Cabozantinib Could Be First-Line Choice in Advanced RCC

Liam Davenport

October 11, 2016

COPENHAGEN — First-line treatment of metastatic kidney cancer could be set for change, with new results showing that the oral tyrosine kinase inhibitor cabozantinib (Cabometyx, Exelixis) significantly improved progression-free survival when compared with the standard-of-care drug sunitinib (Sutent, Pfizer).

In a phase 2 study that focused on patients with an intermediate or poor prognosis, cabozantinib improved progression-free survival by 31% and substantially improved the objective response rate, according to data presented here at the European Society for Medical Oncology (ESMO) Congress 2016.

Lead researcher Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, said in a press release: "Cabozantinib is currently approved for second or later lines of therapies, after patients have progressed on a VEGFR [vascular endothelial growth factor receptor] tyrosine kinase inhibitor, but this data shows that cabozantinib has the potential to become a first-line standard treatment."

Dr Toni Choueiri

However, an expert not involved in the study, Bernard Escudier, MD, chairman of the renal cancer unit at Institut Gustave-Roussy, France, said that the new results "raise a lot of questions" and that more mature data are needed. Sunitinib has been for many years the most commonly used standard of care for first-line metastatic renal cell carcinoma (RCC), he commented.

Previous studies have shown that cabozantinib is a potent inhibitor of not only VEGFRs but also MET and AXL, which may mediate the development of resistance to VEGFR inhibitors, such as sunitinib. In clinical trials in the second-line setting, cabozantinib has shown activity in patients who are no longer responding to sunitinib.

Head-to-Head Comparison in First Line

The phase 2 study (known as CABOSUN) was conducted in 157 patients with untreated clear-cell metastatic RCC who had a European Cooperative Oncology Group performance status of 0 to 2 and were of intermediate or poor prognostic risk. They were randomly assigned to receive oral cabozantinib, 60 mg once daily, or sunitinib, 50 mg once daily, in 6-week cycles of 4 weeks on, 2 weeks off.

The cabozantinib group received a median of five 6-week treatment cycles vs two with sunitinib, and 17% of the cabozantinib group and 3% of the sunitinib group remained on therapy.

Median investigator-assessed progression-free survival (PFS) with cabozantinib was significantly longer than that seen in patients receiving sunitinib, at 8.2 months vs 5.6 months, for a hazard ratio of 0.69 (P = .012).

The overall response rate was also higher with cabozantinib than with sunitinib, at 46% vs 18%.

In addition, preliminary data suggest an increase in overall survival (OS), with a median OS of 30.3 months for cabozantinib vs 21.8 months for sunitinib (adjusted hazard ratio, 0.80; 95% confidence interval, 0.50 - 1.26).

In terms of safety, a similar proportion of patients experienced any grade 3/4 adverse events in the cabozantinib and sunitinib groups (65% and 68%, respectively). The most common grade 3/4 events with cabozantinib were hypertension (28%), diarrhea (10%) and palmar-plantar erythrodysesthesia (8%), and those with sunitinib were hypertension (22%), fatigue (15%), thrombocytopenia (11%), and diarrhea (11%).

More dose reductions occurred with cabozantinib: 58% of patients vs 49% of those in the sunitinib group. However, this did not affect the proportion of patients who discontinued therapy because of an adverse event, at 20% and 21%, respectively.

Speaking at an ESMO press conference, Dr Choueiri said that sunitinib "is the standard of care and the most used agent in first-line metastatic RCC."

However, as cabozantinib was associated with improvements in PFS and overall response over sunitinib, he continued: "I do believe that cabozantinib represents a potential first-line treatment option in patients with advanced RCC."

Dr Choueiri nevertheless noted that, while he would consider using cabozantinib in his patients, "it's all going to depend on if the drug is approved or not [for this indication of first-line use], not just on my personal opinion of the data," adding: "But I think the evidence is there…I would make the leap of faith."

Discussing the study after the findings were presented, Dr Escudier noted the many changes recently made to the recommendations for the treatment of metastatic RCC, but these were primarily in terms of second- and third-line therapy.

In contrast, the first-line therapy recommendations have not changed since 2009, despite many different approaches having been investigated in the interim. He noted that nevertheless several studies are in the pipeline.

Turning to cabozantinib, Dr Escudier asked, "Why should we use cabozantinib in the first line?" One reason is that the drug is a "potent" VEGFR inhibitor; another is that it has activity against MET, expression of which is increased in patients with a poor prognosis.

Although he considers the response rate with cabozantinib in the current findings "very impressive," he added that "we cannot say, so far, that survival is improved," and the findings should be interpreted with "a lot of caution."

The data, Dr Escudier said, are "not convincing enough" to recommend cabozantinib as a first-line therapy at this stage, but it remains "a major breakthrough" for the treatment of metastatic RCC and a phase 3 study "is warranted."

The study was funded by Exelixis. Dr Choueiri has received institutional funds from Exelixis and Pfizer and advisory board compensation from Pfizer. No other relevant financial relationships have been disclosed.

European Society for Medical Oncology (ESMO) Congress 2016. Abstract LBA30_PR. Presented October 10, 2016.

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