No Survival Bump With PARP Inhibitor in Squamous NSCLC

Adding a PARP inhibitor to platinum-based chemotherapy failed to improve overall survival (OS) in smokers with squamous non-small cell lung cancer (NSCLC), but a lung cancer-specific gene array showed promise for identifying patients who might benefit, a randomized trial showed.

Median OS in current smokers was 11.9 months with veliparib and 11.1 months with chemotherapy alone as initial treatment for advanced disease. In the overall study population, the veliparib arm had a median OS of 12.2 months versus 11.2 months in the chemotherapy group, also not significant. Median progression-free survival (PFS) was 5.6 months in both groups, according to Suresh S. Ramalingam, MD, of Emory University and Winthrop Cancer Institute in Atlanta, and colleagues.

Patients who had a positive LP52 gene expression histology classifier had numerically higher OS with veliparib (14.0 vs 9.6 months), they reported in the Journal of Clinical Oncology.

Unfortunately, the results may have little applicability to clinical practice, as treatment has evolved toward immunotherapy, often in combination with chemotherapy, as first-line treatment, Ramalingam stated. However, investigation of PARP inhibitors in lung cancer will continue.

“PARP inhibition is an effective strategy in the treatment of cancer,” he told MedPage Today. “We know that PARP inhibitors have anticancer effects, and we know that they work in specific subsets of patients, such as those with underlying DNA damage repair system deficiencies. Even though our trial failed to show overall benefit, it still gives the same message that when you select the patient population right, they may benefit.”

“We also know that the field is moving fast in a different direction, toward incorporation of immunotherapy, so to me, the combination of a PARP inhibitor with immunotherapies in specific patient populations will be the key question going forward,” he added.

The rationale for the trial came from recognition that squamous NSCLC has a complex genetic makeup, including evidence of DNA damage, which PARP inhibitors target. Smoking adds to the complexity, inducing additional DNA damage.

Squamous NSCLC has relatively few driver mutations, making targeted therapies ineffective in most cases, the authors noted. Chemotherapy plus immunotherapy represents a new standard option, but a substantial proportion of patients do not benefit from the treatment. PARP inhibitors might offer one means to address that unmet need.

Veliparib has been shown to enhance the activity of platinum-based chemotherapy in solid tumors, the authors continued. In a phase II trial of veliparib or placebo plus platinum-based chemotherapy for advanced NSCLC, patients with squamous histology had the best outcomes. The data provided support for a randomized, placebo-controlled phase III trial in 970 patients with previously untreated advanced squamous NSCLC.

Investigators hypothesized that patients with squamous NSCLC and adenocarcinoma molecular characteristics would derive less benefit from veliparib. To test the hypothesis, they developed a binary classifier based on the gene content of a 52-gene lung subtype panel (LP52).

The primary endpoint was OS in current smokers, who accounted for 57% of the total study population. The key secondary endpoint was OS in the overall population. PFS and overall response rate (ORR) in current smokers and the overall population also were secondary endpoints.

With a median follow-up of about 20 months, the results showed no significant difference in OS in current smokers (HR 0.905, 95% CI 0.744-1.101) and slight numeric advantage for veliparib in the overall population (HR 0.853, 95% CI 0.747-0.974). In the 360 patients with biomarker-evaluable tumor samples, the addition of veliparib led to a larger OS benefit in patients who had positive LP52 results (HR 0.66, 95% CI 0.49-0.89), whereas patients with negative test results did worse with the PARP inhibitor (11.0 vs 14.4 months, HR 1.33, 95% CI 0.95-1.86).

The treatment groups had identical ORRs of 37%. The groups did not differ significantly with respect to duration of response, depth of response, quality of life, or changes in performance status.

“Non-small cell lung cancer is now an area of very rapid progress,” said Ramalingam. “We can personalize treatment options for patients. We can personalize based on genomic characteristics. We can also personalize therapies based on immune characteristics. We view such efforts as what we did in this study as developmental efforts to incorporate novel agents to improve the efficacy of existing agents. I feel that the results of this trial will be instructive and will definitely inform future studies of PARP inhibition in the treatment of non-small cell lung cancer.”