As reported in The Lancet Oncology by Eric Pujade-Lauraine, MD, and colleagues, the phase III JAVELIN Ovarian 200 trial showed no significant improvement in progression-free or overall survival with avelumab alone or in combination with pegylated liposomal doxorubicin (PLD) vs PLD alone in patients with platinum-resistant or -refractory ovarian cancer.

Eric Pujade-Lauraine, MD

Study Details

The open-label trial included 566 patients with epithelial ovarian, fallopian tube, or peritoneal cancer from sites in 24 countries. They were randomly assigned 1:1:1 between January 2016 and May 2017 to receive avelumab alone at 10 mg/kg every 2 weeks (n = 188), avelumab plus PLD at 40 mg/m² every 4 weeks (n = 188), or PLD alone (n = 190). Treatment was given until disease progression, unacceptable toxicity, or global deterioration of health status. Random assignment was stratified by platinum-resistant or -refractory status, number of previous anticancer regimens, and bulky disease. The primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with testing to determine whether avelumab alone or avelumab plus PLD was superior to PLD alone. To account for multiple comparisons, significance was set at P = .025.

Survival Outcomes

At data cutoff (September 2018), the median duration of follow-up for overall survival was 18.4 months (interquartile range [IQR] = 15.6–21.9 months) in the combination group, 17.4 months (IQR = 15.2–21.3 months) in the PLD group, and 18.2 months (IQR = 15.8–21.2 months) in the avelumab group.

Median progression-free survival was 3.7 months (95% confidence interval [CI] = 3.3–5.1 months) in the combination group (stratified hazard [HR] = 0.78, repeated 93.1% CI = 0.59–1.24, P = .030, vs PLD), 3.5 months (95% CI = 2.1–4.0 months) in the PLD group, and 1.9 months (95% CI = 1.8–1.9 months) in the avelumab group (stratified HR = 1.68, repeated 93.1% CI = 1.32–2.60, P > .99). Progression-free survival at 12 months was 18% (95% CI = 12%–25%), 9% (95% CI = 5%–16%), and 6% (95% CI = 3%–11%), respectively.

Median overall survival was 15.7 months (95% CI = 12.7­–18.7 months) in the combination group (stratified HR = 0.89, repeated 88.85% CI = 0.74–1.24, P = .21, vs PLD), 13.1 months (95% CI = 11.8–15.5 months) in the PLD group, and 11.8 months (95% CI = 8.9–14.1 months) in the avelumab group (stratified HR = 1.14, repeated 88.85% CI = 0.95–1.58, P = .83, vs PLD). Overall survival at 12 months was 60% (95% CI = 52%–67%), 57% (95% CI = 49%–64%), and 49% (95% CI = 42%–57%), respectively.

Among 508 patients with known PD-L1 expression status, 288 (57%) had PD-L1–positive tumors (≥ 1% expression on tumor cells or ≥ 5% of immune cells within tumor area), and 220 had PD-L1–negative tumors. Unstratified hazard ratios for progression-free survival vs the PLD group were 0.65 (95% CI = 0.46–0.92) for the combination and 1.45 (95% CI = 1.03–2.04) for avelumab. Respective unstratified hazard ratios for overall survival were 0.72 (95% CI = 0.49–1.05) for the combination and 0.83 (95% CI = 0.57–1.23) for avelumab. Among patients with PD-L1–negative tumors, hazard ratios were > 1 for the combination and avelumab groups vs the PLD group for both progression-free and overall survival.

Adverse Events

Grade ≥ 3 adverse events occurred in 69% of patients in the combination group, 59% of the PLD group, and 50% of the avelumab group. The most common grade ≥ 3 treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (10% in the combination group vs 5% in the PLD group vs 0% in the  avelumab group), rash (6% vs 2% vs 0%), fatigue (5% vs 2% vs 0%), stomatitis (5% vs 3% vs 0%), anemia (3% vs 5% vs 2%), neutropenia (5% vs 5% vs 0%), and decreased neutrophil count (5% vs 4% vs 0%). Serious treatment-related adverse events occurred in 18% of the combination group, 11% of the PLD group, and 7% of the avelumab group. Treatment-related adverse events led to treatment discontinuation in 4% (both drugs), 7%, and 6% of patients, respectively. One patient in the PLD group (sepsis) and one in the avelumab group (intestinal obstruction) died of treatment-related adverse events.

The investigators concluded: “Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival vs PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer.”

Dr. Pujade-Lauraine, of ARCAGY-GINECO, Paris, is the corresponding author of The Lancet Oncology article.

Disclosure: The study was funded by Pfizer and Merck KGaA. For full disclosures of the study authors, visit thelancet.com.