From the Journals

Frontline veliparib/cisplatin/etoposide shows efficacy in advanced SCLC



For patients with extensive-stage small-cell lung cancer (ES-SCLC), the addition of the poly (ADP ribose) polymerase (PARP) inhibitor veliparib to frontline chemotherapy with cisplatin and etoposide resulted in a slight but significant improvement in progression-free survival but not overall survival, compared with cisplatin/etoposide alone, investigators reported in the Journal of Clinical Oncology.

Among 128 patients with newly diagnosed ES-SCLC, the median progression-free survival (PFS; the primary endpoint) for those randomized to veliparib/cisplatin/etoposide was 6.1 months, compared with 5.5 months for patients randomized to cisplatin/etoposide alone.

This translated into an unstratified hazard ratio for PFS with veliparib of 0.75 (one-sided P = .06) and a stratified HR of 0.63 (one-sided P = .01), reported Taofeek K. Owonikoko, MD, PhD, and his colleagues at Emory University in Atlanta.

“Although the initial result of our study is promising, additional confirmation in a larger definitive study is warranted, given the mixed results reported by other studies of PARP inhibitors in this patient population,” they wrote.

Median overall survival (OS) with cisplatin/etoposide in ES-SCLC is approximately 9-11 months, and fewer than 5% of patients survive out to 5 years. To see whether the addition of a PARP inhibitor to the standard of care could improve outcomes, the investigators first demonstrated in a phase 1 trial that the combination of veliparib with a platinum doublet of cisplatin and etoposide was safe (Lung Cancer. 2015 Jul;89[1]:66-70), and in the current study, they evaluated efficacy.

A total of 128 eligible patients (median age, 66 years; 52% men) with ES-SCLC were included in the analysis. Extensive-stage disease was defined as the presence of extrathoracic metastatic disease, malignant pleural effusion, and bilateral or contralateral supraclavicular adenopathy.

The patients were stratified by sex and serum lactate dehydrogenase (LDH) levels and then randomized to receive a maximum of four 3-week cycles of of cisplatin 75 mg/m2 intravenously on day 1 and etoposide 100 mg/m2 on days 1 through 3, plus either oral veliparib 100 mg twice daily on days 1 through 7 or placebo.

The primary endpoint of PFS was as noted before. Median overall survival was 10.3 months in the veliparib arm versus 8.9 months in the cisplatin/etoposide alone arm, a difference that was not statistically significant. The respective overall response rates were 71.9% vs. 65.6%, but this difference was also not significant.

Looking at the treatment effect by strata, the investigators found that men with high serum LDH levels had a significant PFS benefit with veliparib (HR, 0.34; one-sided P less than .001), but no significant benefit was seen in men with normal LDH or in women regardless of LDH status.

Grade 3 or greater hematologic toxicities that occurred more frequently in the veliparib arm included CD4 lymphopenia in 8% vs. 0% and neutropenia in 49% vs. 32%.

The investigators noted that the discrepancy between the magnitude of the risk reduction as measured by the hazard ratio and the actual, modest difference in median PFS between the study arms may be explained by the fact that men with elevated LDH represented the largest patient strata.

“Therefore, we hypothesize that this cohort probably contained a sufficient proportion of patients with SCLC who harbored some biologic vulnerability to this therapeutic strategy,” they wrote.

They acknowledged that although toxicities were higher with veliparib combination, the ability to deliver chemotherapy was equal between the arms.

Further exploration of the combination of veliparib/cisplatin/etoposide may be justified if results of another ongoing phase 2 study (NCT02289690) of a carboplatin-based chemotherapy doublet plus veliparib has similar efficacy results, Dr. Owonikoko and his associates concluded.

The study was coordinated by the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group and supported by the National Cancer Institute. Dr. Owonikoko disclosed a consulting or advisory role with AbbVie, developer of veliparib, and other companies, as well as institutional research funding from AbbVie and others.

SOURCE: Owonikoko TK et al. J Clin Oncol. 2018 Dec 5. doi: 10.1200/JCO.18.00264.

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