Michael Serzan, MD, discusses the rationale for evaluating botensilimab/balstilimab for patients with advanced renal cell carcinoma.

Dr Serzan on the Rationale for Evaluating Botensilimab Plus Balstilimab in Advanced RCC

Michael Serzan, MD, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, discusses the rationale for evaluating botensilimab (AGEN1181) plus balstilimab (AGEN2034) in patients with advanced renal cell carcinoma (RCC) in the phase 2 ARCITECT (NCT05928806) trial.

ARCITECT is a multicenter, investigator-initiated trial evaluating the efficacy and safety of botensilimab with balstilimab vs nivolumab (Opdivo) plus ipilimumab (Yervoy) in this patient population. This trial is grounded in preclinical research that suggests a novel approach to improving the effectiveness of immune checkpoint inhibitors, Serzan begins. Additionally, the study was supported by earlier work from a phase 2 trial (NCT03117309) evaluating nivolumab monotherapy followed by a nivolumab plus ipilimumab boost in non-responding patients with treatment-naive RCC, he explains. Translational findings from this study revealed that the presence of regulatory T cells (Tregs) expressing PD-1 on their surface was associated with poor responses to nivolumab monotherapy. This insight suggested that targeting these Tregs could enhance the effectiveness of PD-1-based therapies, Serzan states.

Botensilimab is an immuno-oncology agent designed to enhance T-cell priming, deplete intratumoral Tregs, and activate myeloid cells by leveraging novel FcyR-associated mechanisms of action. When combined with balstilimab, an anti-PD-1 therapy, this anti-CTLA4 agent has shown promising antitumor activity, particularly in cancers where the combination of nivolumab and ipilimumab has proven ineffective, he continues.

The ARCITECT trial will include patients with favorable, intermediate, or poor risk clear cell RCC who have not received prior adjuvant or neoadjuvant systemic therapy, Serzan reports. Patients will be randomly assigned to receive either the botensilimab/balstilimab combination or the standard nivolumab/ipilimumab regimen for up to 2 years. Stratification factors will include IMDC risk groups and the presence of sarcomatoid histology. The primary end point of the trial is the overall response rate as measured by RECIST 1.1 criteria, he notes. This study aims to determine whether the novel combination of botensilimab and balstilimab can offer superior outcomes compared to the established nivolumab/ipilimumab regimen, potentially providing a new therapeutic option for patients with clear cell RCC, Serzan concludes.

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Dr Serzan on the Potential of Botensilimab/Balstilimab to Address Unmet Needs in RCC

Michael Serzan, MD, medical oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, discusses the potential of botensilimab (AGEN1181)/balstilimab (AGEN2034) to address unmet needs in the treatment of patients with advanced renal cell carcinoma (RCC). He also highlights the rationale behind the phase 2 ARCITECT (NCT05928806) trial, a multicenter, investigator-initiated trial evaluating the efficacy and safety of botensilimab/balstilimab vs nivolumab (Opdivo)/ipilimumab (Yervoy) in this patient population.

Serzan emphasizes that although nivolumab plus ipilimumab has elicited durable responses in patients with advanced RCC, particularly at 8 years of follow-up in the phase 3 CheckMate 214 trial (NCT02231749), this combination is associated with significant toxicity. This toxicity often necessitates discontinuation of therapy and treatment with high-dose steroids. Furthermore, approximately 20% of patients exhibit primary progressive disease with nivolumab plus ipilimumab, according to Serzan.

First-line treatment for patients with metastatic clear cell RCC (mccRCC) typically involves PD-1 inhibitors combined with either CTLA-4 inhibitors (IO/IO regimens) or VEGF TKIs (IO/TKI regimens). Despite the durable responses seen with nivolumab plus ipilimumab, over two-thirds of many patients experience disease progression on or following treatment with this regimen, Serzan says. Resistance to nivolumab monotherapy has been associated with an increased presence of a subpopulation of regulatory T cells (Tregs) within the tumor microenvironment.

Botensilimab, a next-generation CTLA-4 inhibitor with enhanced Fc functionality, may improve response rates and decrease complement-mediated toxicity, Serzan explains. This novel agent leverages Fc receptor–associated mechanisms to enhance T-cell priming, deplete intratumoral Tregs, and activate myeloid cells. The combination of botensilimab and balstilimab has demonstrated antitumor activity in diseases where nivolumab/ipilimumab has shown limited efficacy.

Serzan highlights that the combination of botensilimab and balstilimab could offer a new therapeutic option for patients with clear cell kidney cancer. The development of botensilimab/balstilimab is particularly promising because this combination addresses the limitations of existing therapies. By reducing the population of Tregs and enhancing T-cell responses, this combination therapy may overcome resistance mechanisms and provide more durable responses. Additionally, the reduced complement-mediated toxicity associated with botensilimab could improve the safety profile for patients, allowing for sustained treatment without the severe adverse effects seen with current regimens.

Serzan notes that botensilimab/balstilimab represents a significant advancement in the treatment of patients with advanced RCC. The novel mechanism of action and promising clinical activity of this combination indicate that it could fill a critical gap in RCC treatment, offering improved efficacy and safety for patients who have progressed on traditional therapies. The ARCITECT trial will further elucidate the potential of this combination therapy to transform the management of advanced RCC.

Michael Serzan, MD, discusses the use of botensilimab/balstilimab in the treatment of patients with advanced renal cell carcinoma.

Michael Serzan, MD

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Dr Serzan on the Rationale for Evaluating Botensilimab Plus Balstilimab in Advanced RCC

Dr Serzan on the Potential of Botensilimab/Balstilimab to Address Unmet Needs in RCC