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Cabozantinib salvage therapy demonstrates activity in differentiated thyroid cancer
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Salvage therapy with cabozantinib appeared active in patients with radioiodine-refractory differentiated thyroid cancer who experienced disease progression on prior VEGFR-targeted therapies, according to results of a phase 2 trial.
The VEGFR inhibitors sorafenib (Nexavar, Bayer) and lenvatinib (Lenvima, Eisai) are approved for frontline therapies for radioiodine-refractory differentiated thyroid cancer. However, most patients develop resistance to these agents, and there are no approved second- or third-line therapies.
“Although the prognosis is good, with more than 90% of patients experiencing long-term survival, patients who develop advanced or radioiodine-refractory disease represent a major therapeutic challenge,” Maria E. Cabanillas, MD, oncologic endocrinologist in the department of endocrine neoplasia and hormonal disorders at The University of Texas MD Anderson Cancer Center, and colleagues wrote.
A phase 1 trial of cabozantinib (Cometriq, Exelixis) — an oral multikinase inhibitor of c-MET, RET and VEGFR — induced objective response in five (62%) of eight patients with differentiated thyroid cancer who underwent one prior treatment with VEGFR-targeted therapy.
Cabanillas and colleagues conducted a multicenter, single-arm phase 2 stud to evaluate cabozantinib in 25 patients (median age, 64 years; 64% men) with radioiodine-refractory differentiated thyroid cancer that progressed on prior VEGFR-targeted therapy.
Patients received a starting dose of 60 mg oral cabozantinib daily in 28-day cycles. Patients who did not respond to this dose could receive 80 mg.
Objective response rate served as the primary endpoint.
Median follow-up was 22.8 months.
Most patients (n = 21) received only one prior VEGFR-targeted therapy; four patients received two or more lines of such therapy.
Ten patients treated with cabozantinib achieved a partial response, 13 patients achieved stable disease and two had nonevaluable disease.
Median time to partial response was 2 months, and median duration of partial response was 11.3 months (95% CI, 10.3 to not evaluable).
The number of prior VEGFR therapies appeared associated with patient response. Researchers reported partial responses in 10 of 21 patients who received only one prior VEGFR therapy, whereas no patients who received two or more lines of therapy achieved partial response.
“The mechanisms of cabozantinib in inducing partial responses in the second-line setting are not fully established, although they may be related to c-MET-driven resistance induced by previous VEGFR-targeted therapy,” Cabanillas and colleagues wrote. “Neither the thyroid cancer histologic subtype nor dose of cabozantinib was associated with response, whereas one — as opposed to two — prior VEGFR-targeted treatment was associated with a better response rate.”
Researchers reported median PFS of 12.7 months (95% CI, 10.9-34.7), with estimated PFS rates of 55% (95% CI, 38-79) at 12 months and 25% (95% CI, 13-50) at 24 months.
Median OS was 34.7 months (95% CI, 18.3 to not reached), with an estimated OS rates of 80% (95% CI, 65-97) at 12 months and 66% (95% CI, 49-88) at 24 months.
“Although we did not obtain comprehensive genetic profiling of the tumors at study entry, maximum tumor shrinkage was observed in patients with follicular thyroid cancers harboring NRAS mutations and a patient with papillary thyroid cancer harboring KRAS mutation,” Cabanillas and colleagues wrote. “Thus, tumor genotype as a predictor of response to cabozantinib warrants further study.”
Seven patients received 60 mg cabozantinib daily; four patients received escalated doses of 80 mg daily. The researchers reduced dosage for patients who experienced grade 2 or higher adverse events. Six patients received dose reductions to 40 mg daily, and eight patients received reductions to 20 mg daily.
The most common adverse events that led to dose reductions included palmar-plantar erythrodysesthesia (n = 5) and fatigue (n = 4), as well as diarrhea, vomiting, weight loss, mucositis, neutropenia, and increases in aspartate aminotransferase, alanine transaminase and lipase levels.
One death may have been related to treatment with cabozantinib, according to researchers.
Serious adverse events included one case each of grade 1 thrombotic thrombocytopenic purpura, grade 2 deep venous thrombosis and grade 4 perianal hidradenitis suppurativa. Researchers also reported one case each of grade 3 left ventricular systolic dysfunction, asymptomatic increased lipase, osteonecrosis of the jaw, decubitus ulcer, pneumonia and meningitis.
An ongoing trial is comparing 60 mg cabozantinib with the FDA-approved dose of 140 mg cabozantinib to determine whether the agent is better tolerated at lower doses. – by Kristie L. Kahl
Disclosure s : Cabanillas reports a consultant/adviser role with Loxo Oncology, and research funding from Eisai, Exelixis, Genentech/Roche and Kura Oncology. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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