Suresh S. Ramalingam, MD
There remains an unmet need for treatment options for patients with squamous cell non-small cell lung cancer (NSCLC), heightening the need for novel therapies. At the 2014 ESMO Congress, Suresh S. Ramalingam, MD, presented preliminary data from a randomized phase II trial that demonstrated an improvement in outcomes with the combination of the PARP inhibitor veliparib and chemotherapy in patients with this hard to treat histology.
In the study, progression-free survival was improved by 35% and overall survival was extended by 30% with the combination of veliparib with chemotherapy in patients with previously untreated metastatic or advanced NSCLC. In patients with squamous histology, PFS was 6.1 months with veliparib compared with 4.1 months (HR = 0.50; P
= .06) and the OS was 10.3 months with veliparib compared with 8.4 months (HR = 0.71; P
Ramalingam, a professor of medical oncology at the Winship Cancer Institute of Emory University, discussed the results of the trial and the potential of veliparib as a treatment for patients with squamous cell NSCLC in an interview with OncLive
OncLive: How was it discovered that veliparib had utility in lung cancer?
: PARP is a protein that’s involved in DNA repair and veliparib is a very potent inhibitor of PARP1 and PARP2. Basically, when you give a PARP inhibitor, the cell is not able to repair DNA damage effectively. What we’ve seen in the past is if the cells have deficiency in homologous recombination repairs, which is what happens in BRCA
mutation settings, those cells become far more dependent on the basic repair pathway, which is exactly where the PARP comes into play. Even though the role of PARP is well known beyond that.
So essentially by blocking DNA in cells that are critically dependent on that pathway, you are able to induce lethal damage. In lung cancer, if you look at what the common modalities of treatment are, we use platinum compounds, which are the cornerstones of therapy, and then we use radiation and both of these work by inducing DNA damage. Cells that can repair the DNA damage end up not being sensitive to radiation or chemotherapy with platinum-based regimens.
We and other labs have been studying the combination of chemotherapy with PARP inhibition, and veliparib in particular, and they have shown that veliparib is associated with increased efficacy when it is combined with chemotherapy or radiation. That was the basis for our clinical evaluation of veliparib in combination with platinum-based chemotherapy.
What were the findings from this phase II trial?
This was a randomized, placebo-controlled phase II trial where we enrolled patients with previously untreated NSCLC, this is first-line therapy for metastatic disease, and patients were randomized 2:1 to get carboplatin and paclitaxel with either veliparib or placebo. The veliparib was given for the first 7 days of each cycle, chemotherapy was given on day 3, veliparib was given from days 1-7 and the reason we used this strategy was because we wanted to prime the cells with PARP inhibition and then introduce chemotherapy.
Patients were allowed to continue the treatment for a maximum of 6 cycles, there was no maintenance therapy involved, and the primary endpoint for this was progression-free survival. We also looked at overall survival, objective response rates, and the safety of the regimen as secondary endpoints.
We had a total of 158 patients, with 105 randomized to the experimental arm with veliparib and 53 patients that were enrolled to the control arm with chemotherapy and placebo.
In this trial, the baseline characteristics were evenly matched and the main stratification factors were histology- either squamous or non-squamous- and smoking status-never versus current versus past. The randomization resulted in equal distribution of histology and smoking status across the two arms.
As far as for safety, we found that the combination was tolerated really well. There were really no toxicities that occurred more frequently with veliparib-chemo compared to chemotherapy alone with placebo.
Some of the common toxicities that you would see with chemotherapy, like neutropenia, thrombocytopenia, anemia, were all very similar between the two arms of the trial. Grade 1/2 toxicities were also very similar. Notably, there was no evidence of more nausea, vomiting or fatigue with the addition of veliparib to chemotherapy.
When we look at the efficacy, the overall primary endpoint, progression-free survival, was 4.2 months median in the control arm and 5.8 months median with veliparib [HR= 0.74]. The overall survival was 9.1 in the control arm compared to 11.7 in the veliparib arm. These differences, while clinically meaningful, did not reach statistical significance.