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Cabozantinib (XL184), a novel tyrosine kinase inhibitor, caused the deaths of 6 patients in a phase II clinical trial.
Nicholas J. Vogelzang, MD
Cabozantinib (XL184), a novel tyrosine kinase inhibitor, caused the deaths of 6 patients in a phase II clinical trial, according to data presented at ASCO’s annual meeting. The fatalities had not been reported with the cabozantinib data at the May 18 pre-ASCO press briefing. Shares of the drug’s manufacturer, Exelixis, fell 20% as investors reacted to the news.
The fatal cabozantinib-related adverse events affected patients across multiple tumor sites, including breast cancer (respiratory compromise), non—small cell lung cancer (NSCLC, hemorrhage), ovarian cancer (enterocutaneous perforation, intestinal perforation), pancreatic cancer (gastrointestinal hemorrhage), and castrate-resistant prostate cancer (CRPC, unexplained). The 6 deaths comprised 1% of the 490 patients treated in the study.
Reacting to the news, Nicholas J. Vogelzang, MD, Comprehensive Cancer Centers of Nevada in Las Vegas, and a co-author of the study, quoted Shakespeare to note the difficult realities of treating cancer, “Diseases desperate grown / By desperate appliance are relieved, / Or not at all (Hamlet).”
Expanding upon this sentiment, Vogelzang explained that cabozantinib’s toxicities are commensurate with other drugs in its class, and the drug offers a tremendous upside. “Even amazingly good drugs do on rare occasions cause serious injury and sometimes death. We have to be careful and the patients have to be aware of it, but the risk-benefit ratio is still strongly in favor of benefit for the drug.”
Vogelzang did note that altered regimens and lowered doses are being explored.
Cabozantinib inhibits the MET and VEGFR2 pathways, which contribute to the genesis and growth of tumor cells. The 9-arm phase II trial included patients with pancreatic cancer, CRPC, hepatocellular carcinoma (HCC), gastric or gastroesophageal junction cancer, melanoma, small—cell lung cancer, ovarian cancer, breast cancer, and NSCLC.
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All patients initially received 100 mg of cabozantinib daily, and then treatment was either maintained or discontinued based on efficacy.
At 12 weeks’ follow-up, significant disease control rates (partial response + stable disease) were noted in HCC (73%), CRPC (68%), ovarian cancer (53%), melanoma (47%), breast cancer (45%), and NSCLC (40%).
Bone scans also revealed that bone metastases decreased in several arms, including CRPC, melanoma, and breast cancer. Bone scan resolution was highest in patients with CRPC at 86%.
The highly beneficial results for CRPC and ovarian cancer led to the expansion of both tumors’ cohorts. The data for these arms were presented in separate sessions at ASCO (CRPC, abstract 4516; ovarian cancer, abstract 5008).
The most commonly reported adverse events included fatigue (13%), PPE syndrome (7%), diarrhea (5%), and hypertension (5%).
Exelixis plans to commence a pivotal phase III trial of cabozantinib in prostate cancer by the end of the year. The company has already started a phase III trial of cabozantinib in advanced medullary thyroid cancer.
Gordon MS, Vogelzang NJ, Schoffski P, et al. Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors. J Clin Oncol. 2011. (suppl; abstr 3010)