Dr Iglesia on the COSMIC-312 Trial of Cabozantinib Plus Atezolizumab in HCC

Michael Iglesia, MD, PhD, instructor, John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, discusses key efficacy and safety data from the phase 3 COSMIC-312 trial (NCT03755791) of first-line cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) in hepatocellular carcinoma (HCC).

The open-label, randomized COSMIC-312 study compared cabozantinib plus atezolizumab with sorafenib (Nexavar) in the first-line treatment of patients with HCC, Iglesia begins. The primary end points of the study were progression-free survival (PFS) and overall survival (OS) in the intention-to-treat population. At the first interim analysis, the combination of atezolizumab and cabozantinib did not show improvements in median OS, thereby failing to meet the trial's primary end point, Iglesia states. This outcome contrasts with results observed in the phase 3 IMbrave150 trial (NCT03434379), which evaluated the VEGF-targeting agent bevacizumab (Avastin) in combination with atezolizumab in HCC, he adds.

Notably, the addition of cabozantinib to atezolizumab treatment in COSMIC-312 resulted in added toxicities compared with sorafenib, Iglesia states. The rate of grade 3 or worse adverse effects (AEs) was 57%, with 7% of patients experiencing grade 4 AEs and 12% having grade 5 events in the investigational treatment group. Additionally, 60% of patients required dose reductions of at least 1 drug, and approximately 14% discontinued at least 1 drug due to AEs, he details.

The observed safety profile of the COSMIC-312 regimen included expected toxicities of cabozantinib, such as hypertension and diarrhea, along with immune-related AEs associated with atezolizumab, Iglesia continues. This pattern of AEs underscores the need for careful management and monitoring when combining VEGF-targeting TKIs with immune checkpoint inhibitors in the treatment of HCC, he explains.

Although COSMIC-312 did not demonstrate the expected efficacy benefits seen in other trials, the findings contribute valuable insights into the challenges and considerations surrounding the use of combination therapies in advanced HCC, Iglesia emphasizes. The lack of improvement in OS in the COSMIC-312 trial highlights the complexity and variability among VEGF-targeting TKIs when used in immunotherapy combinations, underscoring the challenge of identifying the critical targets or combinations necessary to achieve therapeutic benefit in HCC, he concludes.