Exelixis Inc., a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer, has reported preliminary data from a cohort of heavily pretreated patients with metastatic refractory renal cell carcinoma (RCC) participating in an ongoing phase 1b trial of cabozantinib.

Toni K Choueiri, MD, director of the Kidney Cancer Centre at the Dana-Farber Cancer Institute, will present the data (Abstract #364) in a poster session at the 2012 Genitourinary Cancers Symposium in San Francisco.

As of the January 18, data cut-off, 25 RCC patients were enrolled with 88 per cent having received prior anti-VEGF therapy, 60 per cent having received prior mTOR inhibitor therapy, and 52 per cent having received =1 anti-VEGF and 1 mTOR therapy. Sixty-four percent of patients received = 2 prior anti-cancer agents. Tumour 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%. Kaplan Meier estimate of median progression-free survival is 14.7 months (95% CI, lower limit 7.3 months – upper limit not reached). Ten patients remain on study and progression free with treatment durations ranging up to 16.4 months.

One patient with symptomatic bone metastases was followed by bone scan. A partial bone scan resolution was observed at week 7 in this patient who 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 73.

The data presented are from a cohort of 25 RCC patients enrolled in an ongoing phase 1b drug interaction study of cabozantinib in patients with advanced solid tumours. Patients in this trial receive 140 mg of oral cabozantinib administered daily, and the study endpoints are safety, tolerability, and anti-tumour activity. The RCC 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. Bone metastases were present at baseline in 4 patients (16%), one of whom was followed by bone scan.

“The high rate of durable tumour response, very low rate of primary refractoriness to drug therapy, and the long median progression-free survival observed in these heavily pretreated RCC patients are very encouraging,” said Michael M Morrissey, PhD, president and chief executive officer of Exelixis. “Additionally, the bone scan response and reduction in narcotic usage in two of the four patients with bone metastases are consistent with the positive effects that we have observed for cabozantinib with respect to bone lesions in patients with castration-resistant prostate cancer and metastatic breast cancer. The data presented support continued study of cabozantinib in patients with advanced RCC, and we hope to pursue such studies as part of our recently announced Cooperative Research and Development Agreement with the National Cancer Institute’s Cancer Therapy and Evaluation Programme.”

No new safety signals were observed. The most frequently reported grade = 3 adverse events (AEs), regardless of causality were: hypophosphatemia (36%), hyponatremia (20%), both manageable with substitution with or without cabozantinib dose reduction or interruption, fatigue (16%), diarrhoea (12%), proteinuria (8%), palmar-plantar erythrodyesthesia (4%), and vomiting (4%).

“These data indicate that cabozantinib can provide clinical benefit to patients with advanced RCC, including those who have received anti-VEGF therapy, anti-mTOR therapy, or a sequence of these targeted therapies,” said Dr. Choueiri. “While anti-VEGF and anti-mTOR therapies have advanced the treatment of RCC, many patients are refractory to these agents and experience disease progression. Dual inhibition of both VEGFR2 and MET by cabozantinib may provide an alternative or additional mechanism for controlling disease in these patients, and further study of cabozantinib in this indication is warranted.”

Cabozantinib is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumour cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumour types. MET is upregulated in many tumour types, thus facilitating tumour cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumour environment, which are often exacerbated by selective VEGF-pathway inhibitors.

The vast majority of RCC cases have an inactivation of the von Hippel-Lindau tumour suppressor gene, which mimics a hypoxic state and triggers upregulation of both VEGF and MET expression. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including: extensive apoptosis of malignant cells, decreased tumour invasiveness and metastasis, decreased tumour and endothelial cell proliferation, blockade of metastatic bone lesion progression and disruption of tumour vasculature.