Dual Pathway Inhibitor Shows Broad Activity in Multiple Tumor Types

Roxanne Nelson

May 23, 2011

May 23, 2011 — A novel experimental agent that inhibits 2 pathways of tumor growth has shown broad activity in multiple tumor types and also "unprecedented" activity on bone metastases.

Cabozantinib (Exelixis), which is an oral inhibitor of both MET and vascular endothelial growth factor 2 (VEGFR2), showed strong responses in patients with a variety of advanced cancers. The drug is currently in phase 2 trials.

"Cabozantinib demonstrated antitumor activity in 12 of 13 tumor types studied," explained lead study author Michael S. Gordon, MD, who presented highlights of the findings at a press briefing held in advance of the American Society of Clinical Oncology (ASCO) 47th Annual Meeting.

It also showed "unprecedented bone scan improvement," said Dr. Gordon, a medical oncologist at Pinnacle Oncology Hematology in Scottsdale, Arizona.

Particularly high rates of disease control were observed for advanced prostate, ovarian, and liver cancers, and treatment with cabozantinib also completely or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Dr. Gordon and colleagues evaluated the clinical efficacy and safety of cabozantinib in a phase 2 randomized discontinuation trial in a cohort of 483 patients with advanced solid tumors. All eligible patients had progressive measurable disease with or without bone metastasis, and of 398 evaluable patients, 39% had bone metastases at baseline.

Study participants received 100 mg of cabozantinib during a 12-week lead-in stage, and tumor response was assessed every 6 weeks. Treatment beyond week 12 was dependent on response: patients with a partial response continued with open-label cabozantinib, those with stable disease were randomized to drug vs placebo, and patients with progressive disease discontinued treatment.

High Rates of Disease Control

The primary endpoint in the lead-in stage was overall response rate, and accrual in any cohort could be halted for either high rates of overall response or progressive disease.

The overall response rate at 12 weeks was only 9%; responses rates were 24% for ovarian cancer, 14% for hepatocellular cancer, 5% for prostate cancer, 10% for non–small cell lung cancer, 10% for breast cancer, 5% for small cell lung cancer, and 5% for melanoma. However, high levels of disease control were observed in certain tumor types.

"The disease control rate, characterized by either stable or responding disease, ranged from 40% for non–small cell lung cancer to up to 76% for primary hepatocellular carcinoma, with prostate cancer, ovarian cancer, melanoma, and breast cancer falling between," explained Dr Gordon.

"Importantly," he added, "There was evidence of tumor shrinkage in both lymph nodes and visceral organs."

As a result of what was considered to be high response rates for bone metastases in prostate cancer and soft tissue metastases in ovarian cancer, randomization for those groups was halted. "These cohorts have been expanded to a nonrandomized phase 2 trial with 150 patients in each diagnosis," said Dr. Gordon, "And the results of which will be presented at ASCO."

Table 1. Highest Rates of Disease Control at Week 12

Cancer Type Disease Control at Week 12, %
Hepatocellular 76
Prostate 71
Ovarian 58
Melanoma 45
Breast 45
NSCLC 40

NSCLC = non–small cell lung cancer

Reduction of Bone Metastases

The findings for bone metastases were particularly noteworthy because they included patients with breast cancer, prostate cancer, and melanoma who experienced either partial or complete resolution of the metastasis on bone scans. Overall, 59 of 68 patients with bone metastases achieved a response.

The partial or complete disappearance of bone metastases was generally accompanied by relief of pain and a reduced need for medications, explained Dr. Gordon. Improvement in symptoms was often seen by 6 weeks.

He also emphasized that bone scan improvements were not limited to prostate cancer but have also been seen in patients with bone cancer, melanoma, kidney cancer, and thyroid cancer — the last 2 cancers in separate independent studies of cabozantinib.

They also observed osteoclast effects across tumor types and sustained increases in hemoglobin in anemic patients.

The most common grade 3 or higher adverse events in the study were fatigue (9%), hand-foot syndrome (8%), and hypertension (5%). The discontinuation rate for adverse events was 12%, and dose reductions were required by 41% of the cohort.

"Expansion cohorts are enrolling for prostate and ovarian cancer," Dr. Gordon said, "And additional cohorts are under consideration for expansion. The sponsor Exelixis plans to initiate the first pivotal trial in prostate cancer by the end of 2011 and will evaluate a novel bone metastasis endpoint."

The pivotal trial in medullary thyroid cancer has already full enrolled, he added, and an analysis is under way.

Mark G. Kris, MD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center, New York City, and chair of cancer communications for ASCO, commented that in this study, "we see early signs of the benefit of going after not just one pathway but going after the entire network — the power grid.

"Here we are attacking multiple targets, and in this case, MET and VEGF," said Dr. Kris. "We saw some very important tumor shrinkages."

Even more importantly, he added, this translated into a reduction of pain and stronger bones among those with bone metastases.

The study was funded by Exelixis, the manufacturer of cabozantinib. Dr. Gordon has disclosed no relevant financial relationships. Several coauthors disclosed stock ownership in and/or employment with Exelixis.

American Society of Clinical Oncology (ASCO) 47th Annual Meeting: Abstract 3010. To be presented June 5, 2011.

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