New Paper Alert! Promising Results from Cabozantinib Phase 2 trial in advanced Adrenocortical Tumors

Promising Results from Cabozantinib Phase 2 trial in advanced Adrenocortical Tumors

 Authors: Matthew T Campbell, Vania Balderrama-Brondani, Prof Camilo Jimenez, Gina Tamsen, Prof Leonardo P Marcal, Jeena Varghese, Amishi Y Shah, James P Long, Miao Zhang, Joshua Ochieng, Cara Haymaker.

 Published in Lancet Oncology on April 09, 2024

Introduction:

Adrenocortical carcinoma, a rare and aggressive malignancy, shows limited response to current systemic chemotherapies. Mitotane stands as the sole approved treatment, often paired with cytotoxic chemotherapy due to its restricted efficacy. The potential benefit of tyrosine kinase inhibitors seen across various solid tumors brings forth a new therapeutic avenue, although their utility in adrenocortical carcinoma remains underexplored due to potential pharmacokinetic interactions with mitotane. This phase 2 trial is the first to investigate cabozantinib- a multikinase inhibitor, and its antitumor activity, safety, and pharmacokinetic profile in patients with advanced adrenocortical carcinoma.

Study Design:

This was an investigator-initiated, single-arm, phase 2 trial conducted at the University of Texas MD Anderson Cancer Center. Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for curative surgery, and had measurable disease. The trial’s primary endpoint centered on progression-free survival at four months, evaluated across all participants receiving at least one dose of the study drug, cabozantinib, administered orally at 60 mg daily.

What We Learned:

The trial enrolled 18 patients, meeting its primary endpoint, with a 72.2% progression-free survival at four months and a median progression-free survival of six months. Notably, treatment-related adverse events of grade 3 or worse were reported in 61% of the patients, with manageable and anticipated safety profiles.

Key Results:

• Notable anti-tumor activity was recorded, with 11% (2/18) achieving a partial response and 78% attaining a complete response, partial response, or stable disease.
• Among the 10 patients with cortisol-producing tumors, 7 (70%) had stable disease, and one individual had a partial response.
• Cabozantinib was generally well-tolerated, with 11 (61%) of 18 patients experiencing grade 3 or 4 treatment-related adverse events. The most common were lipase elevation, elevated liver enzymes, and hypertension.
• Pharmacokinetic analysis showed that previous mitotane use reduced cabozantinib concentrations, suggesting the need to consider mitotane exposure in future studies.
• Exploratory analyses indicated that cabozantinib may have immunomodulatory effects, including reducing regulatory T-cell levels in the circulation.

Key Highlights:

• Cabozantinib demonstrated promising anti-tumor activity in advanced adrenocortical carcinoma, with the majority of patients achieving disease control.
• Cabozantinib had a manageable safety profile, with dose reductions effectively managing adverse events.
• Previous mitotane exposure may have reduced cabozantinib efficacy by altering its pharmacokinetics.
• Cabozantinib may have immunomodulatory effects, potentially supporting its use in combination with immunotherapy.

Key Takeaway Messages:

This prospective phase 2 trial provides the first evidence that a targeted therapy, cabozantinib exhibits promising therapeutic potential in advanced adrenocortical carcinoma, with a safety profile consistent with its known pharmacodynamics. The findings support further investigation of cabozantinib, both as a single agent and in combination with immune checkpoint inhibitors, in this rare and aggressive malignancy.

Summary by Amalya Sargsyan, MD

Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial