Cabozantinib Linked to Weight Loss in Patients With Advanced Thyroid Cancer

Lily J. Kwatampora, MD

Tyrosine-kinase inhibitors (TKIs) are a mainstay of therapy for patients with advanced thyroid cancer, more than doubling progression-free survival. Unfortunately, their use is limited not only by gastrointestinal adverse events (AEs), such as diarrhea and anorexia, but also by significant weight loss, which has been reported in 10% to 50% of patients treated with TKI therapies.

In fact, in clinical trials, approximately half of patients with medullary thyroid cancer who are treated with cabozantinib, an oral TKI, experienced significant weight loss (~5% had grade 2-3 [20%] weight loss) compared with placebo-treated patients.

“Cabozantinib-induced weight loss appears to be related not only to its gastrointestinal AEs but also to an independent mechanism that leads to early-onset skeletal muscle and adipose tissue loss,” said Lily J. Kwatampora, MD, of the Baylor College of Medicine in Houston, Texas, on March 5, 2014, at the Endocrine Society’s 97th Annual Meeting and Expo.

Recent evidence suggests that cabozantinib may affect skeletal muscle by directly inhibiting protein synthesis and by generating adipose tissue through adipogenesis. In patients with advanced thyroid cancer, skeletal muscle loss (sarcopenia) has been linked to poor functional status, reduced treatment response, and lower overall survival.

To evaluate the effects of carbozantinib on body composition, independent of gastrointestinal AEs, the investigators retrospectively reviewed weight, height, body mass index (BMI), gastrointestinal-related and other AEs, and tumor response data for 21 patients with advanced, progressive medullary thyroid cancer who had been treated at the MD Anderson Cancer Center. Of these, 13 patients had received no prior chemotherapy or TKI therapy, 5 had previously been treated with 1 or more TKIs, and the remaining 3 subjects had received prior chemotherapy. Over a 12-month period, skeletal muscle and adipose tissues were quantified and correlated with whole body fat and skeletal muscle using cross-sectional images taken at the third lumbar spine.

Contrary to the popular assumption that patients with advanced thyroid cancer are relatively healthy compared with patients with other advanced cancers, weight and skeletal muscle loss was common in these patients, despite patients falling within the ‘normal weight,’ ‘overweight,’ or ‘obese’ BMI categories at baseline. In fact, clinically significant weight loss was apparent as early as 3 months into therapy and continued through 12 months of treatment. After 3 months of cabozantinib treatment, 60% of subjects exhibited >5% (grade 1) weight loss, and 45% had lost ≥1 kg of skeletal muscle. Importantly, weight loss within the first 3 months was indicative of more pronounced weight loss at 12 months.

Overall, 4 of 21 subjects (19%) who experienced weight loss did not report any diarrhea, but 2 of these subjects did experience treatment-related nausea and anorexia. Two subjects who did not experience any gastrointestinal AEs displayed clinically significant weight loss; one of these patients exhibited profound changes in body composition, becoming sarcopenic after only 3 months. Dose reductions and therapy discontinuation from AEs were common, occurring in 71% and 43% of subjects, respectively.

Although the sample size of this retrospective study was small and lacked a comparator group, this is the first study to demonstrate the effect of cabozantinib on body composition in patients with advanced medullary thyroid cancer. These preliminary data are similar to those observed in other studies investigating TKI-related weight loss in other cancers and serve as the basis for a larger interventional study to prevent TKI-induced weight and skeletal muscle loss and to improve drug tolerability and response. Further studies are needed to better understand these independent effects. Ultimately, early intervention to prevent patients from deteriorating into sarcopenia and cachexia could affect treatment outcomes and survival.

“Understanding these effects on body composition will guide identification of at-risk patients, dose selection at initiation of therapy, and identification of patients who would benefit from interventions to decrease sarcopenia. We hope that ultimately ameliorating this adverse event would improve tolerance to therapy, [and] decrease treatment interruptions and early withdrawal from treatment,” Kwatampora concluded.

Kwatampora LJ, Cabanillas ME, Korivi BR, et al. Effect of cabozantinib on body composition in advanced thyroid cancer. Presented at the 2015 Endocrine Society Annual Meeting; March 5-8, 2015; San Diego, CA. Abstract THR 044-059. Poster Board THR-050.

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