Seribantumab Fails to Improve PFS in Ovarian Cancer; Some Patients May Benefit

October 27, 2016

Adding seribantumab to paclitaxel failed to improved progression-free survival in unselected patients with platinum-resistant or -refractory ovarian cancer. Expression of heregulin and HER2, however, could identify a subset of patients that derive benefit from the therapy.

Adding seribantumab to paclitaxel failed to improved progression-free survival (PFS) in unselected patients with platinum-resistant or -refractory ovarian cancer, according to a new open-label phase II study. Expression of heregulin (HRG) and HER2, however, could identify a subset of patients that derive benefit from the therapy.

“In ovarian cancer, ErbB3 promotes cell proliferation in preclinical models, and approximately 30% of patients show evidence of an HRG/ErbB3 autocrine loop in tumor cells derived from malignant ascites,” wrote study authors led by Joyce F. Liu, MD, MPH, of the Dana-Farber Cancer Institute in Boston. This along with other preclinical research suggest that blocking HRG/ErbB3 could increase sensitivity to therapy.

Seribantumab is a fully human immunoglobulin G2 antibody targeting ErbB3 and blocking HRG from binding. In the new study, 223 patients with platinum-resistant or -refractory epithelial ovarian, fallopian tube, or primary peritoneal cancer were randomized to either seribantumab and paclitaxel (140 patients) or paclitaxel alone (83 patients); the results were published online ahead of print in the Journal of Clinical Oncology.

The primary endpoint was not met, with a median PFS with seribantumab of 3.75 months, compared with 3.68 months in the paclitaxel monotherapy arm, for a hazard ratio (HR) of 1.027 (95% CI, 0.741–1.425; P = .864). The median overall survival with the study drug was 13.7 months, compared with 10.12 months in the control group, for an HR of 0.991 (95% CI, 0.62–1.584; P = .972). Objective response rates were also similar at 13.6% with seribantumab and 18.1% without it, with no complete responses in either group.

The study also examined whether any of five prespecified biomarkers might predict response to the therapy. Patients with detectable HRG mRNA and low HER2 expression (57 of 151 patients with available biomarker data) did see increased benefit with seribantumab; the PFS HR was 0.37 (95% CI, 0.18–0.76; P = .007). In those deemed “biomarker-negative,” in contrast, PFS was better with paclitaxel monotherapy, with an HR of 1.80 (95% CI, 1.08–2.98; P = .023).

Almost all patients in both groups experienced at least one treatment-emergent adverse event (TEAE). Grade or 3 or higher TEAEs occurred in 50 patients (35.7%) receiving seribantumab and in 24 patients (30%) receiving paclitaxel alone. Serious TEAEs were observed in 59 patients (42.1%) with the study drug and in 25 patients (31.3%) in the control group. Among the most common grade 3 or higher adverse events with seribantumab were diarrhea (7.1%), fatigue (7.9%), hypokalemia (7.9%), and anemia (9.3%).

The authors noted that several other studies have connected HRG to outcome. “That several independent studies across different cancer types found HRG to be prognostic of poor outcome and predictive of benefit from ErbB3 inhibitors suggest that HRG-mediated resistance may be a broad phenomenon in cancer and that ErbB3 inhibition may be part of a general strategy to combat insensitivity to anticancer agents,” they wrote.

In an accompanying editorial, three experts led by David M. Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York, highlighted the importance of the biomarker portion of the trial. “Their efforts have identified a potential path forward for this drug in ovarian cancer, salvaging what otherwise would have been a negative study,” they wrote. A prospective, phase III trial testing the findings in this study, they noted, would need to include only biomarker-positive patients, given the potential that biomarker-negative patients are actually harmed by the addition of seribantumab.