Higher Dose Cabozantinib Demonstrates Superior Efficacy Over Lower Dose in MTC

Cabozantinib (Cabometyx) 60 mg tablets and cabozantinib 140 mg tablets show similar clinical efficacy in metastatic medullary thyroid cancer (MTC), according to study data presented at the 90th Annual Meeting of the American Thyroid Association. However, the primary end point of demonstrating the non-inferiority of the 60 mg-tablets compared with the 140 mg-tablets was not met. 

Cabozantinib targets multiple receptor tyrosine kinases that are involved with tumor pathology, such as VEGFR-2, MET, RET, KIT, AXL, and FLT. RET mutations and VEGF, in particular, are overexpressed in MTC. This has supported the developed of tyrosine kinase inhibitors (TKIs) in this patient population.

The 140 mg dose of cabozantinib, a TKI, was granted approval in patients with progressive metastatic MTC based on the results of the phase 3 EXAM trial (NCT00704730). Additionally, cabozantinib holds indications for select patients with advanced renal cell carcinoma or advanced hepatocellular carcinoma at the 60 mg/day dose. 

Due to toxicity concerns, dose modification is often used to maximize cabozantinib exposure while also improving tolerability. The phase 3 multicenter, randomized, double-blind EXAMINER study (NCT01896479) aims to compare the efficacy and tolerability of the 60 mg a day dose versus the 140 mg a day dose. The primary end point of the study is progression-free survival (PFS) by blinded independent radiology committee per Response Evaluation Criteria in Solid Tumors.

Between February 25, 2015, and June 2, 2020, 247 patients were randomized 1:1 to receive either the 60mg tablet (n = 123) or the 140mg tablet (n = 124). Baseline characteristics were well balanced with only a modest difference in sex and prior TKI therapy.

In order to participate, patients must be 18 years of age or older, histologically confirmed MTC, measurable disease, and ECOG performance status of 1 or lower, and adequate organ and marrow function. Patients who previously received cabozantinib, a small-molecule kinase inhibitor or hormonal therapy within 28 days prior to randomization, or any other investigational agent 28 days prior to randomization are not eligible to participate. 

Thirty-one percent of patients in the 60-mg arm were ≥65 years of age compared to 37% in the 140 mg arm. In both arms, the majority of patients were male (73% vs 60%, respectively). Approximately 60% of patients in both arms were European, the majority where White (75% vs 82%) and approximately half of patients in each arm where RET M918T-positive. Sixty percent of patients in each arm had an ECOG status of 0. The number of prior therapies included 0 (47% vs 51%), 1 (39% vs 34%), 2 (8.1% vs 8.15), and ≥3 (5.7% vs 7.3%). Prior TKI therapy included any TKI (46% vs 37%), vandetanib (Caprelsa) (39% vs 34%), sorafenib (Nexavar) (6.5% vs 3.2%), and sunitinib (Sutent) (4.1% vs 2.4%).

At a median follow-up of 30 months, the median PFS was 11.0 months (95% CI, 8.3-13.6) with the 60 mg capsules and 13.9 months (95% CI, 9.0-16.6) with the 140 mg capsules (HR, 1.24; 95% CI, 0.90-1.70). Due to the upper 95% CI crossing the NI margin, the study failed to meet its primary end point. The objective response rate was 33% in both arms. The confirmed complete response rate was 0.8% in the 60 mg arm compared with 1.6% in the 140 mg arm. The confirmed partial response rate was 33% in the 60 mg arm versus 31% in the 140 mg arm. Stable disease was seen in 47% of patients in the 60 mg arm compared with 52% in the 140 mg arm. Progressive disease was seen in 11% of patients in the lower-dose arm compared with 8.9% of patients in the higher-dose arm. In the lower-dose arm, the time to objective response was 2.8 months (range, 2.6-13.7) with a median duration of response of 16.6 months (range, 8.4-24.9). In the higher-dose arm, the time to objective response was 2.8 months (range, 1.7-27.9) with a median duration of response of 13.8 months (range, 13.4 to not evaluable [NE]).

The median overall survival was 29.4 months (95%CI, 24.6-41.6) in the 60 mg group compared to 33.0 months (95% CI, 23.6-NE) in the 140 mg group (HR, 1.12; 95%CI, 0.77-1.63). The median duration of exposure was 11.1 months (range, 0.4-60) in the low dose cohort compared with 10.1 months (range, 0.2-60) in the high-dose cohort. The percentage of dose intensity was 64.5% (range, 11.9%-100%) in the low dose cohort and 52.4% (range, 17.8%-100%) in the higher-dose cohort. The average daily dose in the 60 mg arm was 38.7 mg (range, 7.1 mg-60 mg) versus 73.4 mg (range 25 mg-140 mg) in the 140 mg cohort.

“Regarding the pharmacokinetic data, there was a trend for cabozantinib concentrations to decrease over time, which was more marked in the 140 mg arm, which was which had initially higher concentrations but became similar between the two formulations or later time points,” said lead author Jaume Capdevila, MD, an oncologist in the Department of Medical Oncology at Vall d’Hebron University Hospital.

Dose reductions were common in both the low-dose and high-dose cohorts (69% vs 81%). First level dose reduction was seen in 67% of patients in the 60 mg arm versus 73% of patients in 140 mg arm. However, second level dose reduction only occurred in (37% vs 52%), respectively. Seventy-five percent of patients in the 60 mg arm had a dose hold for a median of 3 days (range, 1-9). In the 140 mg arm, 91% of patients experienced a dose hold for a median of 3 days (range, 1-78). In the low-dose cohort, 23% of patients discontinued due to an adverse event (AE). In the higher-dose cohort, 36% discontinued due to an AE.

Ninety-nine percent of patients in the low-dose arm and 100% in the high-dose arm experienced an AE. In the low-dose arm, 50% experienced a grade 3 AE and 12% experienced a grade 4 AE. In the high-dose arm, 61%experienced a grade 3 AE and 10% experienced a grade 4 AE. Common AEs of any grade included diarrhea (67% vs 73%), weight loss (31% vs 52%), and fatigue (35% vs 39%). No treatment related deaths were reported in the 60 mg cohort. One was reported in 140 mg cohort (peritonitis).

“Safety in both arms was consistent with the known profile of cabozantinib, with the 140 mg capsule associated with higher incidences of adverse events and dose modifications,” said Capdevila.

According to investigators, the gradual reduction of dose intensity in both arms highlights the importance of dose modifications to control AEs.

_REFERENCE:

_{Capdevila J, Klochikhin A, Lebolleux et al. Results of the phase IV EXAMINER trial comparing two different cabozantinib formulations (60-mg tablet versus 140-mg capsule) in patients with progressive metastatic medullary thyroid cancer. Presented at the 90th Annual Meeting of the American Thyroid Association; September 30-October 3, 2021; Virtual. Poster 56.}