Suresh S. Ramalingam, MD
In a phase III trial reported in the Journal of Clinical Oncology, Suresh S. Ramalingam, MD, of Winship Cancer Institute, Emory University School of Medicine, and colleagues found that the addition of the PARP inhibitor veliparib to platinum-based chemotherapy did not improve overall survival in current smokers with previously untreated advanced squamous cell non–small cell lung cancer (NSCLC), the primary endpoint of the trial.1 However, a trend toward improvement was observed among all patients and in a subgroup who had tumors with greater nonadenocarcinoma molecular characteristics.
In the double-blind trial, 970 patients (intent-to-treat [ITT] population) from sites in 37 countries were randomly assigned between April 2014 and November 2019 to receive veliparib at 120 mg twice daily (n = 486) or placebo (n = 484) together with carboplatin at AUC 6 and paclitaxel at 200 mg/m2 on day 1 of 21-day cycles for up to six cycles. A total of 276 patients (57%) in each group were current smokers. The primary endpoint was overall survival among current smokers.
It was hypothesized that patients with molecular characteristics of adenocarcinoma might derive less benefit from veliparib vs patients with greater nonadenocarcinoma molecular characteristics. Biomarker analysis of tumor samples was performed using a 52-gene expression histology classifier (LP52) to identify tumors with greater nonadenocarcinoma vs adenocarcinoma molecular characteristics (LP52-positive tumors).
At the time of primary data cutoff, median follow-up for overall survival was 19.3 months and 20.6 months for current smokers in the veliparib and control groups, respectively. Median overall survival among current smokers was 11.9 months (95% confidence interval [CI] = 10.5–13.5 months) in the veliparib group vs 11.1 months (95% CI = 9.6–12.6 months) in the control group (hazard ratio [HR] = 0.905, 95% CI = 0.744–1.101, P = .266).
In the overall ITT population, median overall survival was 12.2 months (95% CI = 10.9–13.5 months) in the veliparib group vs 11.2 months (95% CI = 10.1–12.6 months) in the control group (HR = 0.853, 95% CI = 0.747–0.974, nominal P = .032). Median progression-free survival was 5.6 months (95% CI = 5.6–5.8 months) with veliparib vs 5.6 months (95% CI = 5.5–5.7 months) with placebo (HR = 0.897, 95% CI = 0.779–1.032, P = .107).Subsequent anticancer medication was received by 49% of patients in the veliparib group vs 48% in the control group, with the most common in both groups being platinum-based chemotherapy (17% vs 15%), gemcitabine (20% vs 17%), and immunotherapy (21% vs 21%).
Among a total of 360 patients in whom LP52 status could be determined, 202 (56%) were LP52-positive, including 94 in the veliparib group and 108 in the placebo group; the 158 patients who had LP52-negative disease included 85 in the veliparib group and 73 in the placebo group. Among patients with LP52-positive disease, median overall survival was 14.0 months (95% CI = 11.9–19.2 months) in the veliparib group vs 9.6 months (95% CI = 8.8–12.8 months) in the control group (HR = 0.66, 95% CI = 0.49–0.89). Among patients with LP52-negative disease, median overall survival was 11.0 months (95% CI = 8.2–14.7 months) vs 14.4 months (95% CI = 10.6–17.5 months; HR = 1.33, 95% CI = 0.95–1.86). In the placebo group, LP52-negative status was associated with better survival (HR = 1.6, 95% CI = 1.15–2.22).
Among all patients, the most common adverse events of any grade in both the veliparib and control groups were alopecia (48% vs 46%), anemia (35% vs 35%), neutropenia (33% vs 30%), and peripheral sensory neuropathy (33% vs 31%). Grade ≥ 3 adverse events occurred in 60% of the veliparib group and 58% of the control group, with those occurring in at least 5% of patients consisting of neutropenia (24% vs 20%), anemia (10% vs 11%), and thrombocytopenia (6% vs 7%). Serious adverse events occurred in 32% vs 34% of patients, with pneumonia, febrile neutropenia, and anemia being the most common in both groups (each in ≤ 5% of patients). Adverse events led to discontinuation of veliparib and placebo in 21% and 23% of patients.
The investigators stated: “This study did not meet its primary endpoint of improved [overall survival] in current smokers with veliparib plus [carboplatin/paclitaxel]… despite this being a key observation in the phase II study of the same regimen and treatment schedule…. In the overall ITT population, median [overall survival] was slightly longer in the veliparib arm. The modest but consistent trend was seen from 6 months and retained for over 3 years with an overall decrease in risk of death of approximately 15%...This suggests that within the overall ITT population, there may be a subgroup of patients more likely to derive benefit from veliparib, such as a biomarker-selected population. The exploratory LP52 biomarker analysis … [showed] a consistent trend for improved [overall survival] for the LP52[-positive] population… with approximately 34% decrease in the risk of death compared with the control arm, suggesting this subgroup is deriving greater benefit from veliparib [or other poly (ADP-ribose) polymerase inhibitors].”
They concluded: “In current smokers with advanced [squamous cell] NSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.”
DISCLOSURE: The study was funded by AbbVie. Dr. Ramalingam has served as a consultant or advisor to Amgen, Genentech/Roche, Lilly/ImClone, Bristol Myers Squibb, AstraZeneca, Merck, Takeda, GlaxoSmithKline, Eisai, and Mirati Therapeutics; has received research funding from AbbVie, Bristol Myers Squibb, Pfizer, Merck, AstraZeneca/MedImmune, Vertex, Takeda, EMD Serono, Genmab, Advaxis, and Amgen; has been reimbursed for travel, accommodations, or other expenses by AstraZeneca; and has reported another relationship with the American Cancer Society.
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 39:3633-3644, 2021.