Vandetanib Remains Safe and Effective in Medullary Thyroid Cancer

The tyrosine kinase inhibitor vandetanib (Caprelsa) demonstrated an improvement in progression-free survival (PFS) in patients with symptomatic and progressive medullary thyroid cancer (MTC) in a post-hoc analysis of the phase III ZETA trial. The analysis found no new safety signals during follow-up care, according to a new paper published recently in the Journal of Clinical Oncology.¹

For their analysis, the authors, led by Michael C. Kreissl, MD, of University Hospital of Magdeburg, Magdeburg, Germany, focused specifically on the cohort of ZETA patients with aggressive and symptomatic disease because they corresponded most closely with the medical status described in vandetanib’s approval label for use in the European Union.

At baseline, symptomatic and progressive disease was observed in 184 out of 331 patients. Results from this subgroup of the post-hoc analysis were similar to those observed in the overall trial for PFS (Hazard Ratio [HR], 0.43; 95% Confidence Interval [CI], 0.28-0.64; P < 0.0001). Post-hoc results were also similar for overall survival (OS; HR, 1.08; 95% CI, 0.72-1.61; P = 0.71), and time to worsening of pain (HR, 0.67; 95% CI, 0.43-1.04; P = 0.07). In this subgroup, the objective response rate (ORR) was 37% in the vandetanib arm versus 2% in the placebo arm.

“Vandetanib showed statistically significant prolonged median PFS in both the progression and symptoms subgroup and the symptoms-only subgroup, compared with placebo, but not in the progression-only and no symptoms/no progression subgroups,” wrote Kreissl et al. “It should be noted that the number of patients in the symptoms-only and the no progression/no symptoms subgroups, both in the vandetanib and placebo arms, was low and that these results should be interpreted with caution.”

In ZETA (NCT00410761), patients with unresectable locally advanced or metastatic MTC were randomized 2:1 to receive oral vandetanib (n = 231) or placebo (n = 100) until disease progression. Participants were required to provide a baseline tumor sample unless they had hereditary MTC with a documented germline RET mutation. In addition to baseline analysis, tumor measurements were performed every 12 weeks throughout the trial. Patients were also required to have a WHO performance status of 0-2 and a serum calcitonin level of 500 or more pg/mL.²

At the time of disease progression, ZETA patients discontinued the study drug and were unblinded. Some study sites offered these patients open-label treatment with vandetanib. Patients determined by central review not to have progressive disease also had the option to be unblinded and receive open-label medication.

For the post-hoc analysis, Kreissl et al divided the ZETA trial population into 4 disease severity subgroups: those with both progression and symptoms at baseline, those with symptoms only, those with progression only, and those with no progression and no symptoms at baseline. They defined symptoms as Brief Pain Inventory (BPI) questionnaire pain score > 4, opioid use of at least10 mg/day, diarrhea, flushing, fatigue, pain, nausea, dysphagia, dysphonia, respiratory symptoms, and weight loss.

Disease progression was seen in 163 patients during the primary analysis period, including 103 in patients who had both progression and symptoms at baseline. In the baseline progression and symptoms group, the survival curves for PFS differed significantly between the experimental and control groups (log-rank P < 0.0001). There was a reduced risk of progression in the vandetanib arm compared with placebo (HR, 0.43; 95% CI, 0.28-0.64; P < 0.0001). In the vandetanib group, the median PFS was 21.43 months but only 8.40 months in the placebo group.

When the investigators assessed patients’ ORR, they recorded 92 events, 90 of which occurred in vandetanib groups. As expected, the ORR was uniformly higher in the vandetanib groups than the placebo groups, and no significant OS differences were observed in comparable groups.

The median follow-up times in the progressive/symptomatic disease group was 53.7 months (range, 0.6-104.9 months) and 95.1 months (range, 2.7-104.3 months) for asymptomatic patients with progressive disease. Median follow up was 33.7 months (range, 2.0-104.3 months) for symptomatic patients without progression and 75.5 months (range, 3.3-103.8 months) for patients with neither progressive nor symptomatic disease at baseline.

Kreissl et al reported that 58 patients formerly randomized to placebo entered the open-label period as of July 31, 2009. These patients’ average total exposure to placebo during the primary analysis period was 7.9 months (median, 6.1 months). The median time to progression for these patients during the open-label period was 22.2 months.

About one-third of patients in the vandetanib groups required dose reductions (n = 83, 35.95%), while only 3 patients did who received placebo. Nearly all patients (98%) in the vandetanib group experienced at least one adverse event (AE), as did 92% in the placebo group.

AE profiles were similar across all 4 subgroups. “The types of AEs observed with vandetanib were consistent with its known safety profile and the mechanism of action of VEGFR and EGFR inhibition,” Kreissl et al wrote. “The most frequently reported common AEs across all groups in patients treated with vandetanib were GE disorders and skin and subcutaneous tissue disorders, which is consistent with what was reported in the primary ZETA trial.”

_References:

_{1. Kreissl MC, Bastholt L, Elisei R, et al. Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial. J Clin Oncol. 2020;38. Published on June 25, 2020. DOI: https://doi.org/10.}

_{1200/JCO.19.02790.}

_{2. Wells SA, Jr., Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-141.}