Overall, the treatment was tolerated well. More than 90% of the patients were able to receive the planned dose of veliparib without dose reduction.
—Suresh Ramalingam, MD
Adding veliparib to carboplatin and paclitaxel resulted in “clinically meaningful improvements” in progression-free survival and overall survival among patients with previously untreated metastatic or advanced non–small cell lung cancer (NSCLC), particularly those with squamous histology. The results of the phase II M10-898 trial were presented by Suresh Ramalingam, MD, of Winship Cancer Institute of Emory University, Atlanta, at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology.1
Veliparib (ABT-888) is a potent, orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor that enhances the efficacy of platinum drugs, the current standard of care for metastatic NSCLC. PARP inhibitors, Dr. Ramalingam explained, interfere with the repair of DNA damage and sensitize tumors to chemotherapy and radiation therapy. A previously reported phase I trial combining veliparib with full-dose carboplatin and paclitaxel showed “safety and signs of efficacy in patients with advanced-stage NSCLC,” Dr. Ramalingam reported. “And that formed the basis for this randomized phase II clinical trial.”
Almost Half Had Squamous Histology
The study randomly assigned patients 2:1 to receive carboplatin and paclitaxel plus either veliparib at 120 mg twice daily or placebo, given on days 1 to 7 of each 21-day cycle. Chemotherapy was administered on day 3 of each cycle. Patients could receive a maximum of six cycles of chemotherapy.
Patients were stratified by histology (squamous vs nonsquamous, with 49% squamous) and smoking history (current, past, or never, with 60% having smoked within 1 year of study entry).
The average age of patients was 62 years in the placebo group and 63 years in the veliparib group. Patients were predominantly male, more so in the veliparib group—75 of 105 patients (71%) vs 32 of 53 patients (60%) in the placebo group. All but four patients were Caucasian. Most patients had stage IV disease.
No Increase in Toxicity
“Overall, the treatment was tolerated well,” Dr. Ramalingam reported. “More than 90% of the patients were able to receive the planned dose of veliparib without dose reduction.” Adverse events were similar between the two study arms, “suggesting there was no increase in toxicity with the addition of veliparib to chemotherapy,” Dr. Ramalingam noted.
Adverse events of any grade occurred in 89% of the placebo group and 96% of the veliparib group, and grade 3 or higher events were reported in 58% and 67% of the respective groups. The most common adverse events were alopecia (42% in the placebo group and 39% in the veliparib group), anemia (42% vs 31%), and neutropenia (29% vs 36%). The one area of imbalance was in leukopenia, affecting 11% of patients in the veliparib group but 0% of the placebo group.
Deeper Responses With Veliparib
“The overall response rate was very similar between the two arms of the trial, 28% for placebo and 31% for veliparib. However, the duration of the response was significantly higher for patients treated with veliparib with chemotherapy, 6.9 months vs 3.3 months, with a hazard ratio of 0.11,” Dr. Ramalingam reported.
The median progression-free survival was 4.2 months for those receiving placebo and 5.8 months for those receiving veliparib. “The hazard ratio was 0.74. The P value did not reach significance (P = .193),” Dr. Ramalingam noted. “Similarly, with overall survival, we saw 9.1 months for the control arm and 11.7 months for the combination, with a hazard ratio of 0.77, with a P value that was not significant (P = .205). ”
For patients with squamous cell histology, “there was an improvement in median progression-free survival from 4.1 months to 6.1 months, with a hazard ratio of 0.50,” Dr. Ramalingam stated. “The median overall survival was also increased, from 8.4 months in the control arm to 10.3 months with the combination of veliparib and chemotherapy, with a hazard ratio of 0.71. The P value was .217,” Dr. Ramalingam summarized. “In the patients with nonsquamous disease, there was no difference in progression-free survival or overall survival between the two arms of the trial.”
Based on the results in patients with squamous cell NSCLC, a phase III pivotal trial (M11-089)2 has been initiated for patients with squamous histology. Additional studies are being conducted with tumor specimens from patients in the phase II study “to try to identify specific markers that might predict benefit,” Dr. Ramalingam added. ■
Disclosure: Dr. Ramalingam reported no potential conflicts of interest.
1. Ramalingam S, Blais N, Mazieres J, et al: A randomized, double-blind, phase 2 trial of veliparib (ABT-88) with carboplatin and paclitaxel in previously untreated metastatic or advanced non-small cell lung cancer. Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 8. Presented October 30, 2014.
2. U.S. National Institutes of Health: Randomized, double-blind, multicenter, study comparing veliparib plus carboplatin and paclitaxel versus placebo plus carboplatin and paclitaxel in previously untreated advanced or metastatic squamous non-small cell lung cancer. Available at http://clinicaltrials.gov/ct2/show/NCT02106546. Accessed December 12, 2014.