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

Abstract

PURPOSE Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte–associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882 ) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS In total, 155 women (median age, 50 years [range 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1–positive and programmed death ligand-1–negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte–associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

RGS1 and related genes as potential targets for immunotherapy in cervical cancer: computational biology and experimental validation

“…Currently, the identified immune checkpoints have been identified: CTLA-4, PD-1 and PD-L1, LAG-3, TIM3, IDO and VISTA [ 29 ]. In a clinical trial involving 155 women with advanced cervical cancer, the objective response rate (ORR) of dual PD-1/ CTLA-4 blockade therapy was only 25.6% [ 30 ]. Therefore, an urgent need exists to find an effective immunotherapy target for the advanced cervical cancer treatment.…”

Comprehensive analysis of 7-methylguanosine and immune microenvironment characteristics in clear cell renal cell carcinomas

“…About half of localized tumors have distant metastasis, and the prognosis of metastatic ccRCC patients is poor; ccRCC is the most common renal cell carcinoma ( Gong et al, 2016 ; Navani and Heng, 2021 ). Immune checkpoint inhibitors have been used in clinic ( Hu et al, 2021 ) and have achieved good results in a variety of tumor treatment ( Arbour and Riely, 2019 ; O'Malley et al, 2021 ). Renal cell carcinoma is not sensitive to chemotherapy drugs, and immunotherapy and targeted therapy are effective treatments for advanced renal cell carcinoma ( Bedke et al, 2021 ; Yoshida et al, 2021 ).…”

The Changing Landscape of Systemic Treatment for Cervical Cancer: Rationale for Inhibition of the TGF-β and PD-L1 Pathways

“…Responses to bintrafusp alfa were longlasting, with a median DOR of 11.7 months (range, 1.4-41.2 months), and were observed irrespective of tumor histology or prior bevacizumab treatment. In contrast, anti-PD-(L)1 therapies tend to be less effective in patients with adenocarcinoma (93,102,115) and those who have been exposed to bevacizumab (37,102). Additionally, the safety profile of bintrafusp alfa in patients with heavily pretreated recurrent or metastatic cervical cancer who had disease progression with platinum-containing chemotherapy was consistent with that of anti-PD-(L)1 therapies, except for treatment-related AEs known to be associated with TGF-b inhibitors (e.g., localized skin lesions including keratoacanthomas) (94,109).…”

“…However, limited efficacy in specific histological types of cervical cancer emphasizes the challenges observed previously with anti–PD-(L)1 monotherapies. Similar to balstilimab monotherapy ( 93 ), the combination of balstilimab and zalifrelimab showed lower response rates in patients with cervical adenocarcinoma than those with squamous cell carcinoma (8.8% vs 32.6%) ( 102 ).…”