Cabozantinib Shows Potential for First-Line RCC

Treatment with cabozantinib resulted in significantly improved progression-free survival and overall response compared with sunitinib for patients with previously untreated intermediate- or poor-risk metastatic renal cell carcinoma (RCC), according to the results of the Alliance A031203 trial (abstract LBA30_PR) presented at the European Society for Medical Oncology (ESMO) 2016 Congress, held October 7–11 in Copenhagen, Denmark.

Unlike sunitinib, which targets only vascular endothelial growth factor (VEGF), cabozantinib inhibits MET, AXL, and VEGFR2.

“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 investigator Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston.

In this phase II trial, Choueiri and colleagues enrolled 157 patients with untreated clear-cell RCC and randomly assigned them to cabozantinib (n = 79) or sunitinib (n = 78). All patients had a performance status of 0 to 2 and were classified as intermediate- or poor-risk.

After a median follow-up of 20.8 months, 16.46% of patients remained on cabozantinib compared with 2.56% of patients assigned sunitinib.

The median progression-free survival was significantly higher for patients assigned cabozantinib (8.2 vs 5.6 months), with a 31% reduction in the rate of progression or death (adjusted hazard ratio, 0.69 [95% CI, 0.48–0.98]; P = .012). Forty-six percent of patients assigned cabozantinib had a response compared with 18% for sunitinib.

Grade 3 or worse adverse events occurred in 70.5% of patients assigned cabozantinib compared with 72.2% of patients in the sunitinib arm. The most common adverse events for both treatments included diarrhea, fatigue, hypertension, palmar-plantar erythrodysesthesia, and hematologic events. Sixteen patients in each arm had to end treatment due to toxicity.

Although this study did not include patients with good-risk disease, Choueiri commented that there was no biological or clinical rationale to think that cabozantinib would not be equally effective in those patients.

“For many years, sunitinib has been the most commonly used standard of care for first-line metastatic RCC, and recently, cabozantinib was proven to be active in second line, especially after sunitinib failure,” said Bernard Escudier, MD, chairman of the renal cancer unit at Institut Gustave-Roussy in France, commenting on the study. “Obviously, this study will raise a lot of questions, such as whether these results are expandable to all metastatic RCC 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 III first-line studies which selected sunitinib as the control arm.”