Phase III Trial of Bavituximab in NSCLC Halted After Futility Analysis

At the prespecified analysis from the phase III SUNRISE trial conducted after 33% of events, an Independent Data Monitoring Committee found that the combination of bavituximab combination did not improve overall survival (OS) when compared with docetaxel and placebo in previously treated locally advanced or metastatic nonsquamous NSCLC. In the study, the bavituximab combination showed OS data similar to expectations while patients in the docetaxel-alone arm “dramatically outperformed OS expectations,” according to Peregrine.

“While we are deeply disappointed by this early outcome from the SUNRISE trial, we plan to take a deliberate and detailed approach in reviewing and verifying all available data from the trial in order to understand what subgroups or other patient characteristics may have impacted the performance of the study,” Steven W. King, president and chief executive officer of Peregrine, said in a statement.

Bavituximab is an IgG3 monoclonal antibody that binds to anionic phospholipids to inhibit tumor growth by stimulating antibody-dependent cellular cytotoxicity. The agent is also thought to limit immunosuppressive signals to reactivate the immune system.

In the phase III SUNRISE trial, 582 patients with stage IIIb/IV nonsquamous NSCLC who progressed after standard frontline treatment were randomized in a 1:1 ratio to bavituximab plus docetaxel or docetaxel plus placebo. Patients in each arm received up to 6 21-day cycles of treatment followed by weekly bavituximab or placebo (depending on the arm). Docetaxel was administered at 75 mg/m2 and bavituximab was administered at 3 mg/kg.

The primary endpoint of the trial was OS. Secondary endpoints focused on progression-free survival (PFS), overall response rate (ORR), and safety. The study was started in December 2013. Results from the interim analysis were not released.

In a prior phase II trial that had a similar design as the SUNRISE trial, the combination of bavituximab at 3 mg/kg and docetaxel demonstrated a median OS of 11.7 months compared with 7.3 months with docetaxel plus placebo (HR = .662; P = .113). This study, plus historical data for docetaxel, set the bar for survival expectations in the phase III study.

In the phase II trial, the ORR was 17.1% with bavituximab versus 11.3% for docetaxel. Median PFS was 4.2 months with bavituximab versus 3.9 months with docetaxel alone. Across subgroups, bavituximab demonstrated the most substantial benefit in patients with non-adenocarcinoma histology. In this small group (n = 17), the HR for OS was 0.134 (95% CI, 0.023-0.773).

Adverse events (AEs) of any grade were experienced by 95% of patients treated with bavituximab plus docetaxel versus 82.3% for those in the docetaxel/placebo arm. Grade ≥3 AEs were experienced by 55% of patients in the bavituximab group versus 44.3% of those in the placebo arm. Thrombotic and bleeding AEs were higher in the placebo arm, as were the rates of serious AEs (24.1% vs 22.5%, placebo and bavituximab, respectively).

The most common grade ≥3 AEs with the bavituximab/docetaxel combination included neutropenia (22.5%), anemia (12.5%), palmar-plantar erythrodysesthesia syndrome (7.5%), fatigue (7.5%), asthenia (7.5%), and leukopenia (7.5%).

While data from SUNRISE are analyzed, Peregrine announced that it would be placing its other bavituximab/chemotherapy combination studies on hold. At this time, a phase II/III study is assessing bavituximab with or without taxane therapy for patients with HER2-negative metastatic breast cancer (NCT02651610). Additionally, a study was being formed to assess neoadjuvant bavituximab plus paclitaxel for patients with early-stage triple-negative breast cancer (NCT02685306).

“While this is an unexpected and disappointing setback for the bavituximab chemotherapy combination clinical program, we have not seen anything in this trial result that diminishes our enthusiasm for advancing our immuno-oncology (I-O) combination trials,” said King. “The I-O combination studies are based on different mechanistic synergies that are clearly separate from the chemotherapy combination being evaluated in the SUNRISE study.”

References

1. Shtivelband M, Spigel DR, Gerber DE, et al. Randomized, blinded, placebo-controlled phase II trial of docetaxel and bavituximab as second-line therapy in locally advanced or metastatic non-squamous non-small cell lung cancer. J Clin Oncol. 2013;31 (suppl; abstr 8095).