Immune Stimulant No Help When Added to Chemotherapy for Recurrent Ovarian Cancer

Bradley J. Monk, MD

Adding an immunotherapeutic agent to chemotherapy had no impact on survival in patients with recurrent, platinum-resistant ovarian cancer, according to a late-breaking trial reported at the 2017 Society of Gynecologic Oncology Annual Meeting held in National Harbor, Maryland.¹

Patients who received pegylated liposomal doxorubicin (PLD) plus motolimod (VTX-2337) had a median overall survival (OS) of 18.1 months, whereas PLD alone led to a median OS of 18.9 months. Neither progression-free survival (PFS) nor objective response rate (ORR) improved with the addition of the oral toll-like receptor 8 (TLR8) agonist.

A prespecified subgroup analysis showed that patients who had injection-site reactions (ISRs) with the combination had better survival, but the difference from patients without ISRs did not achieve statistical significance, said Bradley J. Monk, MD, who presented the findings during the meeting.

“No significant association was identified between OS or investigator-reviewed PFS and the type, density, and location of immune cell infiltrates in the primary tumor,” said Monk, professor and director, Division of Gynecologic Oncology, Creighton University School of Medicine, St. Joseph’s Hospital and Medical Center in Phoenix, Arizona. “No associations were seen with TLR8 polymorphisms,BRCA1orBRCA2, and 69 other gene mutations, or with autoantibody markers.”

In vitro analysis of immune biomarkers to TLR8 stimulation did show some associations with improved survival in patients treated with motolimod, specifically higher levels of interferon-gamma, tumor necrosis factor-alpha, or interleukin (IL)-12p, as well as lower levels of IL-10.

Motolimod is a small-molecule agent that activates the immune system to induce an adaptive immune response. Preclinical studies showed the drug enhances response to anthracycline chemotherapy. In a phase I clinical trial, two-thirds of patients with advanced ovarian cancer had objective responses or stable disease when treated with motolimod plus PLD.²

Monk reported findings from the phase II randomized Gynecologic Oncology Group/NRG-3003 trial involving 297 patients with recurrent platinum-resistant ovarian cancer. Eligible patients had received platinum-based therapy as primary treatment, and treatment with one additional cytotoxic regimen was allowed.

Recurrences must have occurred within 12 months of completing a platinum-based first- or second-line therapy. Patients with prior anthracycline exposure were not eligible.

Patients were randomized to PLD alone or with motolimod. Treatment continued until disease progression, and the primary endpoint was OS. Investigator-assessed PFS and adverse events were key secondary outcomes. Exploratory objectives included response rate, duration of response, disease control rate, and translational studies.

The primary analysis showed no significant difference in OS between the 2 treatment groups (HR, 1.22;P= .923). The analysis of investigator-assessed PFS showed a median duration of 5.2 months with PLD alone and 4.8 months with the addition of motolimod (HR, 1.21;P= .943).

Investigator-assessed best overall response also failed to show an advantage for the motolimod arm. PLD plus placebo led to an ORR of 21.5% (2.7% complete response) versus 21.0% for the motolimod group (3.4% complete response). An additional 39.6% of patients in the placebo group and 36.5% in the motolimod group had stable disease, resulting in disease control rates of 61.1% and 57.5%, respectively. An intention-to-treat analysis did not appreciably change the response outcomes.

Investigators performed a prespecified analysis of ISR and its association with survival. Three-fourths of patients in the motolimod arm developed ISRs. Patients with ISRs had a median OS of 19.8 months versus 13.3 months for those without. Though suggestive of a benefit, the difference did not achieve statistical significance (P= .067).

The addition of motolimod to PLD did not lead to any notable increases in treatment-emergent adverse events (TEAEs), including total number of TEAEs, number of patients with ≥1 TEAEs, grade ≥3 TEAEs, serious adverse events, or serious adverse events leading to discontinuation or death.

References:

1. Monk BJ, Brady MF, Aghajanian C, et al. A phase 2, randomized, double-blind, placebo-controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: A Gynecologic Oncology Group partners study. Presented at: 2017 SGO Annual Meeting; March 12-15, 2017; National Harbor, MD. Abstract LBA4.
2. Monk BJ, Facciabene A, Brady WE, et al. Integrative development of a TLR8 agonist for ovarian cancer chemoimmunotherapy. [epub ahead of print]Clin Cancer Res.2016. doi: 10.1158/1078-0432.CCR-16-1453.