A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non–Small Cell Lung Cancer Patients

Abstract

Purpose: EGFR is a well-validated target for patients with non–small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF–EGFR interaction. Experimental Design: To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. Results: Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. Conclusions: Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782–90. ©2016 AACR.

CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients

“…The geometric mean of the maximum antibody titers was 1:12,646 sera dilution, while the maximum anti-EGF titer was 1:1,024,000. Patients developing a GAR as soon as day 32 had a significant survival benefit (MST = 27.28 months) as compared to controls (26). …”

“…Cyclophosphamide was administered before vaccination at a low, immunomodulatory dose (200 mg/m 2 ). Vaccination was maintained until severe patient condition worsening (PS = 3) or unmanageable toxicity (26). …”

“…Vaccination was safe, and the most common adverse reactions were mild or moderate injection site events, fever, headache, chills, vomiting, and general malaise. CIMAvax-EGF significantly augmented overall survival when the Harrington–Fleming test was applied (26). The Harrington–Fleming is a weighted log-rank test that can be used once the non-proportionality of the hazard ratio is confirmed (27, 28).…”

“…The 5-year survival rate was 16.62% for vaccinated patients vs. 6.2% for controls. A subgroup analysis considering demographic or tumor variables was done, and the larger gain was seen in smoker patients bearing squamous cell carcinomas with an ECOG 1 (26). …”

“…Sera from vaccinated patients were then tested for binding to the peptides in an enzyme-linked immunosorbed assay. In the Phase III study, 46% of the patients showed an immune-dominant response against the loop B of the EGF molecule (26). …”