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Cabozantinib superior to everolimus in advanced kidney cancer
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Cabozantinib, a small molecule tyrosine kinase inhibitor, extended survival and increased response rates compared with standard everolimus among patients with previously treated advanced kidney cancer, according to phase 3 study results presented at the Genitourinary Cancers Symposium.
Incidence of renal cell carcinoma — the most common form of kidney cancer — is increasing worldwide. Standard treatments include VEGFR inhibitors, as well as mTOR inhibitors such as everolimus (Afinitor, Novartis).
Bernard J. Escudier
“Current treatments can provide some benefit to patients with advanced kidney cancer, but we need treatments that are more effective,” Bernard J. Escudier, MD, chair of the genitourinary oncology committee at Institut Gustave Roussy in Villejuif, France, said in a press release. “Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope to patients with this aggressive cancer.”
Cabozantinib (Cometriq, Exelixis) received FDA approval for treatment of patients with a specific type of thyroid cancer. The agent is under evaluation in clinical trials for treatment of a variety of other malignancies, including kidney cancer.
Escudier and colleagues conducted the phase 3 METEOR study to compare cabozantinib to standard treatment for previously treated RCC.
The analysis included 658 patients, all of whom progressed during treatment or within 6 months of their last dose of their most recent VEGFR TKI.
Researchers randomly assigned patients 1:1 to receive a daily dose of 60 mg cabozantinib or 10 mg everolimus.
Results of an interim analysis showed the study met its primary endpoint, revealing a statistically significant improvement in median PFS (7.4 months vs. 3.9 months; HR = 0.52; 95% CI, 0.43-0.64) in cabozantinib-treated patients. Researchers also observed a higher overall response rate (ORR) and a trend toward improved OS in the cabozantinib group.
Based on these results, Escudier and colleagues conducted a secondary subgroup analysis that further evaluated PFS and ORR and compared the safety of the two regimens.
The secondary PFS analysis included 187 patients assigned cabozantinib and 188 assigned everolimus.
Most patients (73%) had undergone treatment with one prior VEGFR TKI, whereas 23% had been treated with two or more. The majority of patients had favorable-risk disease (43%) or intermediate-risk disease (41%).
Results showed the PFS benefit associated with cabozantinib persisted across several subgroups, including those defined by prior number of TKIs (one prior TKI, HR = 0.52; two or more, HR = 0.51) and Memorial Sloan Kettering Cancer Center (MSKCC) risk criteria (zero risk factors, HR = 0.51; one risk factor, HR = 0.47; two or more risk factors, HR = 0.7).
Escudier said he was most intrigued by the improvement in median PFS cabozantinib conferred among patients with MSKCC intermediate-risk status (7.5 months vs. 3.8 months; HR = 0.47; 95% CI, 0.35-0.65), as well as those in patients with visceral and lung metastases (5.6 months vs. 1.9 months; HR = 0.26; 95% CI, 0.16-0.43).
Cabozantinib conferred a considerable median PFS advantage among study participants treated with sunitinib (Sutent, Pfizer) in the first-line setting (9.1 months vs. 3.7 months; HR = 0.43; 95% CI, 0.32-0.59). However, the PFS advantage was not as great among study participants treated with pazopanib (Votrient, Novartis) in the first-line setting (7.4 months vs. 5.1 months; HR = 0.67, 0.45-0.99).
Cabozantinib also conferred longer median PFS among patients who failed prior PD-1 or PD-L1 treatment (not yet estimable vs. 4.1 months; HR = 0.22; 95% CI, 0.07-0.65), although Escudier noted that analysis only included 32 patients.
“Based on this information, cabozantinib is going to become the drug of choice following PD-1 failure, which is important in the future of treatment in this setting,” Escudier said during a press conference.
Overall, a greater percentage of cabozantinib-treated patients demonstrated tumor shrinkage (75% vs. 48%).
Treatment-related adverse effects appeared manageable with supportive care or dose modifications. The most common adverse events among cabozantinib-treated patients were diarrhea, fatigue, nausea, decreased appetite and hand–foot syndrome. The most common treatment-related adverse events in the everolimus group were fatigue, anemia, decreased appetite, cough and dyspnea.
“Cabozantinib has a mixed-action mechanism,” Escudier said. “Based on its multitargeted action, there are still quite a lot of side effects, and toxicity has been an issue in this drug leading to a lot of decreases in dosage. This is certainly an issue when compared to nivolumab (Opdivo, Bristol-Myers Squibb), for example.”
The decision about whether cabozantinib or nivolumab is the best option in the second-line setting likely will be debated until the two agents are compared in a clinical trial, according to Sumanta K. Pal, MD, assistant clinical professor in the department of medical oncology and therapeutics research at City of Hope and moderator of the press conference.
“The efficacy data for cabozantinib is incredibly compelling, with a doubling of PFS and a trend toward OS improvement,” Pal, a HemOnc Today Editorial Board member, said during the press conference. “There are toxicity issues to [consider], but there is no fair comparison between the two drugs. … This is all speculative based on two separate randomized clinical trials. However, these statistics are already compelling. The trend toward improving OS makes a crucial argument to use cabozantinib instead of nivolumab in the second-line setting.” – by Anthony SanFilippo
Reference:
Escudier BJ, et al. Abstract 499. Presented at: Genitourinary Cancers Symposium; Jan. 7-9, 2016; San Francisco.
Disclosure: The study was funded by Exelixis. Escudier reports consultant or advisory roles with Bayer, Bristol-Myers Squibb, Exelixis, GlaxoSmithKline, Novartis and Pfizer, as well as honoraria from Bayer, GlaxoSmithKline, Novartis and Pfizer. Please see the abstract for a list of all other researchers’ relevant financial disclosures.