Addition of Veliparib to Frontline Chemo Misses OS End Point in Current Smokers With Advanced Squamous NSCLC

The addition of veliparib to platinum-based chemotherapy in the frontline treatment of current smokers with advanced squamous non–small cell lung cancer (NSCLC) did not significantly improve overall survival (OS), but the LP52 signature may identify a subset of patients who will derive benefit from the combination, according to data from a phase 3 study (NCT02106546).¹

Results, which were published in the Journal of Clinical Oncology, demonstrated that the median OS in current smokers who received veliparib was 11.9 months (95% CI, 10.5-13.5) vs 11.1 months (95% CI, 9.6-12.6) in those who received placebo (hazard ratio [HR], 0.905; 95% CI, 0.744-1.101; P = .266).

In the overall population, OS favored the veliparib arm over the placebo arm, with a median of 12.2 months (95% CI, 10.9-13.5) vs 11.2 months (95% CI, 10.1-12.6), respectively (HR, 0.853; 95% CI, 0.747-0.974), but no difference in progression-free survival (PFS) was observed, with 5.6 months reported in both arms (HR, 0.897; 95% CI, 0.779-1.032; P = .107).

Notably, among patients with biomarker-evaluable tumor samples (n = 360), it was noted that the population with LP52 positivity experienced a better median OS with veliparib vs placebo, at 14.0 months (95% CI, 11.9-19.2) and 9.6 months (95% CI, 8.8-12.8), respectively (HR, 0.66; 95% CI, 0.49-0.89). In the LP52-negative population, median OS favored the placebo arm over the investigative arm, at 14.4 months (95% CI, 10.6-17.5) vs 11.0 months (95% CI, 8.2-14.7), respectively (HR, 1.33; 95% CI, 0.95-1.86).

“We observed no therapeutic benefit of adding veliparib to carboplatin and paclitaxel when using a clinical enrichment strategy focused on current smokers; however, exploratory biomarker analyses suggest that the LP52 signature may define a subgroup more likely to benefit from veliparib,” lead study author Suresh S. Ramalingam, MD, FACP, FASCO, of Winship Cancer Institute, and colleagues wrote.

Veliparib has been shown to enhance the activity of platinum-based chemotherapy regimens when given to patients with solid tumors. Data from a phase 2 trial (NCT01560104) examining veliparib or placebo in combination with carboplatin/paclitaxel in patients with advanced NSCLC showed better outcomes with veliparib in those with a squamous histology.² The HR for PFS was 0.54 and the HR for OS was 0.73. Improved PFS and OS was also reported in current smokers who received veliparib over placebo, with HRs of 0.38 and 0.43, respectively.

These data provided the rationale to launch a phase 3 trial to further evaluate the benefit of veliparib plus carboplatin/paclitaxel in treatment-naïve patients with advanced squamous NSCLC. The hypothesis was that those with squamous disease and molecular characteristics of adenocarcinoma might derive less benefit with veliparib vs those with non-adenocarcinoma molecular characteristics.

To evaluate this, investigators developed a binary gene expression classifier that was based on gene content of an expression-based lung subtype panel (LSP), referred to as LP52. For exploratory analyses, investigators utilized the gene content of the LSP but normalized in squamous histology samples and examined the association between LP52 status and clinical outcomes.

To be eligible for enrollment, patients needed to be at least 18 years of age, have a life expectancy of longer than 12 weeks, and have confirmed advanced or metastatic squamous NSCLC. Patients could not have previously received chemotherapy.

A total of 970 study participants were randomized 1:1 to receive either veliparib at a twice-daily dose of 120 mg (n = 486) or placebo twice daily (n = 484), with carboplatin/paclitaxel. All patients were given carboplatin at area under the curve 6 mg/mL/min and paclitaxel at 200 mg/m² on day 1 of each 21-day treatment cycle. Stratification factors included disease stage, ECOG performance status, geographic region, and smoking history.

The primary end point of the trial was OS in current smokers, and key secondary end points comprised OS in the intention-to-treat (ITT) population, as well as PFS and overall response rate (ORR) in current smokers and the ITT population.

Of those enrolled, the median age was 64 years, with 53.5% under the age of 65 years. Moreover, 82% of patients were male, 50.5% were from Eastern Europe or Russia, 98% were White, 57% were current smokers, and the median pack-years was 42. Thirty-four percent of patients had an ECOG performance status of 0, 77% had metastatic disease, and the majority of patients (62.5%) had 1 to 2 organ sites involved. The median tumor burden was 89 mm, and the median time from diagnosis to first dose of study treatment was 2 months.

The planned 6 cycles of treatment were given to 59% of those on the veliparib arm and 55% of those on the placebo arm. The rest of the patients discontinued treatment early, with main reasons being disease progression and toxicities that were not determined to be associated with progressive disease.

At the time of the primary data cutoff, the median OS follow-up was 19.3 months for current smokers who received veliparib and 20.6 months in current smokers who were given placebo/chemotherapy.

Additional results from the study indicated that the ORR was 37% in the veliparib arm and 37% in the placebo arm, with complete response rates of 2% and <1%, respectively, and partial response rates of 35% and 36%, respectively.

Regarding duration of response (DOR), depth of response, quality of life, or changes in performance status, no clinically meaningful differences were noted between the treatment arms. However, among those who experienced a response to treatment, the median DOR in the

investigative and control arms was 5.4 months and 5.5 months, respectively. Moreover, veliparib/chemotherapy resulted in a mean tumor shrinkage of -35.1% from baseline vs -31.0% with placebo/chemotherapy.

A total of 360 patients had LP52 status that could be determined via tumor tissue samples. Fifty-six percent of these patients were found to have LP52 positivity; 94 of these patients were in the veliparib arm and 108 were in the control arm. A total of 158 patients were LP52 negative, with 85 and 73 patients in the investigative and control arms, respectively.

Baseline characteristics were noted to be comparable between the positive and negative populations within both treatment arms; these characteristics were also comparable to the overall study population. Small imbalances were observed regarding sex and performance status.

When using the final clinical database, PFS in the population with LP52 positivity favored the veliparib arm over the control arm (HR, 0.79; 95% CI, 0.57-1.08). In the LP52-negative population, the PFS favored the placebo arm (HR, 1.38; 95% CI, 0.97-1.98). Moreover, in those with LP52 positivity, the ORR was slightly higher in the investigative arm vs the control arm. In the LP52-negative population, the ORR was higher in the placebo arm.

The majority of study participants experienced at least 1 adverse effect (AE). Twenty-one percent of patients who received veliparib/chemotherapy experienced a toxicity that resulted in discontinuation vs 23% of those who received placebo/chemotherapy. Moreover, 24% of those on the investigative arm and 23% of those on the control arm experienced AEs that required dose interruptions. Few dose reductions were reported.

Forty-five percent of patients on both arms experienced toxicities that were related to study treatment. The most frequently reported toxicities included anemia, fatigue, and neutropenia. Sixty percent of patients who received veliparib/chemotherapy experienced grade 3 or higher AEs vs 58% of those given placebo/chemotherapy.

Grade 3 or higher AEs determined to be associated with study drug were reported by 20% of patients in each arm. Moreover, 32% and 34% of patients in the investigative and control arms, respectively, experienced serious AEs that included pneumonia, febrile neutropenia, and anemia.

“These data support a role for biomarker-guided utilization of PARP inhibition with veliparib in a subset of squamous NSCLC; further studies are warranted to confirm the predictive potential of this novel biomarker,” the study authors concluded.

References

1. Ramalingam SS, Novello S, Guclu SZ, et al. Veliparib in combination with platinum-based chemotherapy for first-line treatment of advanced squamous cell lung cancer: a randomized, multicenter phase III study. J Clin Oncol. Published online August 26, 2021. doi:10.1200/JCO.20.03318
2. Ramalingam SS, Blais N, Mazieres J, et al. Randomized, placebo-controlled, phase II study of veliparib in combination with carboplatin and paclitaxel for advanced/metastatic non–small cell lung cancer. Clin Cancer Res. 2017;23(8):1937-1944. doi:10.1158/1078-0432.CCR-15-3069