In a phase II trial reported in the Journal of Clinical Oncology, Sant P. Chawla, MD, and colleagues found that the addition of the heterologous prime-boost vaccination regimen CMB305 to atezolizumab did not improve survival outcomes in patients with soft-tissue sarcomas expressing the tumor-associated antigen NY-ESO-1.

Sant P. Chawla, MD

The vaccine regimen is designed to prime NY-ESO-1–specific CD8 T-cell populations (priming component, LV305) and activate the immune response with a potent TLR-4 agonist (boost component, G305).

Study Details

In the U.S. open-label multicenter trial, 89 patients with locally advanced, relapsed, or metastatic synovial sarcoma or any-grade myxoid liposarcoma were randomly assigned between April 2015 and March 2019 to receive CMB305 plus atezolizumab (n = 45) or atezolizumab alone (n = 44).

The priming component of CMB305 was injected intradermally at weeks 0, 2, 6, and 10; the boost component was injected intramuscularly at weeks 4, 8, and 12, followed by a booster dose every 6 weeks for up to 1 year or until disease progression. Both groups received atezolizumab at 1,200 mg every 3 weeks starting on day 0 and continuing up to 2 years or until disease progression or unacceptable toxicity.

The primary endpoints were progression-free survival and overall survival.

Key Findings

In October 2018, the sponsor determined that the primary objectives of the study were met and additional clinical development of CMB305 was terminated.

Median progression-free survival was 2.6 months (95% confidence interval [CI] = 1.4–2.9 months) in the combination group vs 1.6 months (95% CI= 1.5–2.7 months) in the control group (hazard ratio [HR] = 0.9, 95% CI = 0.6–1.3, P = .49). Median overall survival was 18 months (95% CI = 10.1–22.1 months) vs 18 months (95% CI = 15.3–26.5 months), with a hazard ratio of 1.2 (95% CI = 0.7–2.1, P = .47).

Patients in the combination group had significantly higher rates of induced NY-ESO-1–specific T-cell response (53.8% vs 15.0%, P = .01) and induced NY-ESO-1–specific antibody response (50.0% vs 0%, P < .0001). In a post hoc analysis, patients who developed anti–NY-ESO-1 T-cell immune response had longer median overall survival (36 months) vs those who did not (HR = 0.3, P = .02).

Treatment-related grade ≥ 3 adverse events occurred in 9% of patients in each group, and treatment-related serious adverse events occurred in 7% vs 2%. Adverse events led to discontinuation of treatment in 13% vs 14%. Adverse events led to death in two patients in the combination group, with causes consisting of acute respiratory failure secondary to disease progression and tumor hemorrhage.

The investigators concluded, “Although the combination of CMB305 and atezolizumab did not result in significant increases in progression-free or overall survival compared with atezolizumab alone, some patients demonstrated evidence of an anti–NY-ESO-1 immune response and appeared to fare better … than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–PD-L1 therapies merits further evaluation in other clinical contexts.”

Robert G. Maki, MD, PhD, of the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Immune Design Corp, a wholly owned subsidiary of Merck & Co Inc. For full disclosures of the study authors, visit ascopubs.org.