Adding Bavituximab To Second-Line Chemotherapy Doubles Response Rate In Late-Stage Lung Cancer Patients
Adding the monoclonal antibody bavituximab to docetaxel chemotherapy doubles overall response rate and improves progression-free survival and overall survival in late-stage non-squamous, non-small cell lung cancer (NS-NSCLC) patients who have already received one prior chemotherapy regimen, according to research presented at the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology. This symposium is sponsored by the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), the International Association for the Study of Lung Cancer (IASLC) and The University of Chicago.
Docetaxel is the standard second-line treatment for stage IIIB and stage IV NS-NSCLC patients. Researchers in this phase II, nine center, double-blind, randomized study evaluated the efficacy and safety of docetaxel plus a placebo (control arm) versus docetaxel plus either 1 mg or 3 mg bavituximab. The 117 evaluable patients were randomized to receive one of the three regimens every 21 days for up to six cycles. Patients received the same regimen for each cycle.
The overall response rate for the 1 mg bavituximab arm was 15 percent and 17.9 percent in the 3 mg arm, approximately double the control arm rate of 7.9 percent. Median progression-free survival was 4.2 and 4.5 months for the bavituximab arms, respectively, compared to three months for the control arm.
The trial was unblinded after 18 months, at which point the median overall survival had been reached in the control arm at 5.4 months (61 percent of patients died); however, neither bavituximab arms had reached median overall survival (fewer than 35 percent of patients died).
“This rigorous phase II trial demonstrates that not only is bavituximab well tolerated when given with docetaxel but it improves response rates, progression free survival and overall survival of second-line chemotherapy in patients with advanced NSCLC,” said David Gerber, MD, lead author of the study and an assistant professor of internal medicine at University of Texas Southwestern Medical Center in Dallas who specializes in lung cancer treatment. “If a phase III trial confirms these findings, bavituximab could become a major component of standard treatment for patients with this challenging disease.”
The abstract, “Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of Bavituximab Plus Docetaxel in Patients with Previously Treated Locally Advanced or Metastatic Non-Squamous Non-small Cell Lung Cancer (Top-line Results),” was presented during the Plenary Session at 12:30 p.m., Central time on September 7, 2012.
Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial of Bavituximab Plus Docetaxel in Patients with Previously Treated Locally Advanced or Metastatic Non-Squamous Non-Small-Cell Lung Cancer (Top-line Results)
D. E. Gerber1, M. Joppert2, D. R. Spigel3, D. P. Singh4, D. Giorgadze5, M. Shtivelband6, O. V. Ponomarova7, J. Shan8, C. P. Belani9, 1Harold C. Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, 2Florida Cancer Specialists, Ft. Myers, Fla., 3Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, 4Department of Radiotherapy and Clinical Oncology, S.M.S. Medical College and Attached Hospitals, Jaipur, India, 5Chemotherapy and Immunotherapy Clinic, Tbilisi, Ga., 6Ironwood Cancer and Research Centers, Chandler, Ariz., 7RE Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, Kiev, Ukraine, 8Peregrine Pharmaceuticals Inc., Tustin, Calif., 9Penn State Hershey Cancer Institute, Hershey, Penn.
Bavituximab (B), a monoclonal antibody directed against phosphatidylserine, (PS) has been shown to localize selectively to tumor vasculature, synergize with chemotherapy, cause vascular shutdown in tumors and reactivate innate and adaptive tumor immunity.
Purpose/Objective(s): To evaluate the efficacy and safety of two separate doses of bavituximab (1 and 3 mg/kg) combined with docetaxel (D) vs. D plus placebo (P) as second line therapy in patients with locally advanced or metastatic non-squamous NSCLC.
Materials/Methods: This phase II, multicenter, double-blind study, randomized patients (1:1:1) to receive 75 mg/m2 of D every 21 days up to 6 cycles and weekly blinded infusion of P, 1 mg/kg or 3 mg/kg of B until disease progression or toxicity. Key eligibility criteria were Stage IIIB and IV, non-squamous NSCLC previously treated with first line systemic chemotherapy, ECOG status ≤2, measurable disease by RECIST and adequate hematologic, hepatic and renal function. The primary efficacy endpoint was overall response rate (ORR) by RECIST 1.1 and secondary endpoints were progression free survival (PFS), duration of response (DR) and overall survival (OS). Safety was evaluated by adverse events, vital signs, laboratory measurements (CBC, biochemistry, urinalysis and coagulation), ECG and human anti-chimeric antibody (HACA) formation.
Results: Of the 121 patients randomized, no significant differences were seen in baseline characteristics (gender, age, ethnicity, ECOG or disease stage.) Based on 117 evaluable patients, the ORR was 7.9% for the D + P, 15.0% for the D + 1 mg/kg B and 17.9 % for the D + 3 mg/kg B cohorts, respectively. Median PFS was 3.0, 4.2 and 4.5 months, respectively. At the time the Independent Data Monitoring Committee (IDMC) recommended to unblind the trial, median OS had been reached at 5.4 months in the control group (61% death events), while <35% of death events had been observed in the bavituximab-containing groups. B + D was well-tolerated and no safety concerns were identified by the IDMC.
Conclusions: In this double-blind, randomized, placebo-controlled, multicenter Phase II study in patients with Stage IIIB and IV non-squamous NSCLC, bavituximab in combination with docetaxel was well-tolerated and all endpoints (response, PFS and OS) demonstrated trends toward superiority for both experimental arms. Importantly, though median OS has not yet been reached in either bavituximab-containing cohort, there is a clear and persistent separation of the survival curves warranting further development of bavituximab.
Author Disclosure Block: D.E. Gerber: E. Research Grant; Peregrine Pharmaceuticals, Inc. M. Joppert: None. D.R. Spigel: None. D.P. Singh: None. D. Giorgadze: None. M. Shtivelband: None. O.V. Ponomarova: None. J. Shan: K. Stock; Peregrine Pharmaceuticals, Inc. Q. Leadership; Peregrine Pharmaceuticals, Inc. C.P. Belani: None.