo twice daily, with a standard chemotherapy regimen temozolomide (TMZ) — all oral agents.
Byers noted that many trial participants had advanced disease with brain metastasis and/or had failed standard chemotherapy.
At four months, researchers found that, in an unselected population, the study did not reach a statistically significant difference in progression-free survival between the TMZ/veliparib cohort (36 percent) and TMZ/placebo cohort (27 percent). In the two groups, the median overall survival also was similar at 8.2 months and 7 months, respectively.
However, the overall response rate, which was defined as the percentage of patients with tumor shrinkage, was almost three times higher in the TMZ/veliparib cohort compared to the TMZ/placebo cohort — 39 percent versus 14 percent, a statistically significant difference.
As part of this trial, researchers also investigated candidate biomarkers that might predict response to PARP inhibitors in SCLC. These included expression of PARP1 and the protein called SLFN11, which previously had been shown by Byers and other groups to confer sensitivity to PARP inhibitors in the laboratory.
In those patients whose tumors expressed the elevated levels of SLFN11, treatment with TMZ/veliparib resulted in significantly prolonged progression-free survival ( 5.7 months versus 3.6 months), and overall survival (12.2 months versus 7.5 months). This is the first study to investigate SLFN11 as a predictive biomarker in the clinical setting.
“My hope is that the PARP inhibitors one day will serve as the first targeted therapy to benefit small cell lung cancer patients,” Byers says. “Now, with the discovery of the biomarker, we have a way to determine which patients potentially could garner the most benefit.”