1. Carlson, Robert H.

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A sub analysis now available from the phase III METEOR trial amplifies that study's initial results, showing that across a wide variety of subgroups, patients with advanced renal cell carcinoma benefit more from the tyrosine kinase inhibitor (TKI) cabozantinib than from the current second-line standard of care, the mTOR inhibitor everolimus.

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The new data on 658 patients reported at the Genitourinary Cancer Symposium 2016 show that cabozantinib's activity was independent of prior treatment, sites of disease, and risk level (Abstract 499).


However, the researchers said that toxicity was an issue with cabozantinib, a multi-targeted TKI.


The symposium is sponsored by the American Society for Radiation Oncology, American Society of Clinical Oncology, and the Society of Urologic Oncology.


Sumanta Pal, MD, an ASCO spokesperson and moderator of a presscast where the report was previewed before the meeting, said the METEOR study is unique in that it accrued a broad base of patients, including patients with brain metastases, those who received any number of prior therapies, including TKIs, and those who could have been exposed to immune-based treatments such as PD-1/PD-L1 inhibitors.


"The magnitude of benefit patients get from cabozantinib far exceeds, in my opinion, what we have seen in this setting both in delay and tumor growth and improving survival," Pal said. Pal is also Assistant Professor and Co-Director of the Kidney Cancer Program, City of Hope. "And it appears that cabozantinib works very well in some very challenging clinical scenarios such as metastases to bone."


Details on METEOR Study

Bernard Escudier, MD, lead author of the paper, said METEOR patients were randomly selected to receive cabozantinib 60 mg daily orally (330 patients), or everolimus 10 mg daily orally (328 patients). No cross-over between the arms was allowed. Tumor assessment was made every eight weeks.


Escudier, Chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France, said an interim analysis published in 2015 on the first 375 METEOR patients showed improvement in progression-free survival of 7.4 months for cabozantinib versus 3.8 months for everolimus, accompanied by a significant improvement in overall response rate and a trend for improved overall survival (Choueiri et al. N Engl J Med. 2015;373:1814-1823).


Escudier reported here that progression-free survival continued to favor cabozantinib in the full METEOR cohort of 658 patients.


All patients had measurable advanced renal cell carcinoma who had progressed on prior VEGFR TKI within six months of enrollment. There was no limit on the number of prior treatments, and prior treatment with antibodies targeting PD-1 or PD-L1 were allowed.


Data Analysis

The new analysis of data showed a response rate of 75 percent in patients treated with cabozantinib, compared with 48 percent of everolimus-treated patients. There was again a trend for improved overall survival for patients receiving cabozantinib compared with everolimus.


Importantly, improvement in progression-free survival was seen in all subgroups, including those with poor Memorial Sloan Kettering Cancer Center (MSKCC) and Eastern Cooperative Oncology Group (ECOG) performance status (5.4 months versus 3.5 months), patients with three or more organ metastases (7.3 months versus 3.7 months), tumor burden (5.6 months versus 1.9 months), and two or more prior VEGF TKIs (7.4 months versus 4 months).


Cabozantinib is an oral small molecule inhibitor of tyrosine kinases, including MET, VEGF, and AXL. Inactivation of the von Hippel-Lindau tumor suppressor protein in clear cell renal cell carcinoma results in upregulation of VEGF, MET, and AXL, associated with poor prognosis and resistance to VEGF inhibitors.


Toxicity an Issue

Escudier said cabozantinib's mechanism is not "pure," as it inhibits several tyrosine kinases. These are all triggered by previous VEGF exposure, and the multi-targeted action has led to numerous side effects.


"The toxicity issue has led to a decrease in cabozantinib dosing in many patients," he said. "We started at 60 mg, a lot below what has been used in thyroid and prostate cancer, and still we had to decrease the dose in quite a few patients."


Skin toxicity, fatigue, diarrhea, and hypertension are all common toxicities with TKIs in general, he said.


Pal, the session moderator, said clinicians will have to choose a balance between an immunotherapy agent such as nivolumab, or cabozantinib in the second-line setting.


"I certainly think the efficacy data Dr. Escudier has shown is compelling, with a doubling in progression-free survival and an improvement in overall survival, but certainly there is the toxicity issue to weight out."


The most common side effects in METEOR related to cabozantinib were diarrhea, fatigue, nausea, decreased appetite, and hand-foot syndrome. The most common side effects associated with everolimus included fatigue, anemia, decreased appetite, cough, and dyspnea.


New Option for Previously Treated Advanced Kidney Cancer

During the presscast, moderator Pal said to bear in mind that kidney cancer is not common, comprising only 3 percent of all cancers, though the incidence has been steadily rising over the past three decades.


"Given the fact that cabozantinib has a very compelling benefit in terms of delay in tumor growth and a hint in terms of overall survival, I would personally favor it as a second-line option as compared to other drugs such nivolumab in that setting," Pal said.


There are certain merits with nivolumab, Pal added, such as a more favorable toxicity profile compared with cabozantinib. "But in broad terms, patients are very focused on clinical efficacy, and with that in mind the data for cabozantinib truly speaks for itself," he said.


The METEOR study received funding from Exelixis, Inc.


Cabozantinib was approved by the U.S. Food and Drug Administration in November 2012, for the treatment of medullary thyroid cancer (OT 12/25/12 issue). It is undergoing clinical trials in a wide variety of solid tumors, including prostate, bladder, ovarian, and brain.