Radioembolization With Chemotherapy for Colorectal Liver Metastases: A Randomized, Open-Label, International, Multicenter, Phase III Trial

Abstract

Purpose: To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).

Methods: In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and KRAS mutation status.

Results: Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided P = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided P < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided P = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided P = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% v 49.3%). Both groups received full chemotherapy dose intensity.

Conclusion: The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.

Trial registration: ClinicalTrials.gov NCT01483027.

Conflict of interest statement

Mary F. MulcahyResearch Funding: BTG Armeen MahvashHonoraria: Sirtex MedicalConsulting or Advisory Role: Sirtex Medical, Boston Scientific, AbbiskoSpeakers' Bureau: SIR-TexResearch Funding: BTG, Sirtex MedicalTravel, Accommodations, Expenses: BTG, SIR-TexOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1192235 Marc PrachtTravel, Accommodations, Expenses: MSD Steve BandulaHonoraria: Varian Medical Systems Robert C. G. MartinConsulting or Advisory Role: Angiodynamics Ken HerrmannLeadership: Sofibio, Theragnostics, Pharma15Stock and Other Ownership Interests: Sofibio, Theragnostics, Pharma15, Aktis OncologyConsulting or Advisory Role: Novartis, Bain Capital, Bayer, Advanced Accelerator Applications, Amgen, BTG, Ipsen, ITG, ROTOP Pharmaka, Siemens Healthineers, GE Healthcare Ewan BrownResearch Funding: MSD Oncology Gregory WilsonStock and Other Ownership Interests: Tandem Diabetes Care, Regeneron, Novacyt, Spire Hospital GroupConsulting or Advisory Role: Delcath Systems Paul RossStock and Other Ownership Interests: Perci Health LtdHonoraria: Sirtex Medical, Eisai, Servier, Pierre Fabre, Shire, Roche, AstraZeneca, MerckConsulting or Advisory Role: Sirtex Medical, Eisai, Servier, Roche, AstraZeneca, AmgenSpeakers' Bureau: Amgen, Merck, Servier, Boston ScientificResearch Funding: Sanofi, BayerTravel, Accommodations, Expenses: Roche, Ipsen William P. HarrisConsulting or Advisory Role: Neo Therma, Eisai, Exelixis, Bristol Myers Squibb, QED Therapeutics, Zymeworks, BD Medical, MerckResearch Funding: ArQule, Exelixis, Halozyme, Bristol Myers Squibb, MedImmune, Agios, Bayer, Merck, BTG, Boston Scientific, Koo Foundation, ZymeworksTravel, Accommodations, Expenses: Eisai Janet GrahamHonoraria: Merck Serono, Bristol Myers Squibb, Nucana, BayerConsulting or Advisory Role: Merck KGaATravel, Accommodations, Expenses: Nucana Jamie MillsTravel, Accommodations, Expenses: GenesisCare UK Matthew S. JohnsonStock and Other Ownership Interests: Endoshape, FluidXConsulting or Advisory Role: Argon Medical Devices, Boston Scientific, Cook MedicalResearch Funding: Argon Medical Devices, Boston Scientific, Black SwanExpert Testimony: Argon Medical Devices Constantinos T. SofocleousHonoraria: Ethicon/Johnson & JohnsonConsulting or Advisory Role: Varian Medical Systems, BTG, Sirtex Medical, TerumoSpeakers' Bureau: Ethicon/Johnson & JohnsonResearch Funding: BTG, Ethicon, Sirtex MedicalTravel, Accommodations, Expenses: Ethicon/Johnson & Johnson, Terumo Siddharth A. PadiaConsulting or Advisory Role: Boston Scientific, Bristol Meyer Squibb, Johnson & Johnson, Teleflex Medical, Varian Medical SystemsResearch Funding: Varian Medical Systems Robert J. LewandowskiConsulting or Advisory Role: Boston Scientific, BD Bard, Varian Medical Systems, ABKSpeakers' Bureau: Boston Scientific Etienne GarinHonoraria: BTG/Boston ScientificConsulting or Advisory Role: BTG/Boston ScientificTravel, Accommodations, Expenses: BTG/Boston Scientific Philip SinclairEmployment: Boston ScientificStock and Other Ownership Interests: Boston Scientific Riad SalemConsulting or Advisory Role: Eisai, Bard Medical, Cook Medical, Boston Scientific, Sirtex Medical, AstraZeneca, QED Therapeutics, Genentech/Roche, SiemensResearch Funding: Boston ScientificNo other potential conflicts of interest were reported.

Figures

FIG 1.

CONSORT diagram showing subject enrollment, treatment allocation, patient disposition, and data analysis. aIncludes patients on study when study was terminated by sponsor. bIncludes 16 patients randomly assigned to TARE but who received chemotherapy only. TARE, transarterial yttrium-90 radioembolization.

FIG 2.

Kaplan-Meier analysis of overall PFS for TARE plus chemotherapy versus chemotherapy in the intention-to-treat population. PFS, progression-free survival; TARE, transarterial yttrium-90 radioembolization.

FIG 3.

Kaplan-Meier analysis of hPFS for TARE plus chemotherapy versus chemotherapy in the intention-to-treat population. hPFS, hepatic progression-free survival; TARE, transarterial yttrium-90 radioembolization.

FIG A1.

Kaplan-Meier analysis of OS for transarterial yttrium-90 radioembolization plus chemotherapy versus chemotherapy in the intention-to-treat population. OS, overall survival; TARE, transarterial yttrium-90 radioembolization.