The complementary action of two novel agents has opened the door for patients with recurrent or metastatic cervical cancer to achieve a real clinical benefit after progression on platinum-based therapy.
Patients who received two investigational checkpoint inhibitors — anti-PD-1 agent balstilimab and anti-CTLA-4 drug zalifrelimab — as second-line therapy had an overall response rate of 25.6% and a median overall survival of almost 13 months, according to an open-label, single-arm, phase 2 study.
“The options after somebody has progressed on a platinum-based doublet are limited with overall short survival times,” David O’Malley, MD, professor of gynecologic oncology, the Ohio State University and James Comprehensive Cancer Center, Columbus, told Medscape Medical News. This combination therapy represents “a much-needed option for patients in this setting,” O’Malley said in a statement.
Steven O’Day, MD, chief medical officer of Agenus, which developed both agents, also highlighted the promise of this dual therapy. “The combination data with balstilimab (AGEN2034) and zalifrelimab (AGEB1884) in recurrent/metastatic cervical cancer represents a meaningful improvement over currently available therapies while demonstrating a well-tolerated safety profile,” O’Day said in the statement.
The study, funded by Agenus, was published online December 22 in the Journal of Clinical Oncology.
The trial included 125 patients with recurrent or metastatic squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix who had received one prior line of platinum-based therapy in the advanced disease setting. Patients received three doses of biweekly balstilimab at 3 mg/kg plus 1 mg/kg of zalifrelimab once every 6 weeks over the 6-week cycle. Treatment was continued until disease progression or unacceptable toxicity.
The median age at enrollment was 50 years. More than half of patients had PD-L1-positive tumors, while about 1 in 4 had PD-L1-negative tumors, and the remaining cases could not be evaluated.
For the primary endpoint, the combination of the PD-1 inhibitor and anti-CTLA-4 antibody produced an overall response rate of 25.6%, including 10 complete responses and 22 partial responses. The response rate is considerably higher than that achieved with current second-line therapies, which ranges from 4% to 14%.
Among patients with PD-L1-positive tumors, the overall response rate was even higher at 33%, while the rate with PD-L1-negative tumors was 9%.
Although the biggest impact of this regimen will likely be in PD-L1-positive patients, O’Malley noted, a 9% overall response rate in those with PD-L1-negative tumors still represents an improvement over the 0% response rate observed in patients receiving pembrolizumab — which is currently approved for PD-L1-positive cervical cancer, but not PD-L1 negative tumors.
The overall disease control rate was 52%. The authors reported median progression-free survival of 2.7 months and a 12-month progression-free survival of 21%.
Median overall survival was 12.8 months. At 6 months, 69.2% of patients were alive, and at 12 months, 53.3% were alive. By comparison, the median overall survival after progression on platinum therapy is between 7 to 8 months.
Responses to the novel regimen were also durable, with a median duration of response not yet reached following a median follow-up of 21 months. As observed with other immunotherapies, the responses often persisted after the agent was discontinued.
In addition, “responses were observed across histologic subtypes,” including in almost one third of patients with squamous tumors and 9% of those with adenocarcinomas.
In terms of treatment-related adverse events, the most common were hypothyroidism, diarrhea, fatigue, and nausea. The majority of events were grade 1 or 2, though about 20% of patients experienced events considered grade 3 or higher.
Adverse events leading to dose interruptions occurred in 12.3% of patients, and those leading to treatment discontinuation occurred in 7.7% of patients. Immune-mediated adverse events were common, occurring in 44.5% of patients, while death attributed to the treatment occurred in three patients.
“Having treatments that are durable and well-tolerated are essential,” O’Malley observed, “as these patients are often symptomatic from their disease as well as potentially fighting fatigue and quality-of-life issues.”
According to the authors, dual-targeted immunotherapy is a “feasible and promising” strategy for optimizing antitumor activity compared to anti-PD-1 monotherapy alone.
The authors also highlighted how the two agents may work in concert.
“Mechanistically, inhibition of PD-1 and/or PD-L1 signaling can restore the responsiveness of tumor reactive T cells that become inactivated after prolonged exposure to chronic stimulation within the tumor microenvironment,” while CTLA-4 blockade activates effector T cells and reduces the suppressive activity of regulatory T cells, leading to enhanced antitumor immunity, the authors write.
“These distinct yet complementary mechanisms of action underlie the improved outcomes seen with concomitant blockade of the PD-1 and CTLA-4 pathways,” O’Malley and colleagues said. “On the basis of these findings, further evaluation of balstilimab plus zalifrelimab as second-line treatment in this disease setting is warranted.”
The authors are currently pursuing a randomized phase 2 study evaluating the safety and efficacy of balstilimab alone and in combination with zalifrelimab in the second-line setting for recurrent and/or metastatic cervical cancer.
O’Malley reports serving as a consultant or in an advisory role for Janssen Oncology, AstraZeneca, Clovis Oncology, Tesaro, Novocure, AbbVie, Genentech/Roche, OncoQuest, Immunogen, GOG Foundation, Translational Genomics Research Institute,
J Clin Onc. Published online December 22, 2021. Full text