European Journal of Cancer 177 (2022) 154e163 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Original Research A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial) Guillem Argilés a,r,s,*, Nuria Mulet a, Manuel Valladares-Ayerbes b, José M. Viéitez c, Cristina Grávalos d, Pilar Garcı́a-Alfonso e, Cristina Santos f, Marı́a Tobeña g, Beatriz Garcı́a-Paredes h, Manuel Benavides i, Marı́a T. Cano j, Fotios Loupakis k, Mercedes Rodrı́guez-Garrote l, Fernando Rivera m, Richard M. Goldberg n, Chiara Cremolini o, Jaafar Bennouna p, Fortunato Ciardiello q, Josep M. Tabernero a, Enrique Aranda i, on behalf of theSpanish Cooperative Group for the Treatment of Digestive Tumors (TTD) and UNICANCER GI, The, REARRANGE investigators, Principal investigatorGuillem Argilés a, Josep Tabernero a, Steering Committee, Investigators a Vall d’Hebron University Hospital and Institute of Oncology (VHIO), CIBERONC, Barcelona, Spain b Virgen del Rocı´o University Hospital and Institute of Biomedicine (IBIS), Sevilla, Spain c Hospital Universitario Central de Asturias, Oviedo, Spain d Universitary Hospital 12 de Octubre, Madrid, Spain e Gregorio Marañón Hospital, Madrid, Spain f Institute Català d’Oncologia (ICO), Duran i Reynals Hospital e ONCOBELL, CIBERONC, Barcelona, Spain g Santa Creu i Sant Pau Hospital, Barcelona, Spain h Clı´nico San Carlos Hospital, Instituto de Investigación Hospital Clinico San Carlos (IdISSC) CIBERONC, Madrid, Spain i Regional University Hospital, Málaga, Spain j IMIBIC, Reina Sofı´a Hospital, University of Córdoba, CIBERONC, Instituto de Salud Carlos III, Spain k Istituto oncologico Veneto, Italy l Ramon y Cajal University Hospital-IRYCIS, CIBERONC, Alcalá University, Madrid, Spain m University Hospital Marqués de Valdecilla (IDIVAL) Santander, Spain n West Virgina University Cancer Institute, Morgantown, USA o Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy p University Hospital of Nantes, Digestive Oncology, Nantes, France q Università della Campania L. Vanvitelli, Italy r Universitat Autònoma de Barcelona, Barcelona, Spain s Memorial Sloan Kettering Cancer Center, New York, USA * Corresponding author. Medical Oncology Department University Hospital Vall d’Hebron, Barcelona, Spain. E-mail address: argilesg@mskcc.org (G. Argilés). https://doi.org/10.1016/j.ejca.2022.09.037 0959-8049/ª 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/). G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 155 Received 15 June 2022; received in revised form 28 September 2022; accepted 30 September 2022 Available online 14 October 2022 KEYWORDS Abstract Purpose: The purpose of this article is to evaluate the safety of two regorafenib Colorectal cancer; dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Drug administration Patients and methods: Patients with mCRC and progression during or within 3 months schedule; following their last standard chemotherapy regimen were randomised to receive the approved Metastasis; dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of Regorafenib treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. Results: There were 299 patients randomly assigned to arm A (n Z 101), arm B (n Z 99), or arm C (n Z 99); 297 initiated treatments (arm A n Z 100, arm B n Z 98, arm C n Z 99: pop- ulation for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 pa- tients), and handefoot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0e13.7) months in arm A, 8.6 (IQR 3.8e13.4) in arm B, and 7.1 (IQR 4.4e12.4) in arm C. Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher nu- merical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924. ª 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction [8,9]. Unfortunately, in both studies, many patients experienced toxicity that required dose modifications While <25% of patients with CRC have metastatic dis- and interruptions, leading to lower dose intensity than ease at diagnosis, up to 70% of patients eventually planned and adversely affecting the incorporation of the develop metastases [1]. For decades, the backbone of drug into clinical practice. therapy for patients with metastatic colorectal cancer In the CORRECT, the highest incidence of (mCRC) was 5-fluorouracil (5-FU) with leucovorin. In treatment-related adverse events (AEs) occurred dur- the late 1990s, oxaliplatin and irinotecan were added to ing the first two cycles of treatment [8]. Moreover, the therapeutic arsenal, and when administered with 5- regorafenib’s recommended dose and schedule that FU improved median overall survival (OS) to nearly 24 was used in the study and incorporated to drug months [2e4]. In the last two decades, the development labelling was determined in a small phase 1 trial that of targeted biologic agents, improvements in surgical recommended a dose of 160 mg QD administered for 3 techniques, and a better understanding of the molecular weeks followed by 1 week off treatment in 4-week biology of cancer have improved median OS to nearly 30 cycles. Of note, with this dose and schedule, 2 of the months [5e7]. However, a large majority of patients who total 12 patients (16.7%) had a dose limiting toxicity develop disease progression despite standard therapies (DLT), while at the next lower tested dose of 120 mg maintain a good performance status, creating a demand QD 3 weeks on 1 week off, among 7 patients treated, for active antineoplastic drugs in the refractory setting. none experienced any DLT [10]. Additional studies Regorafenib is a multityrosine kinase inhibitor (TKI) tested other dose and schedule strategies similar to with a broad biological spectrum of action. In two those used in the development of other multi-TKIs randomised, controlled, phase III trials (the CORRECT [11,12]. One alternative intermittent dose approach and the CONCUR studies), regorafenib treatment used regorafenib at 160 mg administered once daily increased the overall survival of patients with mCRC (QD) for 1 week on 1 week off. This strategy was after disease progression on multiple drug regimens tested in a population receiving first-line therapy for 156 G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 Fig. 1. Trial design. mCRC in combination with modified FOLFOX6 in 2. Patients and methods the CORDIAL trial [13], demonstrating a favourable safety profile. 2.1. Trial design Integrating the data resulting from the CORRECT, CONCUR, and CORDIAL trials, with the observations This multinational randomised, three-arm, open-label, on the phase 1 study, we designed the REARRANGE phase 2 trial, carried out by the Spanish Cooperative trial to evaluate the feasibility, tolerability, and potential Group for the Treatment of Digestive Tumors (TTD) impact on efficacy of two different dose-escalation ap- Group, was conducted in accordance with the Decla- proaches of regorafenib in refractory mCRC patients on ration of Helsinki and Good Clinical Practice Guide- a European practice environment. lines. Prerandomisation written informed consent was Fig. 2. CONSORT diagram. G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 157 Table 1 Baseline characteristics: intention-to-treat population (n Z 299). Arm A (n Z 101) Arm B (n Z 99) Arm C (n Z 99) Median age (years, Q1-Q3)a 65 (56e70) 63 (56e70) 63 (56e69) Sex Men 59 (58%) 53 (54%) 52 (53%) Women 42 (42%) 46 (46%) 47 (47%) ECOGa 0 36 (36%) 33 (33%) 35 (35%) 1 65 (64%) 66 (67%) 64 (65%) Primary site of disease Colon 53 (52%) 59 (60%) 49 (50%) Right 22 (22%) 13 (13%) 15 (15%) Transverse 9 (9%) 6 (6%) 5 (5%) Left 22 (22%) 40 (41%) 29 (29%) Rectum 31 (31%) 22 (22%) 39 (39%) Both 17 (17%) 18 (18%) 11 (11%) KRAS mutation No 29 (29%) 40 (40%) 39 (39%) Yes 72 (71%) 59 (60%) 60 (61%) BRAF mutation No 32 (32%) 31 (31%) 31 (31%) Yes 2 (2%) 3 (3%) 3 (3%) Unknown 67 (66%) 65 (66%) 65 (66%) Prior surgery 83 (82%) 81 (82%) 79 (80%) Prior radiotherapy Yes 28 (28%) 22 (22%) 27 (27%) No 73 (72%) 77 (78%) 72 (73%) Number of previous systemic 4 (3e5) 4 (3e5) 3 (3e5) anticancer lines after diagnosis of metastatic disease (median, Q1-Q3) Previous systemic anticancer drugs with palliative intention Fluoropyrimidines 101 (100%) 98 (99%) 98 (99%) Oxaliplatin 85 (84%) 83 (84%) 86 (87%) Irinotecan 101 (100%) 99 (100%) 99 (100%) Bevacizumab/Aflibercept 99 (98%) 96 (97%) 99 (100%) Cetuximab/Panitumumab 31 (31%) 40 (40%) 40 (40%) Others 26 (26%) 41 (41%) 26 (26%) a Stratification factor. obtained from all patients. The Institutional Ethics followed by 1 week off therapy during the first cycle), Review Board of all participating centres approved the or arm C (160 mg/d 1 week on/1 week off during the protocol. first cycle) (Fig. 1). In patients allocated to arms B or C, doses were escalated to 160 mg QD for 3 weeks 2.2. Patient selection followed by 1 week off from cycle 2 onwards, unless they experienced relevant toxicity (Supplementary file Eligibility criteria were identical to the CORRECT and S2 details the prespecified toxicities that preclude dose CONCUR trials (see Supplementary file S1). escalation and Supplementary file S3 the administered dose levels to patients enrolled on each of the study’s 2.3. Randomisation and dose modification arms). At the discretion of the investigator, once toxicities Randomisation was centralised, using permuted resolved, patients could have their doses escalated to blocks with stratification by ECOG performance sta- the standard dose. Treatment was discontinued tus (0 vs.1) and age (70 years or less vs. > 70 years), permanently if the patient did not recover from the with a block size of six patients who were randomly toxicities after a 4-week delay or after dose reduction assigned in an 1:1:1 ratio to arm A (the approved by two dose levels. The protocol called for treatment to regorafenib regimen of 160 mg/d for 3 weeks followed continue until disease progression, intolerance, with- by 1 week off therapy), arm B (120 mg/d for 3 weeks drawal of consent by the patient, or at physician 158 G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 Table 2 Treatment compliance (safety population). Arm A (n Z 100) Arm B (n Z 98) Arm C (n Z 99) p-value Treatment duration (months): mean (SD) 3.2 (2.4) 3.8 (3.4) 3.8 (3.3) 0.39 RDI cycles 1 and 2: mean (SD) 71.2 (25.9) 70.2 (26.6) 79.7 (24.7) 0.006 At least one dose delay: n (%) 35 (35.0) 33 (33.7) 29 (29.3) 0.49 At least one dose reduction: n (%) 39 (39.0) 38 (38.8) 25 (25.3) 0.09 At least one dose interruption: n (%) 81 (81.0) 77 (78.6) 69 (69.7) 0.11 RDI, relative dose intensity; SD, standard deviation. Table 3 Summary of type of adverse events per patient (safety population). Arm A (n Z 100) Arm B (n Z 98) Arm C (n Z 99) p-value At least one TRAE: n (%) 97 (97.0) 96 (98.0) 98 (99.0) 0.79 At least one grade 3/4 AE 74 (74.0) 66 (67.4) 67 (67.7) 0.52 At least one grade 3/4 TRAE 60 (60.0) 55 (56.1) 54 (54.5) 0.73 Discontinued due to AEs 28 (28.0) 29 (29.6) 20 (20.2) 0.27 Grade 5 TRAE 1 (1.0) 0 (0.00) 1 (1.0) 1.00 At least one SAE 29 (29.0) 29 (29.6) 24 (24.2) 0.65 At least one TR-SAE 9 (9.0) 10 (10.2) 9 (9.1) 0.95 AE, adverse event; SAE, serious adverse event; TRAE, treatment-related adverse event; TR-SAE, treatment-related serious adverse event. discretion. After treatment discontinuation, patients were graded using the National Cancer Institute Com- were monitored at least once every 3 months via clinic mon Toxicity Criteria for Adverse Events (NCI- visit or telephone. CTCAE) version 4.03 and recorded from randomisation to the final study visit. 2.4. Evaluations during the study 2.5. Statistical analysis Baseline and follow-up evaluations included a complete medical history, physical examination, haematological Based on the safety data from the CORRECT trial [8], and biochemical blood analyses, thyroidal hormones, we assumed that 54% of patients in arm A would urinalysis, carcinoembryonic antigen, electrocardio- develop G3/G4 treatment-related AEs. A sample size of gram, and abdominal-pelvic and thoracic computerised 93 patients per treatment group would provide at least axial tomography or magnetic resonance imaging (see 80% of power to detect a 20%-point difference in the supplementary file S4 for study’s flow chart). Toxicities percentage of patients with G3/G4 treatment-related Fig. 3. Treatment-related grade 3-4 adverse events occurring in >2% of patients. G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 159 Table 4 Comparison of G3 adverse events (occurring in 5% of patients) in cycles 1 and 2 versus subsequent cycles. Arm A (n Z 100) Arm B (n Z 98) Arm C (n Z 99) Cycles 1 þ 2 Cycles 3þ Cycles 1 þ 2 Cycles 3þ Cycles 1 þ 2 Cycles 3þ Total  G3 AEs 55% 15% 55% 8% 45% 14% Asthenia þ fatigue 16% 4% 14% 1% 11% 4% Hypertension 17% 4% 12% 0% 18% 2% Hypokalemia 10% 4% 7% 1% 7% 6% HFSR 6% 2% 4% 3% 3% 0% GGT increased 2% 0% 7% 0% 2% 0% Proteinuria 6% 0% 3% 0% 1% 0% Rash 1% 0% 3% 1% 2% 0% AST increased 0% 1% 4% 0% 1% 0% Decreased appetite 2% 0% 4% 0% 2% 0% AE, adverse event; HFSR, handefoot skin reaction. AEs in arm B and arm C, assuming a 0.05 one-sided cycles 1 and 2 was significantly higher in arm C than in significance level and after adjusting for multiple com- the other two arms although the number of patients parisons using the Bonferroni method. Considering a requiring dose delay, reduction, and interruption was 5.5% drop-out rate, a total of 295 patients should be similar in all three study arms (Supplementary file S6). included. The protocol did not plan for nor was it AEs, mainly handefoot skin reaction (HFSR) and hy- powered for comparisons between arm B versus arm C. pertension, were the most common reasons for dose Patients who received at least one dose of study modification (Supplementary file S7). treatment comprised the safety population. The All subjects (100%) reported at least one AE. Table 3 intention-to-treat population was defined as all rando- summarises the incidence and type of AEs by treatment mised patients, irrespective of whether they receive study arm. One-hundred and sixty-nine subjects (57%) pre- medication. sented at least one grade 3/4 treatment-related AE: 60% The primary end-point was the percentage of patients arm A, 56% arm B, and 55% arm C. These differences with G3/G4 treatment-related AEs in each arm using between arms were not statistically significant CTCAE v4.03 criteria. The safety population was used (p Z 0.7262). The most frequently reported AEs to analyse the primary and secondary objectives related (occurring in 30% of subjects) were fatigue (67%), to safety and tolerability. AEs and laboratory abnor- hypertension (46%), dysphonia (46%), HFSR (45%), malities were reported by treatment group, category, decreased appetite (43%), and diarrhoea (41%). Fig. 3 and worst grade (see Supplementary file S5 for the and Supplementary file S8 show treatment-related complete statistical assumptions). grade 3e4 AEs that occurred in 2% of patients. There were two deaths (arm A n Z 1, 1%; arm C n Z 1, 3. Results 1%) attributed to AEs unassociated with disease progression. Between July 2016 and September 2017, 299 patients A detailed analysis of G3 or higher AEs occurred from 19 (13 Spanish, 2 Italian and 4 French) hospitals during C1 and C2 in different arms showed a numerical decrease of G3 or higher overall AE (45 versus 55%), were randomised to arm A (n Z 101), B (n Z 99), or C (n Z 99) and 297 received at least one dose of study fatigue (11 versus 16%), HFSR (3 versus 6%), and treatment (arm A n Z 100, arm B n Z 98, arm C proteinuria (1 versus 6%) in the intermittent versus n Z 99: population for safety analyses) (Fig. 2). Baseline standard dosing arm comparison, not being this trend as patient characteristics, which were stratified according pronounced on the reduced-dose schedule (Table 4). ECOG (0 versus 1) and age (70 years or less versus > 70 years), were well balanced between groups (Table 1). 3.2. Treatment efficacy 3.1. Treatment compliance and safety As of November 26, 2018, there were 80, 78, and 83 patients that had died in arm A, arm B, and arm C, The mean duration of treatment was 3.0, 3.7, and 3.8 respectively. Those deaths were attributed to disease months for arms A, B, and C, respectively, with no progression in 87% of cases. Median OS was 7.39 (IQR statistically significant differences (Table 2). After the 3.96e13.70) months in arm A, 8.58 (IQR 3.78e13.38) first cycle, 45% of patients in arm B and 64% in arm C months in arm B, and 7.13 (IQR 4.37e12.43) months in escalated to the full dose (160 mg QD for 3 weeks fol- arm C (Fig. 4a), with no statistically significant differ- lowed by 1 week off). The relative dose intensity in ence (p Z 0.7222) between the arms. At 1 year, 32.41%, 160 G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 Fig. 4. a: Overall survival KaplaneMeier curve. b: Progression-free survival KaplaneMeier curve. 32.3%, and 27.8% of the patients in arms A, B, and C Two patients assigned to arm A, two in arm B, and three were alive. in arm C had a partial response. The overall disease Median progression-free survival (PFS) was 1.94 control rate was 33% (95% CI 23.67e42.72) in arm A, (IQR 1.78e3.68) in arm A, 2.00 (IQR 1.78e5.52) 36% (95% CI 26.93e46.64) in arm B, and 35% (95% CI months in arm B, and 2.00 (IQR 1.81e4.80) months in 26.01e45.60) in arm C (p Z 0.8515). arm C, with no statistically significant difference When the classical prognostic factors used in COR- (p Z 0.3795) between the three arms (Fig. 4b). RECT trial [8] were applied to PFS and OS analysis, we Median time to treatment failure (TTF) was 1.87 saw a trend towards a more favourable PFS on the two (IQR 1.71e3.48) months in arm A, 1.94 (IQR experimental arms taken as a whole and a neutrality in 1.68e4.24) months in arm B, and 1.94 (IQR 1.74e3.93) OS (Supplementary file S10). The post hoc nature of this months in arm C, with no statistically significant dif- analysis, though precluding the establishment of any ference (p Z 0.2114) between the three arms (Supple- conclusion per se, reinforces the lack of any detrimental mentary file S9). No patients had a complete response. effect in efficacy derived from the initial dose-reduction. G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 161 4. Discussion in the ranges reported by other regorafenib studies conducted in the setting [8,9,14,15]. The REARRANGE trial showed a modest numerical Furthermore, the overall tolerability and efficacy improvement in patient overall tolerability profiles, figures were consistent with those reported by the failing to meet its primary end-point of significantly American postmarketing Phase II study ReDOS, which decreasing the percentage of patients presenting G3/4 explored an alternative starting dose of 80 mg and AEs during the entire course of regorafenib treatment. specified 40 mg weekly regorafenib dose scalations We attribute this observation to (1) stringency of the during the first cycle dependent on observed toxicities primary end-point, (2) duration of the initial dose [8,9,14,15]. However, relevant differences are seen when deintensification in relation to median TTF, and (3) the the percentage of patients starting C3 eprimary end- high proportion of patients escalating to full dose point of REDOS study e is compared. While similar beyond C1 in both experimental arms. However, the proportion of patients started C3 in the experimental particularities of the European regulatory and practice arms of both trials (43% REDOS versus 45% and 46% environments requested pursuing simplified alternative REARRANGE B and C), a higher percentage of pa- dose schedules while keeping up as much as possible tients initiated C3 in the control arm of our study 39% with the labelling of the drug, since the incorporation to versus 26%. Differences may be explained due to normal clinical practice of our alternative schedules was different practice environments and patient populations. pursued. Nevertheless, a detailed analysis revealed some relevant qualitative toxicity improvements in both 5. Conclusions REARRANGE experimental arms that should be taken into consideration. The incidence of grade 3 REARRANGE is the largest study reported so far HFSR was half as lower in the intermittent dosing arm showing the feasibility and efficacy of alternative than in the control arm. We do believe this is of clinical regorafenib dose-escalation schedules in patients with relevance since to patients HFSR is one of the most chemorefractory mCRC, with a trend towards a better bothersome AEs resulting from regorafenib treatment. safety profile compared with the current recommended Remarkably, while some authors have reported that dosing schedule of this drug, particularly for the clini- mCRC patients treated with regorafenib who experi- cally relevant AEs of fatigue and HFSR. Out of the two enced severe HFSR showed better OS, we did not alternatives explored, intermittent dosing seems to observe this trend in our study [16]. Fatigue is another favour a better tolerability during C1 and C2. However, AE typical form TKIs with impact on patient’s quality the lack of double-blinding and the limited sample size of life. Reported grade 3 fatigue figures were numeri- in this randomised Phase II study, while informative, cally lower in arms B (14%) and C (15%) than in the lack the power inherent in a Phase III randomised standard dose arm (20%). In contrast, the most clinical trial, and such a study is unlikely to be frequent regorafenib-related AE of grade 3 was hy- completed. Therefore, the outcome of this trial has to be pertension with 20% of patients affected in arms A and interpreted as one more piece of data that supports the C, almost doubling the rate reported in CORRECT, implementation of alternative regorafenib starting CONCUR, or REBECCA. However, this AE tends to schedules in normal clinical practice on a European be manageable and rarely interfered with patients practice environment. quality of life in other regorafenib trials [17]. Moreover, hypertension is a pharmacodynamic effect of multi- Author contributions TKIs and might be in relation with the high proportion of patients starting C2 at full dose on arms A and C in Guillem Argilés and Josep M. Tabernero: Con- our trial [18]. The initial intermittent dosing was the ceptualisation, Methodology, Project administration, explored alternative schedule that showed a trend to- Writing e Original draft preparation. Guillem Argilés: wards a greater reduction on rates of G3/4 fatigue, Supervision and Visualisation All authors: Investigation, HFSR and proteinuria versus normal dose during the Writing e reviewing and editing. first two cycles, an observation of relevance since this period corresponds to regorafenib’s median PFS. Although the study was not powered to find differ- Role of the funding source ences on efficacy, numbers show that dose dein- tensification during the first treatment cycle had no Financial support for this research was provided by significant numerical impact on OS, PFS, TTF, or dis- Bayer HealthCare Pharmaceuticals Inc., which has no ease control rate, being confidence intervals for these role in the design of the study; collection, analysis, and parameters in each of the arms almost overlapping, and interpretation of data; and in writing the manuscript. 162 G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 The results reported in this manuscript are originals Universitario Regional y Virgen de la Victoria, Málaga, and were presented in part as oral presentation at the Spain; E. Aranda and M.T. Cano, H. Universitario ESMO World Congress on Gastrointestinal Cancers Reina Sofı́a, Córdoba, Spain. 2019. F. Loupakis, IOV (Istituto oncologico Veneto), Italy; M. Rguez Garrote and C. Guillén, H. Ramón y Cajal, Madrid, Spain; F. Rivera, H. Marqués de Valdecilla, Conflict of interest statement Santander, Spain. J. Safont, H. General Universitario, Valencia, Spain; The authors declare the following financial interests/ S. Hiret, Institut de Cancérologie de l’Ouest, France; J. personal relationships which may be considered as po- Bennouna, CHU-Nante, France; D. Pannier, Centre tential competing interests: G. Argilés received advisory Oscar Lambret, France; D. Malka, Gustave Roussy , honoraria, from Gadetta BV. Amgen, Bayer and Serv- France; A. Falcone and C. Cremolini, A. O. Uni- ier; M. Valladares-Ayerbes received honoraria, travel versitaria Pisana, Italy. grants, and research grants from Hoffman La Roche, TTD Data Center: Inmaculada Ruiz de Mena and Bristol-Myers Squibb, Bayer, Servier, Amgen, Merck Susana Rodriguez Statistics and Data Management: Serono and Sanofi. N. Mulet received grants and non- Pivotal. financial support from Merck Serono, Amgen and Support for third-party writing assistance for this Roche, outside the submitted work; M. Tobeña received manuscript was provided by Pivotal. personal fees from Amgen, Kyowa Kirin and Grunen- thal, non-financial support from Merck, Roche and Appendix A. Supplementary data Rovi, outside the submitted work; B. Garcı́a received personal fees from Advanced Accelerator Applications Supplementary data to this article can be found online (a Novartis company), Amgen, Bayer Hispania, Eisai, at https://doi.org/10.1016/j.ejca.2022.09.037. Lilly, MSD and Roche Farma, personal fees and non- financial support from Ipsen, Merck, Novartis, Sanofi- Aventis and Servier, outside the submitted work; E. References Aranda received honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche and Sanofi; C. [1] Shah MA, Renfro LA, Allegra CJ, et al. Impact of patient factors Cremolini received honoraria for Advisory Board/ on recurrence risk and Time dependency of oxaliplatin benefit in Speaker from Amgen, Bayer, Merck, MSD, Roche, patients with colon cancer: analysis from modern-era adjuvant studies in the adjuvant colon cancer end points (ACCENT) Servier and Research, grants from Bayer, Roche and database. J Clin Oncol 2016;34:843e53. Servier. The other authors have stated that they have no [2] Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized conflicts of interest. trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale. J Clin Oncol 2005;23: Acknowledgements 4866e75. [3] Goldberg RM, Sargent DJ, Morton RF, et al. A randomized The authors thank the medical and nursing staff from controlled trial of fluorouracil plus leucovorin, irinotecan, and all the participating institutions, the patients, and their oxaliplatin combinations in patients with previously untreated families for participating in the study, and the study metastatic colorectal cancer. J Clin Oncol 2004;22:23e30. [4] Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by investigators for their cooperation and support. FOLFOX6 or the reverse sequence in advanced colorectal cancer: The REARRANGE investigators are as follows: a randomized GERCOR study. J Clin Oncol 2004;22:229e37. Principal investigator: Guillem Argilés and Josep [5] Grothey A, Marshall JL. Optimizing palliative treatment of Tabernero. metastatic colorectal cancer in the era of biologic therapy. Oncology (Williston Park) 2007;21:553e64. 566; discussion 566- Steering Committee: Josep Tabernero, Guillem Arg- 558, 577-558. ilés, Alfredo Falcone, Fortunato Ciardiello, Richard [6] Loree JM, Kopetz S, Raghav KP. Current companion diagnostics Goldberg, and Jaafar Bennouna. Investigators: in advanced colorectal cancer; getting a bigger and better piece of Argilés and J. Tabernero and N. Mulet, H. Uni- the pie. J Gastrointest Oncol 2017;8:199e212. versitari Vall d’Hebron, Barcelona, Spain; M. L. Limón [7] Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus and M. Valladares. H. Virgen del Rocı́o, Sevilla, Spain; guidelines for the management of patients with metastatic colo- rectal cancer. Ann Oncol 2016;27:1386e422. P. Jiménez and J. Ma Vieitez, H. Universitario Central [8] Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib mon- de Asturias, Spain; C. Grávalos. H. 12 de Octubre, otherapy for previously treated metastatic colorectal cancer Madrid, Spain; P. Garcı́a-Alfonso, H. Gregorio Mar- (CORRECT): an international, multicentre, randomised, añón, Madrid, Spain; C. Santos, ICO. placebo-controlled, phase 3 trial. Lancet 2013;381:303e12. H. Duran i Reynals, Barcelona, Spain; D. Páez and [9] Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with M. Tobeña, H. Santa Creu i Sant Pau, Barcelona, Spain; previously treated metastatic colorectal cancer (CONCUR): a J. Sastre and B. Garcı́a Paredes, H. Universitario Clı́n- randomised, double-blind, placebo- controlled, phase 3 trial. ico San Carlos, Madrid, Spain; M. Benavides, Hospital Lancet Oncol 2015;16:619e29. G. Argilés et al. / European Journal of Cancer 177 (2022) 154e163 163 [10] Mross K, Frost A, Steinbild S, et al. A phase I dose-escalation standard therapy: results of the large, single-arm, open-label study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, phase IIIb CONSIGN study. Oncol 2019;24:185e92. angiogenic, and stromal kinases, in patients with advanced solid [15] Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose- tumors. Clin Cancer Res 2012;18:2658e67. optimisation in patients with refractory metastatic colorectal [11] Kondo T, Takagi T, Kobayashi H, et al. Superior tolerability of cancer (ReDOS): a randomised, multicentre, open-label, phase 2 altered dosing schedule of sunitinib with 2-weeks-on and 1-week- study. Lancet Oncol 2019;20:1070e82. off in patients with metastatic renal cell carcinoma–comparison to [16] Kobayashi K, Kawakami K, Yokokawa T, et al. Association standard dosing schedule of 4- weeks-on and 2-weeks-off. Jpn J of hand-foot skin reaction with regorafenib efficacy in the Clin Oncol 2014;44:270e7. treatment of metastatic colorectal cancer. Oncology 2019;96: [12] Strumberg D, Clark JW, Awada A, et al. Safety, pharmacoki- 200e6. netics, and preliminary antitumor activity of sorafenib: a review [17] Sastre J, Argiles G, Benavides M, et al. Clinical management of of four phase I trials in patients with advanced refractory solid regorafenib in the treatment of patients with advanced colorectal tumors. Oncol 2007;12:426e37. cancer. Clin Transl Oncol 2014;16:942e53. [13] Argiles G, Saunders MP, Rivera F, et al. Regorafenib plus [18] Jesus-Gonzalez de N, Robinson E, Penchev R, et al. modified FOLFOX6 as first-line treatment of metastatic colo- Regorafenib induces rapid and reversible changes in rectal cancer: a phase II trial. Eur J Cancer 2015;51:942e9. plasma nitric oxide and endothelin-1. Am J Hypertens 2012;25: [14] Van Cutsem E, Martinelli E, Cascinu S, et al. Regorafenib for 1118e23. patients with metastatic colorectal cancer who progressed after