Cabozantinib Extends Progression-Free Survival in Metastatic Carcinoma

Cabozantinib significantly improved progression-free survival and response rate compared to sunitinib in patients with metastatic renal cell carcinoma during a recent trial.

Just like sunitinib, cabozantinib targets vascular endothelial growth factor receptors (VEGFR). However, this tyrosine kinase inhibitor also inhibits the action of AXL and MET.

“Both MET and AXL seem to be associated with tumor progression but more importantly, animal models showed that the development of resistance to VEGFR inhibitors like sunitinib can be mediated through AXL and MET,” said principal study investigator Toni Choueiri.

The multicenter phase 2 trial involved 157 patients with untreated clear-cell metastatic renal cell carcinoma of intermediate or poor risk. Participants were randomized to receive either 60-mg oral cabozantinib once daily, or 50-mg sunitinib once daily, 4 weeks on and 2 weeks off.

The results of the study showed that patients who received cabozantinib had a 31% reduction in the median rate of progression or death compared with patients treated with sunitinib (8.2 months versus 5.6 months, p=0.012). Additionally, the objective response rate was also found to be significantly higher in the cabozantinib group (46%) compared with the sunitinib group (18%).

“Cabozantinib is currently approved for second or later lines of therapies, after patients have progressed on a VEGFR tyrosine kinase inhibitor, but this data shows that cabozantinib has the potential to become a first-line standard treatment,” Choueiri said.

Adverse events were found to be similar among the 2 study arms, with an incidence of grade 3 or higher in 70% of patients in the cabozantinib arm and 72.2% in the sunitinib arm. The most common adverse events for both treatment groups included diarrhea, fatigue, hypertension, palmar-plantar erythrodysesthesia, and hematological events.

There were 16 patients from each study arm that ended treatment early due to toxicity.

“For many years, sunitinib has been the most commonly used standard of care for first-line metastatic renal cell carcinoma, and recently, cabozantinib was proven to be active in second-line, especially after sunitinib failure,” commended Bernard Escudier, chairman of the renal cancer unit at Institut Gustave-Roussy.

The authors noted that the study excluded good-risk patients, but that there was no biological or clinical rationale to believe that cabozantinib would not be equally effective in that population.

“Obviously, the study will raise a lot of questions, such as whether these results are expandable to all metastatic renal cell carcinoma patients, including the good prognosis group; whether cabozantinib should become a new standard of care in the first-line setting; and how we should interpret all the ongoing phase 3 first-line studies which selected sunitinib as the control arm,” Escudier said. “While more mature data and additional studies using cabozantinib in the first-line setting will be required, this study raises a lot of new expectations for the treatment of metastatic renal cell carcinoma.”