Cabozantinib extended PFS in progressive, metastatic medullary thyroid cancer

Cabozantinib improved PFS by more than 7 months and was associated with a 28% confirmed response rate in patients with documented progressive metastatic medullary thyroid cancer, according to phase 3 results of the EXAM trial.

Phase 1 results indicated cabozantinib (Cometriq, Exelixis) — a tyrosine kinase inhibitor of the hepatocyte growth factor receptor — induced clinical activity in a cohort of patients with medullary thyroid cancer.

In the current double-blind trial, researchers compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic medullary thyroid cancer.

Researchers randomly assigned 220 patients to 140 mg daily cabozantinib; the other 110 received placebo. PFS served as the primary outcome measure. Secondary outcome measures included OS, safety and tumor response rate.

Median PFS was 11.2 months in the cabozantinib group and 4 months in the placebo group (HR=0.28; 95% CI, 0.19-0.40). Researchers observed the PFS benefit across all subgroups (age, prior tyrosine kinase inhibitor therapy, and RET mutation status).

The response rate was 28% in the cabozantinib group and 0% in the placebo group. Researchers observed responses regardless of RET mutation status.

Kaplan-Meier estimates indicated 47.3% of patients assigned to cabozantinib were alive and progression free at 1 year, compared with 7.2% assigned to placebo.

Researchers reported grade 3 or grade 4 adverse events in 69% of patients assigned to cabozantinib and 33% of patients assigned to placebo. Seventy-nine percent of patients in the cabozantinib group reduced the treatment dose, and 65% withheld treatment due to adverse events such as diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea and fatigue. Treatment was discontinued in 16% of those assigned to cabozantinib and 8% of those assigned to placebo.

Robert I. Haddad

In an accompanying editorial, Robert I. Haddad, MD, of Dana-Farber Cancer Institute and Brigham and Women’s Hospital, noted another tyrosine kinase inhibitor — vandetanib (Caprelsa, AstraZeneca) — also has been shown to confer a PFS benefit in patients with medullary thyroid cancer who have RET mutations.

“Incorporating RET testing into routine clinical practice might become important as we try to identify who will benefit the most from these therapies,” Haddad wrote. “Currently, this testing is not part of the routine care for patients with medullary thyroid cancer ... It is also important to better define the patient population at risk so that patients with indolent disease are not exposed to toxic agents prematurely when survival is not affected. This is a common problem that is encountered with slow-growing malignancies such as medullary thyroid cancer, papillary thyroid cancer and adenoid cystic carcinoma.”

For more information:

Elisei R. J Clin Oncol. 2013;doi:10.1200/JCO.2013.51.5098.
Hadaad HI. J Clin Oncol. 2013;doi:10.1200/JCO.2012.48.4659.

Disclosure: The researchers report research funding and honoraria from, employment or leadership positions with, consultant or advisory roles with, and stock ownership in Exelixis. Haddad reports research funding from Boehringer Ingelheim, as well as consultant or advisory roles with AstraZeneca, Boehringer Ingelheim and Exelixis.