Data from the phase 3 JAVELIN Ovarian 200 trial indicated that avelumab with or without pegylated liposomal doxorubicin did not yield a significant improvement in overall or progression-free survival over the chemotherapy alone in platinum-resistant/refractory ovarian cancer.
Single-agent avelumab (Bavencio) and combination avelumab plus pegylated liposomal doxorubicin (PLD) did not significantly improve survival over PLD alone in patients with platinum-resistant/refractory ovarian cancer, according to findings from the phase 3 JAVELIN Ovarian 200 trial (NCT02580058).1
Results of the study that were published in The Lancet Oncology showed that the median progression-free survival (PFS) by blinded independent central review was 3.7 months in the combination arm (95% CI, 3.3-5.1), 3.5 months in the PLD-alone arm (95% CI, 2.1-4.0), and 1.9 months in the single-agent avelumab arm (95% CI, 1.8-1.9). The 12-month PFS rates were 18% (95% CI, 12%-25%), 9% (95% CI, 5%-16%), and 6% (95% CI, 3%-11%) in each group, respectively. When comparing both active therapy arms with PLD alone, neither the combination (HR, 0.78; 93.1% CI, 0.59-1.24; one-sided P = .03) nor the avelumab-alone group (HR, 1.68; 93.1% CI, 1.32-2.60; one-sided P > .99) saw a statistically significant PFS benefit.
Moreover, corresponding median overall survival (OS) for each group was 15.7 months (95% CI, 12.7-18.7), 13.1 months (95% CI, 12.7-18.7), and 11.8 months (95% CI, 8.9-14.1), with investigators reporting 12-month OS rates of 60% (95% CI, 52%-67%), 57% (95% CI, 49%-64%), and 49% (95% CI, 42%-57%) in each group, respectively. When comparing both active therapy arms with PLD alone, neither the combination (HR, 0.89; 88.85% CI, 0.74-1.24; one-sided P = .21) nor the avelumab-alone group (HR, 1.14; 88.85% CI, 0.95-1.58; one-sided P = .83) saw a statistically significant OS benefit.
“The JAVELIN Ovarian 200 trial did not meet its primary objectives,” the authors of the study wrote. “However, key aspects of the immunobiology of ovarian cancer were explored and, for the first time in a randomised setting, to our knowledge, subpopulations were identified in whom future studies of immune checkpoint inhibitors in combination with PLD could be directed.”
Patients with platinum-refractory ovarian cancer are known to have poor prognoses without many treatment options. Currently, patients are treated with a standard-of-care, non-platinum chemotherapy that yields notably low response rates and poor survival benefit.2 PD-L1 expression has been observed in ovarian tumor cells and approximately half of all patients are found to have tumor-infiltrating lymphocytes.3 In particular, the anti–PD-L1 antibody, avelumab, has previously demonstrated promising antitumor activity as a single agent in patients with heavily pretreated recurrent or refractory ovarian cancer in the phase 1b JAVELIN Solid Tumor trial (NCT01772004).4 Due to the immune-priming and suppressive microenvironment modifications that chemotherapy agents can offer, investigators theorized that chemotherapy may be able to enhance the activity of PD-L1 inhibitors in this patient population.5
The open-label, parallel group, randomized JAVELIN Ovarian 200 trial took place at 149 trial sites across 24 counties. The trial enrolled patients who were 18 years or older with histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer who had either platinum-resistant or platinum-refractory disease. Patients were allowed a maximum of 3 prior lines of therapy for platinum-sensitive disease, but no previous systemic treatments for platinum-resistant disease were allowed. Additionally, patients were required to have 1 or more irradiated lesions, an ECOG performance status of 0 or 1, and a life expectancy of 3 months or more.
Avelumab was administered at a dose of 10 mg/kg in an intravenous infusion every 2 weeks and 40 mg/m2 of PLD was administered intravenously every 4 weeks. Among those in the combination cohort, the PLD infusion was administered prior to avelumab. Additionally, premedication could be repeated at the investigator’s discretion. Although avelumab could not be dose adjusted, dose reduction with PLD was allowed provided that clinically significant toxicities were observed.
The primary end points of the trial were PFS by blinded independent central review and OS. Key secondary end points included objective response, duration of response, and disease control by blinded independent central review.
Investigators enrolled 566 patients between January 5, 2016, to May 17, 2017, who were randomized to receive avelumab plus PLD (n = 188), PLD (n = 190), or avelumab (n = 188). Among those enrolled, 69% had high-grade serous histology and 13% had clear cell histology. In total, 48% of patients had primary resistant disease, 37% had bulky disease, and 25% were platinum refractory.
The median follow-up for OS was 18.4 months in the combination arm (interquartile [IQR] range, 15.6-21.9), 17.4 months for the PLD arm (IQR range, 15.2-21.3), and 18.2 months for the single-agent avelumab arm (IQR range, 15.8-21.2) at the final analysis. In the combination group, patients received avelumab for a median duration of 16.9 weeks (IQR range, 9.1-35.9) and 16.3 weeks (IQR range, 8.1-32.0) with PLD. Moreover, patients in the PLD group had a median treatment duration of 16.0 weeks (IQR range, 8.0-25.0) and 10.1 weeks in the avelumab cohort (IQR range, 7.0-19.4).
At the time of data cutoff, 71% of patients in the combination cohort experienced disease progression or death, as well as 66% of those in the PLD cohort and 82% of those in the single-agent avelumab cohort. Moreover, 54%, 55%, and 58% of patients had died at the time of data cutoff from each group, respectively.
Confirmed objective responses by blinded independent central review were observed in the combination arm (13%; 95% CI, 9%-19%), the PLD group (4%; 95% CI, 2%-8%), and avelumab group (4%; 95% CI, 2%-8%). Patients across all arms had disease control rates of 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 33% (95% CI, 26%-40%), respectively.
No new safety signals were observed for avelumab across any of the study arms. Adverse effects (AEs) of any grade occurred in nearly all patients across all arms of the study, according to investigators. Notably grade 3 or higher AEs occurred in 69% of those in the combination arm, 59% in the PLD arm, and 50% in the avelumab arm.
The most common grade 3 or higher treatment-related AEs (TRAEs) in the combination, PLD, and avelumab groups, respectively, were palmar-plantar erythrodysesthesia syndrome (10%, 5%, and 0%), rash (6%, 2%, and 0%), fatigue (5%, 2%, and 0%), and neutrophil count decrease (5%, 4%, and 0%). Serious TRAEs that occurred in the combination cohort included pyrexia (3%), infusion reaction (2%), fatigue (1%), nausea (1%), stomatitis (1%), and dyspnea (1%). The most common serious TRAEs were vomiting (2%) and febrile neutropenia (2%) in the PLD cohort and pyrexia (2%) and diarrhea (1%) in the avelumab cohort.
Dose reduction of avelumab occurred in 3% of those in the single-agent group and in none of those the combination group. Dose reduction with PLD occurred in 26% of those in the combination group and 14% of those in the PLD group.
Of note, the investigators documented PFS and OS hazard ratios below 1 for avelumab plus PLD versus PLD alone in patients with PD-L1–positive tumors and those with 2 or 3 prior lines of therapy. These data, they noted, open doors for future research and suggest certain subpopulations of patients with ovarian cancer may still benefit from immune checkpoint blockade plus PLD.