Real-World Date Confirm Vandetanib and Cabozantinib Are Effective 1L/2L Treatments for Medullary Thyroid Cancer

For the majority of patients with medullary thyroid cancer (MTC), vandetanib (Caprelsa) and cabozantinib (Cabometyx) are both effective treatment options, according to results from a retrospective analysis. Both agents are approved by the FDA as treatment of patients with MTC, but prior to this analysis it was unclear how to provide treatment benefit for patients who fail vandetanib in the frontline setting and present with a poor prognosis in the second-line setting where cabozantinib is administered.

The retrospective analysis evaluated 48 patients with MTC who were diagnosed in Germany between 1990 and 2018. For the analysis, patients’ clinical characteristics, the treatment regimens they received, efficacy, and treatment-emergent adverse events (TEAEs) associated with vandetanib and cabozantinib were assessed.

To determine efficacy in the patients with MTC treated with vandetanib and cabozantinib, the Kaplan-Meier method was utilized to assessed progression-free survival (PFS) and overall survival (OS) benefit, and these were compared by log-rank testing. Assessment of response to TKI therapy was the primary end point of the retrospective analysis. The secondary end points were PFS, OS, and the prognostic factors of survival.

The patient population, the median age at diagnosis was 46 years (range, 15-80). In terms of disease characteristics, germline RET mutations were known in 13% of patients, and 67% of patients demonstrated progressive disease prior to treatment with either tyrosine kinase inhibitor (TKI). The majority of the patients showed sporadic MTC at baseline (75%), while the remaining 13% had a hereditary MTC type.

At initial diagnosis of MTC, metastasis of the locoregional lymph node was found in 42 patients, and distant metastasis was found in 25 patients. In addition, the site of metastasis was the mediastinal lymph node for 8 patients, lung for 11 patients, liver for 11 patients, and bone for 13 patients. The median age at the time of metastasis diagnosis was 50 years.

Comparing Vandetanib and Cabozantinib in Patients With MTC

Overall, 47 patients received vandetanib and 23 received cabozantinib. Vandetanib was administered in the frontline setting for 41 patients (85%), and cabozantinib was administered in the frontline for 7 patients (15%). At a median follow-up of 25 months (range, 0-46), the partial response (PR) rate was 26% among patients treated with vandetanib and 22% among those treated with cabozantinib. Stable disease was observed in 34% of patients who received vandetanib and 13% of those who received cabozantinib.

The median PFS observed in patients on treatment with vandetanib was 17 months (95% CI, 9.3-24.6). For patients who received cabozantinib, the median PFS was 4 months (95% CI, 3.1-4.9). In patients treated with vandetanib and cabozantinib, the 6-month survival rates were 98% and 78%, and the 12-month survival rates were 86% and 70%, respectively.

Patient treated with vandetanib had a median OS of 53 months (95% CI, 43.7-62.3) compared with those treated with cabozantinib, who had a median OS of 24 months (95% CI, 5.9-42.1).

It was notable in this analysis that patients on treatment with vandetanib had significantly longer PFS and OS compared if they were 60 years old or younger at the time of TKI initiation and had ≥ 5 TEAEs. The vandetanib-treated population also had superior PFS if they did not have bone metastases. Gender, germline RET mutation status, and liver metastases were not significantly associated with PFS and OS.

In the cabozantinib-treated population, having ≥ 5 TEAEs and being 60 years old or younger shortened PFS compared with those who experienced TEAEs and were 60 year of age or older. OS in this population was significantly associated with the total number of TEAEs and having ≥ 5 TEAEs correlated with a significantly longer OS compared with those who had 4 or fewer. Similar to the vandetanib-treated group, survival outcome in patients treated with cabozantinib did not correlate with gender, germline RET mutation status, and/or liver metastases

TKI Treatment in the Front- Versus Second-Line Setting

On frontline treatment with vandetanib, the PR rate was 24% versus 22% with frontline cabozantinib. SD was also observed in 39% of the patients treated with vandetanib in the front-line setting compared with 13% of those treated with cabozantinib. In comparison, second-line therapy with vandetanib led to 33% PR rate versus a 31% with cabozantinib. Achievement of SD in the second-line setting was not seen with vandetanib and was seen in 43% in the cabozantinib group.

Safety of TKI Treatment in MTC

Treatment discontinuation due to TEAE were observed in 19% of the vandetanib-treated population compared with 52% of the cabozantinib-treated population. The most frequently observed were diarrhea (40%), skin rash (38%), and fatigue (28%). Among patients treated with cabozantinib, the most frequently reported TEAEs were loss of appetite/loss of weight (56%), diarrhea (57%), and fatigue (39%).

Notably, a higher incidence of laboratory abnormalities was observed in patients who received vandetanib, which included blood count changes, change in electrolytes and thyroid-stimulating hormone. In addition, 21% of those treated with vandetanib had QT prolongation compared to 0% of the cabozantinib population. Finally, hand-foot syndrome was more commonly associated with cabozantinib (30%) compared with 2% in the vandetanib.

Overall, the real-world data from this retrospective analysis confirm the efficacy of both vandetanib and cabozantinib as treatment of patient MTC who have an aggressive course of disease.

_References:

_{Koehler VF, Adam P, Frank-Raue K, et al. Real world efficacy and safety of cabozantinib and vandetanib in advanced medullary thyroid cancer. Thyroid. Published online ahead of print, Septmeber 23, 2020. http://doi.org/10.1089/thy.2020.0206}