Balstilimab With Zalifrelimab Elicits High, Durable Responses in Recurrent/Metastatic Cervical Cancer


In patients with recurrent and/or metastatic cervical cancer, the second-line combination of balstilimab and zalifrelimab may offer meaningful clinical benefit, but further research is needed.

The combination of the anti-PD-1 agent, balstilimab and the anti-CTLA4 antibody, zalifrelimab showed promising clinical activity and an acceptable safety profile for the treatment of recurrent and/or metastatic cervical cancer, according to a study published in the Journal of Clinical Oncology.

Patients with cervical cancer who progress after first-line chemotherapy doublet plus bevacizumab (Avastin), current treatment remains suboptimal. Currently, pembrolizumab (Keytruda) is the only immunotherapeutic agent approved in this setting.

A phase 1/2 trial (NCT03495882) was designed to test the validity and safety of the balstilimab/zalifrelimab combination as secondline treatment for the advanced cervical cancer patient population. The study has an actual enrollment of 154 participants and an estimated study completion date of May 2023. The primary end point of the study is the objective response rate (ORR) of the investigational combination. Secondary end points include safety and tolerability, maximum drug concentration, minimum observed concentration at steady-state, area under the drug concentration-time curve, time to maximum concentration, terminal elimination of half-life, systemic clearance, volume of distribution, duration of response, disease control, duration of stable disease, time to response, progression-free survival, and overall survival.

Phase 1 was a dose-escalation study, which utilized a 3 + 3 dose escalation. Phase 2 was a dose expansion in advanced cervical cancer.

The median age of patients enrolled was 50 (range, 24-76) and 95.5% were White. Tumor histologies included squamous cell carcinoma (70.3%), adenocarcinoma (27.1%), adenosquamous (2.6%). Fifty-seven percent of patients had an ECOG performance status of 0, and 42.6% had an ECOG performance status of 1. Additionally, 58.8% were PD-L1 positive. Eighty-nine percent of patients received prior radiotherapy. The patients had received a median of 1 (range, 0-2) prior line of therapy. Prior antineoplastic agents included platinum (99.4%), taxane (78.75), and bevacizumab (32.9%).

The ORR was 25.6%. The complete response rate was 8%, the partial response rate was 17.6%, and the stable disease rate was 27.2%. Progressive disease was seen in 40% of patients. The DCR was 52%. The median DoR was not reached, with the median time to response being 2.7 months (range, 1.3-15.8). Twenty-five percent of responses lasted for 6 months or more, 20% of responses lasted for 9 months or more, and 12% of responses lasted for 12 months or more.

For patients who were PD-L1 positive, the ORR was 32.8%. For patients who were PD-L1 negative, the ORR was 9.1%, and 28% for those with an unknown PD-L1 status. For patients with squamous cell carcinoma, the ORR was 32.6%. For patients with adenocarcinoma, the ORR was 8.8%. No responses were seen in patients with adenosquamous histology.

Overall, the 12-month PFS probably was 21.%. The predicated 6-month OS was 69.2%, and the predicted 12-month OS was 53.3%.

In terms of safety, any grade treatment-emergent adverse events (TRAEs) occurred in 71% of patients. Common TRAEs included hypothyroidism (16.8%), diarrhea (14.2%), and fatigue (11.6). TRAEs grade 3 and higher occurred in 20% of patients. Common grade 3 or higher TRAEs included ALT increase (2.6%), diarrhea (1.9%), and anemia (1.3%). TRAEs lead to dose interruption in 12.3% of patients and lead to dose discontinuation in 7.7% of patients.

“The balstilimab plus zalifrelimab doublet elicited high ORRs, durable responses, and an acceptable safety profile as second-line treatment for patients with recurrent and/or metastatic cervical cancer. The high proportion of complete responders and activity irrespective of tumor PD-L1 status or histology were particularly promising outcomes that confirm the feasibility of dual-targeted immunotherapy for this disease,” wrote study authors.

O’Malley D, Neffa M, Monk B, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: An open-label phase II study. J Clin Oncol. 2021. Published online. doi: 10.1200/JCO.21.02067

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