New Trial Demonstrates the Efficacy of a More Flexible Dose of Regorafenib to Relieve Side-effects in Patients with Metastatic Colon Cancer

BARCELONA, Spain – Medical oncologists administer anticancer drug regorafenib to try to improve overall survival in patients with metastatic colorectal cancer who have ceased to respond to standard therapy (known as refractory mCRC). However, some of the adverse events related to the use of this drug often limits its use in clinical practice. A study reported at the ESMO World Congress on Gastrointestinal Cancer 2019 suggests the usefulness of a more flexible dosing, which improves patients’ quality of life without jeopardising efficacy. (1)

This international trial, led by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD), included 299 patients from over a dozen hospitals in Spain, Italy and France. The average age of the participants was 64 and they had received an average of four treatment lines prior to inclusion in the trial with regorafenib between July 2016 and September 2017.

“Regorafenib has been approved since 2013 for patients with metastatic colorectal cancer (mCRC) who have progressed to standard treatments,” said study author, Dr. Guillem Argilés, medical oncologist and clinical investigator, Gastrointestinal & Endocrine Tumors Group, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain.

“Its adverse toxicity profile often limits its use in routine clinical practice. This clinical trial attempted to show the usefulness of different dose strategies in order to improve its tolerability and quality of life in patients who can benefit from the medicine in the context of advanced disease.”

In the trial, patients were randomised 1:1:1: standard dose 160 mg/day for three weeks followed by a week off; reduced dose of 120 mg/day for three weeks followed by a week off (reduced dose group); or intermittent dose of 160 mg/day a week, followed by a week off (intermittent dose group). The patients in the latter two groups (reduced or intermittent dose) were escalated to the standard of care dose if, after a first treatment cycle, no limiting toxicities that prevented to continuing to stay in the trial occurred. “We reduced the dose in the first cycle and then escalated because it has been shown that the toxicity is higher in the first and second months of treatment”, explained Argilés.

The investigators observed that flexible dosing showed numerical improvement on several parameters that improved tolerance, such as fatigue, hypertension or hand-foot syndrome (reaction due to redness, swelling and pain caused in the palms), although REARRANGE did not meet its primary endpoint of improving regorafenib global tolerability in the reduced and intermittent dose groups. The average treatment duration was 3.2 months in the standard group; 3.7 in the reduced dose group; and 3.8 in that with alternating weeks. Median progression-free survival was not different across groups (approximately 2 months).

“Although statistical significance was not achieved, we did observe a numerical reduction in some side-effects that can be very troublesome for the patients”, explained Argilés. “These results, interpreted in the context of other trials, like the American study ReDOS (2), tell us that the more flexible doses of regorafenib are an effective alternative in order to improve quality of life in patients with metastatic refractory colorectal cancer”.

Commenting on the results, Prof. Eric Van Cutsem, from the University Leuven, Belgium, said: “This study will change clinical practice with regard to the use of regorafenib in patients with metastatic colorectal cancer, because it demonstrates and supports something that many clinicians have already observed and were carrying out in regular clinical practice”. In his opinion, the trial shows that this reduction in regorafenib initial dose limits the drug toxicity while maintaining its efficacy.

References

1. Abstract O-026 – ‘Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC)’will be presented by Guillem Argilés during Session XX: Colorectal Cancer (Part I) on 6 July, 09:20-10:50 CEST. Annals of Oncology 30 (Supplement 4): iv137–iv151, 2019
   The participating Spanish institutions were, together with the Vall d’Hebrón University Hospital, the Catalan Institute of Oncology in l’Hospitalet de Llobregat, the University Hospital of A Coruña, MD Anderson Cancer Centre in Madrid, the Madrid hospitals 12 de Octubre, Gregorio Marañón, San Carlos Clinic and Ramón y Cajal; the Santa Creu i Sant Pau Hospital in Barcelona, the Carlos Haya Regional University Hospital in Malaga, the Reina Sofía University Hospital in Cordoba and the Marqués de Valdecilla University Hospital in Santander.
2. Tanios S. Bekaii-Saab et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC). Journal of Clinical Oncology 36, no. 4_suppl (February 1 2018) 611-611.

Abstract O-026 – Results of REARRANGE trial: A randomized phase 2 study comparing different dosing approaches for regorafenib (REG) during the first cycle of treatment in patients (pts) with metastatic colorectal cancer (mCRC)

G Argiles¹, N Mulet Margalef², M Valladares-Ayerbes³, J Vieitez de Prado⁴, C Gravalos⁵, P Garcia Alfonso⁶, C Santos⁷, M Tobeña⁸, J Sastre⁹, M Benavides¹⁰, T Cano¹¹, F Loupakis¹², M Rodriguez Garrote¹3, F Rivera¹⁴, R Goldberg¹⁵, A Falcone¹⁶, J Bennouna¹⁷, F Ciardiello¹⁸, J Tabernero¹⁹, E Aranda²⁰

¹Department of Medical Oncology, Vall d’Hebron Institute of Oncology, Barcelona, Spain, ²Institut Catala d’Oncologia de l’Hospitalet, Hospitalet de Llobregat, Spain, ³Complejo Hospitalario Universitario La Coruña, La Coruña, Spain, ⁴Medical Oncology, MD Anderson, Madrid, Spain, ⁵Hospital Universitario 12 de Octubre, Madrid, Spain, ⁶Medical Oncology Department. Hospital General Universitario Gregorio Marañón, Madrid, Spain, ⁷Portuguese Institute of Oncology, Lisboa, Portugal, ⁸Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, ⁹Hospital Clínico San Carlos Madrid, Spain. Center affiliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto Carlos III, Spanish Ministry of Science and Innovation, Madrid, Spain, ¹⁰Hospital Regional Universitario Carlos Haya, Málaga, Spain, ¹¹Hospital Universitario Reina Sofía, Córdoba, Spain, ¹²Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy, ¹³Ramón y Cajal University Hospital, Madrid, Spain, ¹⁴Hospital Universitario Marqués de Valdecilla, Santander, Spain, ¹⁵Mayo Clinic and Mayo Cancer Center, Rochester, USA, ¹⁶Department of Translational Research and New Technologies in Medicine and Surgery, Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, ¹⁷Institut de Cancerologie de L’Ouest, Nantes, France, ¹⁸Universita degli Studi della Campania L., Dipartimento di Medicina di Precisione, Napoli, Italy, ¹⁹Vall d’Hebron University Hospital, Barcelona, Spain, ²⁰IMIBIC, Reina Sofía Hospital, University of Córdoba, CIBERONC, Instituto de Salud Carlos III, Córdoba, Spain.

Introduction: REG is a multi-kinase inhibitor that improves overall survival vs placebo in refractory mCRC. However, REG adverse tolerability profile often limits its use on normal clinical practice. Different dose-repurposing strategies have been explored to improve REG tolerability. Here we report the results of the largest trial exploring the impact of initial flexible dosing on REG tolerability.

Methods: Refractory mCRC pts were randomized 1:1:1 to standard dose 160 mg/day 3 weeks (w) on 1 w off (SD), reduced dose 120 mg/day 3 w on 1 w off (RD) or intermittent dose 160 mg 1 w on 1 w off (ID). Pts in RD or ID escalated to SD after cycle 1 if no limiting toxicity occurred. Primary endpoint was % of pts with G3/4 treatment related adverse events (AE) on each arm. Secondary endpoints were: OS, PFS, TTF, DCR, % of pts starting C3, dose intensity and tolerability. Trial positivity threshold was established on 20% decrease in the%of pts with G3/4 AEs in RD or ID compared to SD.

Results: From Jul 2016 to Sept 2017, 299 pts were randomized. Safety population set was: 100 SD, 98 RD, 99 ID. Median num. of prior lines and age were 4 and 64 years.% of pts with G3/G4 AE were: 60 SD, 56 RD, 55 ID (c2 0.7262). Forty-five %of pts on RD and 64% on ID were escalated to SD after C1 and % of pts starting C3 were: SD 39%, RD 44%, ID 35% (c2 0.6309). OS/arm was: 7.4 months (m) SD, 8.6mRD and 7.1mID (long rank 0.7222). PFS: SD 1.94 m, RD 2.0 m, ID 2.0m(long rank 0.3795). DCR: SD 33%, RD 36%, ID 35%. Median treatment duration was: SD 3.2 m, RD 3.7 m, ID 3.8. Safety profile is in the table.

Conclusion: Though REARRANGE did not meet its primary endpoint of improving REG global tolerability in either RD or ID arms, flexible dosing showed numerical improvement on relevant AEs like fatigue, HFSR and hypertension, without jeopardizing efficacy. These findings support the use of REG flexible dosing as an alternative option.