Now in its 21st annual edition, the European Society for Medical Oncology’s (ESMO) World Congress on Gastrointestinal Cancer, taking place in Barcelona, 03-06 July, has drawn an attendance of over 3.600 delegates from over 120 countries for the greatest gathering of renowned experts and innovators who are pushing the boundaries in advancing translational science, treatment and care in gastrointestinal malignancies.

Co-chaired by renowned leaders within the field, Mario Dicato, Centre Hospitalier de Luxembourg (Luxembourg), and Eric Van Cutsem, University of Leuven, (Belgium), and vice-chaired by VHIO’s Director and ESMO President, Josep Tabernero, this premier, must-attend meeting is making the headlines as participants and speakers share, debate and discuss first-outing clinical data and the very latest updates on novel strategies and treatment approaches against gastrointestinal cancer.

On such study, especially selected for coverage by ESMO’s Media Program, has just been presented by speaker and first author Guillem Argilés, Medical Oncologist and Clinical Investigator of VHIO’s Gastrointestinal & Endocrine Tumors Group headed by Teresa Macarulla.

Presented during today’s Selected Abstracts in Colorectal Cancer Session co-chaired by Eric Van Cutsem and Josep Tabernero, results from this international REARRANGE* trial, led by the Spanish Cooperative Group for the Treatment of Digestive Tumors, point to the practice changing, flexible dosing of regorafenib to relieve adverse events and toxicities often suffered by patients with refractory metastatic colon cancer, and, as importantly, without impacting on efficacy.

Commenting for VHIO Communications Guillem Argilés observed, “As we seek to collectivley advance discovery in gastrointestinal malignancies in pace with the increasing promise of precision medicine, we must also strive to more effectively manage advanced disease while reducing adverse side-effects without compromising efficacy.”

He continued, “Striking the essential balance between improved outcomes in treating advanced disease and ensuring the very best quality of life possible for our patients is paramount.”

To discover more, please see below for the official press communication issued by ESMO this week.

* 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) 

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Source: European Society for Medical Oncology (ESMO)

New trial demonstrates the efficacy of a more flexible dose of regorafenib to relieve side-effects in patients with metastatic colon cancer

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. doi:10.1093/annonc/mdz155

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 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 Gr_avalos5, P Garc_ıa 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, 18Universit_a 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 ocurred. 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 stablished 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.

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