A Randomized, Double-Blind Noninferiority Study to Evaluate the Efficacy of the Cabozantinib Tablet at 60 mg Per Day Compared with the Cabozantinib Capsule at 140 mg Per Day in Patients with Progressive, Metastatic Medullary Thyroid Cancer

Abstract

Background: Cabozantinib inhibits pathways involved in medullary thyroid cancer (MTC). Cabozantinib is approved as 140 mg/day in capsules for MTC and 60 mg/day in tablets for other solid tumors. This study compared the two doses in progressive metastatic MTC. Methods: In this Phase 4, randomized, double-blind noninferiority (NI) trial (NCT01896479), patients with progressive metastatic MTC were randomized 1:1 to cabozantinib 60 mg/day tablet or 140 mg/day capsules. The primary end point was progression-free survival (PFS) by blinded independent radiology committee (BIRC) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. NI would be concluded if the upper 95% confidence interval [CI] for the PFS hazard ratio (HR) was less than the NI margin, 1.58. The secondary end point was objective response rate (ORR) by BIRC per RECIST v1.1; additional end points included safety and pharmacokinetics. Results: At data cutoff (July 15, 2020), 247 patients were randomized to the 60 mg/day tablet arm (n = 123) and the 140 mg/day capsules arm (n = 124). NI was not met (median PFS 11.0 months vs. 13.9 months in the 60 and 140 mg/day arms [HR 1.24; CI 0.90-1.70; p = 0.19]). The ORR was 33% in both arms. Generally, adverse event (AE) incidence was lower in the 60 mg/day arm (Grade 3/4, 63% vs. 72%), as were dose reductions (69% vs. 81%) and treatment discontinuations due to AEs (23% vs. 36%). Initially, cabozantinib plasma concentrations were higher in the 140 mg/day arm but became similar between arms at later time points. Conclusions: PFS NI of the cabozantinib 60 mg/day tablet vs. 140 mg/day capsules was not met. The 60 mg/day tablet had the same ORR and lower rates of AEs. Clinical Trial Registry: ClinicalTrials.gov NCT01896479.

Keywords: cabozantinib; capsule; medullary thyroid cancer; noninferiority; tablet; tyrosine kinase inhibitor.

Conflict of interest statement

J.C.: Consulting or Advisory Role—Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Hutchinson Pharma, ITM, and Merck Serono; Research Funding—Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Amgen, and Bayer; Leadership Roles—Chair of the Spanish Task Force for Neuroendocrine and Endocrine Tumors Group (GETNE), Advisory member of the European Neuroendocrine Tumor Society (ENETS), and Treasurer of the Spanish Multidisciplinary Group of Digestive Cancers (GEMCAD).

S.L.: Consulting or Advisory Role—Bayer, Eisai, and Loxo; Research Funding—Genzyme, Novartis, and Sanofi.

B.R.: Leadership—Cochlear and Mayne Pharma; Stock and Other Ownership Interests—Cochlear and Mayne Pharma; Consulting or Advisory Role—Eisai and Loxo; Speakers’ Bureau—Eisai; Travel, Accommodations, Expenses—Eisai.

B.G.M.H.: Consulting or Advisory Role—AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, MSD Oncology, Pfizer, Roche, and Sanofi/Regeneron; Research Funding—Amgen (Inst); Travel, Accommodations, Expenses—AstraZeneca and Bristol-Myers Squibb.

B.K.: Consulting or Advisory Role—ABL Bio, AstraZeneca, Cellid, Genexine, and MSD Oncology; Research Funding—AstraZeneca, MSD Oncology, and Ono Pharmaceutical.

R.E.: Consulting or Advisory Role—Eisai, Sanofi Genzyme, Loxo, Ipsen, Eli Lilly, Bayer.

P.G.: Consulting or Advisory Role—Ipsen, Roche, Eisai, and Bayer; Speakers’ Bureau—Ipsen, Roche, Pfizer, Novartis, and Eisai; Travel, Accommodations, Expenses—Ipsen and Pfizer.

H.K.G.: Consulting or Advisory Role—BMS and MSD; Speakers’ Bureau—Eisai and Merck Serono; Research Funding—AbbVie.

E.K.: Consulting or Advisory Role—Bayer, Eisai, Ipsen, Bristol-Myers Squibb, Novartis, Merck, and Pierre Fabre; Research Funding—Bristol-Myers Squibb and Novartis.

L.L.: Honoraria—Eisai, MSD, Merck Serono, McCann Healthcare, SunPharma and Sanofi-Regeneron, and Eli Lilly; Consulting or Advisory Role—Bristol Myers Squibb Foundation, Eisai, IPSEN, Eli Lilly, Merck Serono, and Biogen; Research Funding—Eisai (Inst).

M.M. and L.F.: Employees and stockholders of Exelixis, Inc.

J.K.: Consulting or Advisory Role—Exelixis, LOXO, Bayer Health Care, and Sanofi Genzyme; Honoraria: AstraZeneca, Eisai, Ipsen, Lilly, Oxigene, and Sanofi Genzyme.

B.J.: Honoraria—Eli Lilly, Exelixis, Bayer, Ipsen, Amgen, Pfizer, Roche, Sanofi Genzyme, Eisai, Novartis, and Oxigene; Consulting or Advisory Role—AstraZeneca, Sobi, and EwoPharma; Speakers’ Bureau—Exelixis and Bayer; Travel, Accommodations, Expenses—Sanofi Genzyme and Ipsen. All remaining authors have declared no conflicts of interest.

Figures

FIG. 1.

Patient disposition. aTwo additional patients (one in each arm) were summarized as having non-PD AEs (regardless of causality) leading to study treatment discontinuation in Supplementary Table S3: one patient in the 60 mg/day arm (decubitus ulcer, Grade 2, treatment not related) and one patient in the 140 mg/day arm (AST increased, Grade 1, treatment related). However, on this flowchart, they were not included because these two patients discontinued study treatment owing to an AE after the data cutoff date for this report. bClinical deterioration comprises AEs or serious AEs related to disease progression. cOne patient was treated with study drug beyond PD, which was not permitted under Protocol Amendment 3. The subsequent protocol amendment allowed treatment beyond disease progression if patients were eligible. AE, adverse event; AST, aspartate aminotransferase; ITT, intention-to-treat; PD, progressive disease.

FIG. 2.

Cabozantinib plasma pharmacokinetic concentrations by visit for (A) patients in the 60 mg/day tablet arm and the 140 mg/day capsules arm and (B) censored to select analysis-eligible records before any dose modifications from the initial protocol-assigned cabozantinib dose. SD, standard deviation; W, week; D, day.

FIG. 3.

Kaplan–Meier plot for progression-free survival per BIRC. BIRC, blinded independent radiology committee; CI, 95% confidence interval; HR, hazard ratio.

FIG. 4.

Kaplan–Meier plot for OS. OS, overall survival; NE, not estimable.