The data presented are from a cohort of 25 RCC patients enrolled in an ongoing phase 1b drug-drug interaction study of cabozantinib at the phase 1 maximum tolerated dose (MTD) in patients with advanced solid tumors. Patients in this trial receive 140 mg of oral cabozantinib administered daily and a single dose of rosiglitazone at day 22. The study endpoints are safety, tolerability, and anti-tumor activity. All patients had histologically confirmed RCC (with clear cell components) and metastases, were refractory to or had progressed following standard therapy, and had measurable disease per RECIST. This was a heavily pre-treated population, with 68% of patients receiving >2 prior systemic agents and 32% receiving >4 prior systemic agents. Prior therapies included anti-VEGF pathway therapy (88%) and mTOR inhibitor therapy (60%), with 52% of patients receiving both an mTOR inhibitor and at least 1 anti-VEGF pathway therapy. Bone metastases were present at baseline in 4 patients (16%), one of whom was followed by bone scan.
Tumor Regression. Objective evidence of tumor regression was observed in 19 of 21 patients (90%) with =1 post-baseline assessment. Best overall response was determined per RECIST criteria with 7 of 25 patients (28%) showing a confirmed partial response (PR). Importantly, PRs were observed in heavily pretreated patients, including 3 patients with 2-4 prior systemic therapies, and 2 patients with >4 prior systemic therapies. Thirteen additional patients (52%) had stable disease (SD) as their best response, and only a single patient (4%) demonstrated evidence of primary refractoriness to cabozantinib with a best overall response of progressive disease. The rate of disease control (PR + SD) at week 16 for all 25 patients is 72%.
Progression-Free Survival, Overall Survival, and Treatment Duration. Kaplan Meier estimate of median progression-free survival (PFS) is 14.7 months (95% CI, lower limit 7.3 months – upper limit not reached). Median overall survival (OS) has not yet been reached after median follow-up of 14.7 months. The estimated 1-year survival rate is 60%. Seven patients remain on study and progression free with treatment durations ranging up to 21.8+ months.
Radiographic and Bone Scan Response. One patient with sarcomatoid differentiation and bone and soft tissue involvement who had previously been treated with four systemic agents including sunitinib and everolimus had a radiographic response at week 8. Also, as previously reported, a partial bone scan resolution was observed at week 7 in a patient with bone metastases who was followed by bone scan and had previously been treated with sorafenib, sunitinib, and everolimus. The patient also substantially reduced narcotic use by week 7 and continued on reduced narcotics until week 25. A second patient with bone metastases and bone pain at baseline reported complete resolution of pain by week 4 and remains pain free at week 90.
“Up to 25% of RCC patients initially treated with anti-VEGF pathway therapy are refractory to such agents, and these patients have few treatment options,” said Dr. Choueiri. “The clinical benefit observed with cabozantinib is encouraging, particularly in highly pretreated patients who are refractory to anti-VEGF and anti-mTOR therapies or who have had disease progression while on these agents. Additionally, the improvements in bone lesions and bone pain are also encouraging, especially given that bone metastases occur in up to 30% of RCC patients. Existing RCC therapies have minimal impact on bone disease, and cabozantinib may be able to address this medical need. Cabozantinib has the potential to be a meaningful addition to the treatment of RCC.”
Safety results for the Phase 1 MTD of 140 mg are consistent with those observed in other trials of cabozantinib and with other tyrosine kinase inhibitor therapies. The most frequently reported adverse events (AEs) Grade = 3 or higher, regardless of causality, were: hypophosphatemia (36%), hyponatremia (20%), fatigue (16%), diarrhea (12%), proteinuria (8%), decreased appetite (4%), vomiting (4%), hand-foot syndrome (4%). Grade = 3 hypertension was seen in 8% of patients and was considered an AE of interest due to the increased incidence of hypertension observed with other VEGF inhibitors. No grade 5 AEs were reported.
“We continue to be encouraged by the high tumor response rate, PFS time, and the estimated 60% 1-year survival rate from this trial in a very heavily-pretreated patient population,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “Taken together, the data demonstrate cabozantinib’s potential role to improve care and outcomes for patients with RCC. A randomized phase 2 trial in first-line RCC using a 60 mg dose is planned under our Cooperative Research and Development Agreement with the National Cancer Institute’s Cancer Therapy Evaluation Program and should provide further insight into cabozantinib’s clinical and commercial potential in this indication.”
