
==== Front
Future Oncol
Future Oncol
Future Oncology
1479-6694
1744-8301
Taylor & Francis

38861286
10.1080/14796694.2024.2340422
2340422
Version of Record
Rapid Communication
Rapid Communication
Regorafenib in patients with metastatic colorectal cancer in Spain: from clinical trials to real-world evidence
Cervantes Andres * a b
Tabernero Josep c
Garcia-Carbonero Rocio d
Sastre Javier e
Feliu Jaime f
Carmen Guillén-Ponce g
Paredes Beatriz García e
Carral Alberto h
Muñoz Jorge i
a Medical Oncology Department, Biomedical Research Institute INCLIVA, Hospital Clínico de Valencia, Universidad de Valencia, Valencia, Spain
b CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
c Medical Oncology Department, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain
d Medical Oncology Department, Hospital Universitario 12 de Octubre, Imas12, UCM, CIBERONC, Madrid, Spain
e Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain
f Medical Oncology Department, Hospital Universitario La Paz, IDIPAZ, CIBERONC, Cátedra UAM-AMGEN, Madrid, Spain
g Medical Oncology Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
h Medical Oncology Department, Hospital Universitario Lucus Augusti, Lugo, Spain
i Medical Oncology Department, Hospital San Pedro de Alcántara, Cáceres, Spain
* CONTACT: Tel.: +34 961973543; andres.cervantes@uv.es
11 6 2024
2024
11 6 2024
20 20 14011413
Aptara6 4 2024
10 6 2024
29 3 2023
04 4 2024
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

Aim: To describe the evolution of regorafenib use, since its approval, in patients with previously treated metastatic colorectal cancer (mCRC) in routine clinical practice in Spain.

Methods: We extracted patient characteristics, dosing, safety and efficacy data for the Spanish cohorts of the CORRECT and CONSIGN trials, and the real-world CORRELATE study.

Results: The Spanish cohorts represented 10.7–13.8% of the global cohorts. Efficacy and safety in the Spanish cohorts reflected findings from the global cohorts, with evidence of a flexible dosing approach being adopted in routine clinical practice.

Conclusion: Regorafenib use in patients with mCRC has evolved in the real-world setting, emphasizing the need for further research evaluating dosing patterns that can optimize clinical outcomes in these patients.

Clinical trial registration: The CORRECT trial is registered at ClinicalTrials.gov, number NCT01103323; the CONSIGN trial is registered at ClinicalTrials.gov, number NCT01538680; the CORRELATE study is registered at ClinicalTrials.gov, number NCT02042144.

Plain Language Summary

Bowel cancer (also called colorectal cancer) affects the large bowel, including the colon and rectum. Approximately one in ten patients with advanced bowel cancer that has spread to other areas of the body (metastatic bowel cancer) survive 5 years after diagnosis or the start of treatment.

Regorafenib is a treatment for patients with advanced bowel cancer that has continued to spread after receiving other treatments. It can slow down cancer growth, as shown in three international studies (CORRECT, CONSIGN and CORRELATE). In Spain, bowel cancer is the most common type of cancer and the cancer that causes the second most deaths. This study describes how the use of regorafenib in Spain has changed since it was approved in 2012, by looking at the patients from Spain who made up 11–14% of the participants in the three international studies.

The CORRECT trial that compared regorafenib with a non-therapeutic placebo and the CONSIGN trial of regorafenib alone showed that treatment with regorafenib prolonged life and was well tolerated in patients with metastatic bowel cancer who had previously received or were not suitable to receive other treatments. The CORRELATE study showed that in the real world (i.e., outside of a controlled clinical trial), patients are sometimes prescribed regorafenib at lower starting doses than the recommended dose, without an apparent overall effect on how well regorafenib works or side effects. In the future, it will be important to continue researching how doctors prescribe regorafenib in daily clinical practice in Spain.

Tweetable Abstract

This article describes how #Stivarga use in Spain has evolved since its approval for metastatic #colorectalcancer, by analyzing data from Spanish patients enrolled in three international studies (CORRECT, CONSIGN and CORRELATE).

Summary points

In Spain, metastatic colorectal cancer (mCRC) is ranked first among cancers in terms of incidence and second in terms of mortality.

An increasing number of patients with mCRC reaching third or further line therapy are able to receive additional treatment, including anti-tumor therapy.

The oral multikinase inhibitor regorafenib was first approved in 2012, based on the results of the international, phase III randomized controlled trial CORRECT (NCT01103323).

Safety was further evaluated in a larger population in the international, phase IIIb, single-arm trial CONSIGN (NCT01538680).

Safety and efficacy were subsequently evaluated in an unselected, real-world population of patients in the international, prospective, observational CORRELATE study.

This report presented data for the Spanish cohorts of these three prospective studies, representing 10.7–13.8% of the corresponding global cohorts.

Overall, efficacy and safety in the Spanish cohorts reflect the findings from the corresponding global cohorts.

Importantly, a proportion of the Spanish cohort of CORRELATE initiated treatment at a dose lower than the approved 160 mg/day, with 9.1% of patients starting at 120 mg/day and 7.7% starting at 80 mg/day.

These three studies, separated by time, design and sample size, showed that a flexible dosing approach has been adopted in routine clinical practice since initial regorafenib approval.

Regorafenib use in patients with mCRC has evolved in the real-world setting, emphasizing the need for further research evaluating dosing patterns that can optimize clinical outcomes in these patients.

Keywords: 

evolution
clinical trial
metastatic colorectal cancer
real-world evidence
regorafenib
Spain
Bayer HealthCare 10.13039/501100000801 This study was funded by Bayer. The CORRECT, CONSIGN and CORRELATE studies were supported by Bayer HealthCare Pharmaceuticals. A Carral: advisory role honoraria and speaker honoraria from Amgen, Bayer, Bristol Myers Squibb (BMS), Eisai, Eli Lilly, Grunenthal, Kyowa Kirin, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi and Servier. A Cervantes: institutional research funding from Astellas, Bayer, BeiGene, BMS, Eli Lilly, FibroGen, Genentech, Merck Serono, MSD, Novartis, Roche, Servier and Takeda; and advisory board or speaker fees from Amgen, Bayer, Merck Serono, Pierre Fabre, Roche and Servier in the last 5 years. BG Paredes: advisory role honoraria and speaker honoraria from Advanced Accelerator Applications (a Novartis company), Amgen, Bayer Hispania, Eisai, Eli Lilly, Ipsen, Merck, MSD, Novartis, Roche Farma, Sanofi-Aventis and Servier. C Guillén-Ponce: contracts for clinical trials from AstraZeneca, Boston Scientific, ERYTECH, IPSEN and QED Therapeutics; and support for attending meetings and/or travel from AstraZeneca, General Electric, Merck Serono and Sanofi-Aventis. J Feliu: has received consulting and advisory honoraria from Amgen, Eisai, Ipsen, Merck, Novartis, Organon, Roche, Sirtex and Viatris; and research funding from Amgen and MSD. J Sastre: scientific consultancy role for Amgen, Bayer, BMS, Celgene, Ipsen, Merck, Roche, Sanofi and Servier; speaker honoraria from Eli Lilly, Ipsen, Merck, MSD, Pfizer, Roche, Servier and Shire. J Tabernero: personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, HalioDx SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Menarini, Merck Serono, Merus, Mirati, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, SOTIO Biotech, Taiho, Tessa Therapeutics and TheraMyc; stocks: Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource. R Garcia-Carbonero: provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, Boehringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier and Sanofi; and has received research support from BMS, MSD and Pfizer.
==== Body
pmc1. Background

In Spain, colorectal cancer (CRC) is ranked first among cancers in terms of incidence, with 40,441 estimated new cases, and second in terms of mortality, with an estimated 16,470 deaths each year, based on 2020 statistics [1]. Despite treatment advances over the past two decades, metastatic CRC (mCRC) remains associated with a poor prognosis, having a 5-year survival rate of 14% [2–4]. However, an increasing number of patients with mCRC reaching third-line or further line therapy still have a good performance status, which offers opportunities for additional treatment options, including active antitumor therapy [4,5].

Regorafenib is an oral multikinase inhibitor that targets several tyrosine kinases involved in the regulation of tumor angiogenesis, oncogenesis, tumor immunity and the tumor microenvironment [6]. It was first approved in 2012 for the treatment of patients with mCRC who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy, and, if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy, based on the results of the international, phase III randomized controlled trial (RCT) CORRECT (NCT01103323) [7–9]. The safety of regorafenib was subsequently evaluated in a larger population in the international phase IIIb single-arm study CONSIGN (NCT01538680), which reported consistent frequency and severity of adverse events. Progression-free survival (PFS) was the only efficacy variable assessed and was similar to that reported in other phase III trials [10]. In the international, prospective, observational CORRELATE study (NCT02042144), safety and efficacy of regorafenib were evaluated in an unselected, real-world population of patients. A key finding was that safety and efficacy were in the range observed in RCTs, despite evidence that regorafenib was sometimes started at lower doses than the recommended 160 mg daily dose [11].

As these global studies included patients from countries with varying incidence trends of CRC, differences in patient characteristics, including genetic/lifestyle factors and treatment patterns, it is of interest to analyze individual country data and outcomes that cannot be extrapolated from global datasets [12]. Data for the French cohort of CORRELATE were published recently [13] and suggest different practice patterns, although outcomes were generally consistent with those of the global cohort. In Taiwanese CORRELATE patients, different practice patterns were also evident, including more frequent reductions in starting dose; outcomes were consistent with those seen in Asian patients in clinical trials [14]. In this analysis, we present clinical and real-world data for the Spanish cohorts of the CORRECT, CONSIGN and CORRELATE studies, which provide insights into the use of regorafenib in Spain.

2. Patients and methods

CORRECT, CONSIGN and CORRELATE were prospective, international studies that evaluated the safety and efficacy of regorafenib in patients with mCRC. CORRECT (2013) and CONSIGN (2019) were phase III clinical trials conducted according to strict protocols (including a prospectively defined starting daily dose of 160 mg) in patients meeting specific inclusion criteria. CORRELATE (2019) further expanded these findings by evaluating real-world use, safety and effectiveness of regorafenib in routine clinical practice between 2014 and 2017. The methodology of each study, including the complete inclusion/exclusion criteria, definition of end points, procedures, statistical analyses and primary results has been published previously (CORRECT [7], CONSIGN [10] and CORRELATE [11]). The key study design elements are summarized below and in Table 1.

Table 1. Summary of study design for the global cohorts of CORRECT, CONSIGN and CORRELATE.

Study	Key eligibility criteria	Study design	Treatments	Patients enrolled in the global cohort, (n/N, % patients from Spanish sites)	Primary and secondary endpoints	Ref.	
CORRECT	Patients with mCRC and disease progression within 3 months after the last approved standard therapy (must have included as many of the following as were licensed, depending on country: fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab for patients with KRAS wild-type tumors) or standard therapy termination due to unacceptable toxicity; ECOG PS 0/1	Randomized, double-blind, placebo-controlled, phase III	Regorafenib 160 mg once daily for 3 weeks on/1 week off in 4-week cycles + BSC
Placebo + BSC	Total: N = 760 (83/760, 10.9%)
Regorafenib: N = 505 (58/505, 11.5%)
Placebo: N = 255 (25/255, 9.8%)	Primary: OS
Secondary: PFS, ORR, DCR and safety	[7]	
CONSIGN	Same as CORRECT (a protocol amendment allowed inclusion of patients from Mexico and Russia who had not received bevacizumab or cetuximab/panitumumab)	Open-label, single-arm, phase IIIb	Regorafenib 160 mg once daily for 3 weeks on/1 week off in 4-week cycles + BSC	Regorafenib: N = 2864† (307/2864, 10.7%)	Primary: safety, including TEAEs %, grade 3 or more TEAEs, drug-related AEs and dose modifications due to AEs
Secondary: PFS	[10]	
CORRELATE	Patients with mCRC who were previously treated with, or who were not considered candidates for, other approved therapies and for whom a decision was made by the treating physician to treat with regorafenib, according to the local health authority approved label	Prospective, observational, cohort study	Regorafenib 160 mg/day: 57% patients
Regorafenib 120 mg/day: 30% patients
Regorafenib 80 mg/day: 12% patients	Regorafenib: N = 1037 (143/1037, 13.8%)	Primary: safety, including TEAEs %, grade 3 or more TEAEs, drug-related AEs and dose modifications due to AEs
Secondary: OS, PFS and DCR	[11]	
† Safety analysis set.

AE: Adverse event; BSC: Best supportive care; DCR: Disease control rate; ECOG PS: Eastern Cooperative Oncology Group performance status; mCRC: Metastatic colorectal cancer; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; TEAE: Treatment-emergent adverse event.

CORRECT was an RCT evaluating patients with mCRC who had Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and disease progression within 3 months of receiving approved standard therapies [7]. Between April 2010 and March 2011, 760 patients from 114 centers across 16 countries in North America, Europe, Asia and Australia were randomized 2:1 to receive best supportive care plus oral regorafenib 160 mg/day or placebo for the first 3 weeks of each 4-week cycle. The primary end point was overall survival (OS). Tumor assessments were conducted radiologically by investigators every 8 weeks according to the Response Evaluation Criteria in Solid Tumors version 1.1, or by investigator's clinical assessment if a patient could not have a radiological examination (e.g., because of deterioration of their medical condition).

The prospective, single-arm phase IIIb CONSIGN trial also enrolled patients with mCRC who had ECOG PS of 0 or 1 and disease progression within 3 months of receiving approved standard therapies [10]. Between April 2012 and December 2013, 2872 patients across 25 countries in Europe, North America, Israel and Australia were assigned to open-label regorafenib 160 mg/day for the first 3 weeks of each 4-week cycle. The primary end point was safety. PFS was the only efficacy variable assessed. Tumor assessments were conducted at intervals and with methods that complied with each institution's best standard of care.

The prospective observational CORRELATE study enrolled patients with mCRC who had previously received approved standard therapies, and for whom the treating physician had decided to prescribe regorafenib according to the local health authority-approved label [11]. The primary objective was to characterize safety in the real world, measured by treatment-emergent adverse events (TEAEs; assessed according to the National Cancer Institute – Common Terminology Criteria for Adverse Events version 4.03). The secondary objective was to evaluate effectiveness, measured by PFS and OS. The frequency of tumor assessments was not defined; assessments were conducted according to the treating physician's routine practice. Between April 2014 and July 2017, 1037 patients were treated across Europe, Asia and Latin America.

3. Results

A total of 4669 patients participated in the international CORRECT [7], CONSIGN [10] and CORRELATE [11] studies, of whom the Spanish cohorts comprised 508 patients treated with regorafenib and evaluable for the primary end points (58 in CORRECT, 307 in CONSIGN and 143 in CORRELATE; Table 1). In the Spanish cohort of the CORRECT trial, 83 patients (10.9% of the global cohort) were randomized to regorafenib or placebo (58 patients were randomized to receive regorafenib). All 83 patients were evaluable for efficacy, and 82 patients were evaluable for safety. In the Spanish cohort of the CONSIGN trial, 308 patients (10.7% of the global cohort) were assigned to treatment, and 307 patients were evaluable for safety. In the Spanish cohort of the CORRELATE real-world study, 147 patients were enrolled, and 143 patients (13.8% of the global cohort) were evaluable for safety and effectiveness.

3.1. Patient demographics and clinical characteristics

Main demographic and clinical characteristics of patients from the Spanish and global cohorts of CORRECT, CONSIGN and CORRELATE at the start of regorafenib therapy are presented in Table 2. Median age was slightly higher in the Spanish cohort of the real-world CORRELATE study (64.0 years) compared with CORRECT (61.5 years) and CONSIGN (62.0 years). Sex and body mass index were largely consistent in the Spanish cohorts of the three studies. CORRELATE included a larger proportion of patients of Hispanic or Latino ethnicity (20.3%) compared with the CORRECT (12.1%) and CONSIGN (6.8%) trials. An ECOG PS of 1 was reported for most Spanish patients across the three studies (58.6–67.2% of patients), although, unlike CORRECT and CONSIGN, CORRELATE did not restrict inclusion to patients with an ECOG PS of 0 or 1. Nevertheless, only three patients (2.1%) in CORRELATE had an ECOG PS of 2.

Table 2. Demographics and clinical characteristics in patients from the global and Spanish cohorts of CORRECT (regorafenib arm), CONSIGN and CORRELATE.

 	CORRECT	CONSIGN	CORRELATE	
 	Global cohort (N = 505) [7]	Spanish cohort (N = 58)	Global cohort (N = 2872) [10]	Spanish cohort (N = 308)	Global cohort (N = 1037) [11]	Spanish cohort (N = 143)	
Age, median (range), years	61.0 (22.0–82.0)	61.5 (36.0–82.0)	62.0 (19.0–89.0)	62.0 (32.0–83.0)	65.0 (24.0–93.0)	64.0 (37.0–83.0)	
Male, n (%)	311 (61.6)	35 (60.3)	1692 (58.9)	186 (60.4)	629 (60.7)	80 (55.9)	
Race, n (%)†	
  White	392 (77.6)	58 (100.0)	2374 (82.7)	302 (98.1)	643 (62.0)	142 (99.3)	
  Black	6 (1.2)	0	49 (1.7)	0	2 (0.2)	1 (0.7)	
  Asian	76 (15.0)	0	25 (0.9)	3 (1.0)	133 (12.8)	0	
  Other/missing	31 (6.1)	0	424 (14.8)	3 (1.0)	261 (25.2)	0	
BMI, median (range), kg/m2	24.8 (14.4–47.3)	25.5 (17.2–38.8)	25.6 (13.6–53.3)	26.3 (15.0–53.0)	24.4 (14.4–42.8)	26.2 (15.5–38.4)	
ECOG PS, n (%)	
  0	265 (52.2)	24 (41.4)	1357 (47.2)	98 (31.8)	426 (41.1)	51 (35.7)	
  1	240 (47.5)	34 (58.6)	1509 (52.5)	207 (67.2)	477 (46.0)	84 (58.7)	
  ≥2	0	0	0	0	66 (6.4)	3 (2.1)	
  Missing	0	0	6 (0.2)	3 (1.0)	68 (6.6)	5 (3.5)	
Primary site of disease, n (%)†	
  Colon	323 (64.0)	41 (70.7)	1846 (64.3)	204 (66.2)	721 (69.5)#	108 (75.5)	
  Rectum	151 (29.9)	14 (24.1)	808 (28.1)	74 (24.0)	315 (30.4)#	35 (24.5)	
  Colon and rectum	30 (5.9)	3 (5.2)	217 (7.6)	30 (9.7)	21 (2.0)#	3 (2.1)	
  Missing	1 (0.2)	0	1 (<0.1)	0	1 (0.1)	0	
Presence of liver or lung metastases at study entry, n (%)‡	
  Liver	360 (71.3)	38 (65.5)	2200 (76.6)	241 (78.2)	747 (72.0)	100 (69.9)	
  Lung	376 (74.5)	44 (75.9)	NR	NR	592 (57.1)	90 (62.9)	
KRAS mutation, n (%)§	273 (54.1)	34 (58.6)	1465 (51.0)	165 (53.6)	581 (56.0)	79 (55.2)	
Time from diagnosis of metastatic disease to initiation of regorafenib	
  Median (IQR or range), months	31.0 (IQR 20.6–43.3)	31.8 (IQR 20.6–40.4)	30.8 (range 0.6–200.7)	32.0 (range 0.9–195.0)	26.0 (range 0.4–169.2)	27.8 (range 4.4–122.2)	
  <18 months, n (%)	91 (18.0)	8 (13.8)	514 (17.9)	63 (20.5)	314 (30.3)	44 (30.8)	
  ≥18 months, n (%)	414 (82.0)	50 (86.2)	2350 (81.8)	244 (79.2)	714 (68.9)	98 (68.5)	
  Missing, n (%)	0	0	8 (0.3)	1 (0.3)	9 (0.9)	1 (0.7)	
Prior systemic anticancer therapies at any time, n (%)	
  Yes	505 (100)	58 (100)	2872 (100)	308 (100)	1025 (98.8)	139 (97.2)	
  No	0	0	0	0	12 (1.2)	4 (2.8)	
  Prior anti-VEGF	505 (100)	58 (100)	2754 (95.9)	299 (97.1)	896 (86.4)	118 (82.5)	
  Prior anti-EGFR	264 (52.3)¶	30 (51.7)	1479 (51.5)#	157 (51.0)	408 (39.3)	52 (36.4)	
Prior systemic anticancer therapies on or after diagnosis of metastatic disease, n (%)	
  0	0	0	17 (0.6)	1 (0.3)	12 (1.2)	0	
  1–2	135 (26.7)	15 (25.9)	743 (25.9)	94 (30.5)	316 (30.5)	49 (34.3)	
  3	125 (24.8)	15 (25.9)	777 (27.1)	91 (29.5)	307 (29.6)	43 (30.1)	
  ≥4	245 (48.5)	28 (48.3)	1335 (46.5)	121 (39.3)	402 (38.8)	47 (32.9)	
Data presented for the full analysis sets (CORRECT and CONSIGN) and safety analysis set (CORRELATE).

† In CORRELATE, multiple answers were possible for race and for primary site of disease.

‡ Patients may have had >1 metastatic site. Other metastatic sites may have been present.

§ KRAS mutational rate in archival tumor tissue in the CORRECT trial (reported) was based on historical record, with an exploratory analysis using BEAMing technology subsequently reporting mutation frequencies of 69.4% (349/503) in plasma and 58.6% (140/239) in archival tumor tissue in the global cohort [14]; BRAF mutation frequency was 3.4% (17/502) in plasma and 1.5% (4/269) in archival tumor tissue in this exploratory analysis of the global cohort of CORRECT [14].

¶ Panitumumab and/or cetuximab.

# Previously unpublished data.

BMI: Body mass index; ECOG PS: Eastern Cooperative Oncology Group performance status; EGFR: Epidermal growth factor receptor; IQR: Interquartile range; NR: Not reported; VEGF: Vascular endothelial growth factor.

KRAS mutational status was unknown in a small proportion of patients from the Spanish cohorts (CORRECT: 1.7%, CONSIGN: 2.6%, CORRELATE: 3.5%), with a KRAS mutation reported in more than half of patients with available data (CORRECT: 58.6%, CONSIGN: 53.6%, CORRELATE: 55.2%). BRAF mutational status was also unknown in a large proportion of patients from the Spanish cohorts (CORRECT: 96.6%, CONSIGN: 93.8%, CORRELATE: 69.9%). NRAS mutations were not reported in CORRECT and CONSIGN, and were unknown in 60.1% of patients from the Spanish cohort of CORRELATE, with low mutation frequency reported among those with available data (2.1%).

Where reported, the most common metastatic sites at study entry were the liver (CONSIGN: 78.2%; CORRELATE: 69.9%) and the lung (CORRELATE: 62.9% of patients). The Spanish cohort of CORRECT had a higher proportion of patients with time from diagnosis of metastases to treatment initiation ≥18 months (86.2%) compared with CONSIGN (79.2%) and CORRELATE (68.5%).

All, or almost all, patients across the three studies in Spain had received prior systemic anticancer therapies, and the median time from diagnosis of metastatic disease to initiation of regorafenib was 27.8–32.0 months in the three studies. Among the Spanish cohorts, 48.3% of patients in CORRECT, 39.3% of patients in CONSIGN and 32.9% of patients in CORRELATE had at least four lines of prior systemic anticancer therapies. The proportion of patients receiving one or two lines of prior therapy was 25.9% in CORRECT, 30.5% in CONSIGN and 34.3% in CORRELATE.

3.2. Dosing, treatment duration and modifications

In CORRECT and CONSIGN, patients initiated regorafenib at 160 mg/day, whereas the initial dose was at the discretion of the prescribing physician in the real-world CORRELATE study. Details of dosing, treatment duration and modifications in the Spanish and global cohorts of the real-world CORRELATE study are provided in Table 3. Spanish patients assigned to regorafenib received 80.9% (standard deviation [SD] 21.5%) of the planned dose (mean daily dose 149.9 mg [SD 16.8 mg]) in CORRECT; the equivalent values in CONSIGN were 76.1% (SD 19.4%) and 146.8 mg (SD 18.4 mg), respectively. In CORRELATE, three doses were initiated in Spain: 80 mg/day in 7.7% of patients, 120 mg/day in 9.1% of patients and the approved daily dose of 160 mg/day in 83.2% of patients; the last documented daily dose was 120 or 160 mg/day in most patients (36.4 and 45.5%, respectively). Median duration of treatment was 2.1 months (range 0.1–10.1 months) in CORRECT, 2.5 months (range 0–21.2 months) in CONSIGN and 2.6 months (range 0.1–19.8 months) in CORRELATE (across all dose cohorts).

Table 3. Dosing and treatment duration in patients from the Spanish and global cohorts of CORRELATE.

 	CORRELATE
Global cohort (N = 1037) [11]	CORRELATE
Spanish cohort (N = 143)	
Duration of treatment, months	
  Median (range)	2.5 (<0.1–29.5)	2.6 (0.1–19.8)	
Starting daily dose, mg, n (%)	
  80	127 (12.3)	11 (7.7)	
  120	315 (30.4)	13 (9.1)	
  160	591 (57.0)	119 (83.2)	
Last documented daily dose, mg, n (%)	
  80	255 (24.6)	26 (18.2)	
  120	393 (37.9)	52 (36.4)	
  160	373 (36.0)	65 (45.5)	
Other	16 (1.5)	0	
Patients with any dose modification, n (%)†	678 (65.4)	97 (67.8)	
  Dose reduction	415 (40.0)	62 (43.4)	
  Dose interruption/delay	501 (48.3)	84 (58.8)	
† Modifications include reductions, interruptions, delays, re-starts, escalations and re-escalations for all dose cohorts combined.

Dose modifications (defined as reductions, interruptions, delays, escalations and re-escalations, as applicable) were required in 75.9% of patients in CORRECT, 87.3% of patients in CONSIGN and 67.8% of patients in CORRELATE. Adverse events were the most common reason for dose modification. The median time to a first dose modification was 20 days (range 3–403 days) in CORRELATE. Dose re-escalations occurred in 49.8% of patients in CONSIGN and 9.1% of patients in CORRELATE. The most common reason for discontinuing treatment was radiological disease progression, which occurred in 59.4–62.1% of patients across the three studies.

3.3. Safety

TEAEs and drug-related TEAEs reported in the Spanish cohorts of CORRECT, CONSIGN and CORRELATE are presented in Tables 4 and 5. All, or almost all, patients across the three studies experienced TEAEs (any grade). Of these, 50.0, 61.9 and 46.9% in CORRECT, CONSIGN and CORRELATE, respectively, were grade 3, 8.6, 4.9 and 5.6% were grade 4, and 19.0, 15.0 and 14.7% were grade 5 (Table 4).

Table 4. Safety (TEAEs and drug-related TEAEs) in patients from the Spanish cohorts of CORRECT (regorafenib arm), CONSIGN and CORRELATE.

TEAE, n (%)	CORRECT (N = 58)	CONSIGN (N = 307)	CORRELATE (N = 143)	
 	All TEAEs	Drug-related TEAEs	All TEAEs	Drug-related TEAEs	All TEAEs	Drug-related TEAEs	
Any TEAE	58 (100)	55 (94.8)	306 (99.7)	287 (93.5)	141 (98.6)	128 (89.5)	
Grade 3	29 (50.0)	24 (41.4)	190 (61.9)	172 (56.0)	67 (46.9)	56 (39.2)	
Grade 4	5 (8.6)	0	15 (4.9)	8 (2.6)	8 (5.6)	3 (2.1)	
Grade 5	11 (19.0)	2 (3.4)	46 (15.0)	3 (1.0)	21 (14.7)	1 (0.7)	
Serious	28 (48.3)	7 (12.1)	136 (44.3)	32 (10.4)	60 (42.0)	14 (9.8)	
Requiring discontinuation	14 (24.1)	7 (12.1)	81 (26.4)	29 (9.4)	45 (31.5)	21 (14.7)	
Requiring dose modification†	36 (62.1)	30 (51.7)	222 (72.3)	181 (59.0)	103 (72.0)	81 (56.6)	
Requiring dose reduction	19 (32.8)	NR	132 (43.0)	NR	34 (23.8)	33 (23.1)	
Data presented for the safety analysis sets. CORRECT: NCI-CTCAE version 3.0; CONSIGN: NCI-CTCAE version 4.0; CORRELATE: NCI-CTCAE version 4.03.

† Modifications due to drug-related TEAEs include delays, interruptions and reductions, as applicable.

NCI-CTCAE: National Cancer Institute Common Terminology for Adverse Event; NR: Not reported; TEAE: Treatment-emergent adverse event.

Table 5. Most common (occurring in ≥10% of patients in any study) drug-related TEAEs in patients from the Spanish cohorts of CORRECT (regorafenib arm), CONSIGN and CORRELATE.

Drug-related TEAE, n (%)	CORRECT (N = 58)	CONSIGN (N = 307)	CORRELATE (N = 143)	
 	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3	
Decreased platelet count	6 (10.3)	2 (3.4)	16 (5.2)	6 (2.0)	9 (6.3)	0	
Hypertension	16 (27.6)	2 (3.4)	102 (33.2)	50 (16.3)	25 (17.5)	14 (9.8)	
Fatigue	30 (51.7)	8 (13.8)	189 (61.6)	55 (17.9)	77 (53.8)	20 (14.0)	
Anorexia	11 (19.0)	0	90 (29.3)	17 (5.5)	27 (18.9)	1 (0.7)	
Constipation	6 (10.3)	0	34 (11.1)	0	9 (6.3)	0	
Diarrhea	20 (34.5)	3 (5.2)	86 (28.0)	15 (4.9)	32 (22.4)	2 (1.4)	
Mucositis (oral)	17 (29.3)	2 (3.4)	107 (34.9)	7 (2.3)	34 (23.8)	1 (0.7)	
Nausea	6 (10.3)	0	36 (11.7)	2 (0.7)	7 (4.9)	1 (0.7)	
Hyperbilirubinemia	6 (10.3)	2 (3.4)	40 (13.0)	14 (4.6)	2 (1.4)	0	
Voice changes	12 (20.7)	0	104 (33.9)	2 (0.7)	12 (8.4)	0	
Hand-foot skin reaction	21 (36.2)	6 (10.3)	148 (48.2)	47 (15.3)	44 (30.8)	12 (8.4)	
Rash/desquamation†	15 (25.9)	3 (5.2)	48 (15.6)	15 (4.9)	12 (8.4)	2 (1.4)	
Vomiting	4 (6.9)	0	34 (11.1)	6 (2.0)	6 (4.2)	0	
Data presented for the safety analysis sets. CORRECT: NCI-CTCAE version 3.0; CONSIGN: NCI-CTCAE version 4.0; CORRELATE: NCI-CTCAE version 4.03.

† In CONSIGN and CORRELATE, these data included patients with rash acneiform and maculopapular rash.

NCI-CTCAE: National Cancer Institute Common Terminology for Adverse Events; TEAE: Treatment-emergent adverse event.

The incidence of TEAEs requiring dose modification was 62.1% in CORRECT, 72.3% in CONSIGN and 72.0% in CORRELATE. The incidence of TEAEs requiring discontinuation was 24.1% in CORRECT, 26.4% in CONSIGN and 31.5% in CORRELATE (Table 4). Drug-related TEAEs of any grade were reported in 94.8% of patients in CORRECT, 93.5% in CONSIGN and 89.5% in CORRELATE, of which 41.4, 56.0 and 39.2%, respectively, were grade 3. Grade 5 drug-related TEAEs were rare (3.4% in CORRECT, 1.0% in CONSIGN and 0.7% in CORRELATE; Table 4).

The incidence of drug-related TEAEs requiring dose modification ranged from 51.7% in the CORRECT trial to 59.0% in CONSIGN, whereas the incidence of drug-related TEAEs requiring discontinuation was 12.1% in CORRECT, 9.4% in CONSIGN and 14.7% in CORRELATE (Table 4). The most common (occurring in ≥10% of patients) drug-related TEAEs reported by all three studies were fatigue, hand–foot skin reaction (HFSR), diarrhea, hypertension, oral mucositis and anorexia (Table 5). Most of these were grades 1 or 2.

3.4. Efficacy and effectiveness

The CORRECT and CORRELATE studies assessed OS, PFS and objective response rate (complete response, partial response, stable disease and disease control rate), whereas CONSIGN evaluated PFS only (Table 6).

Table 6. Survival and tumor response in patients from the Spanish cohorts of CORRECT (regorafenib arm), CONSIGN and CORRELATE.

 	CORRECT (N = 58)	CONSIGN (N = 308)	CORRELATE (N = 143)	
Overall survival, months, median (95% CI)	5.6 (4.2, 8.3)	NR	7.7 (6.2, 9.1)	
<160 mg starting daily dose	NR	NR	5.2 (2.9, 14.5)	
160 mg starting daily dose	5.6 (4.2, 8.3)	NR	7.9 (6.5, 9.5)	
Progression-free survival, months, median (95% CI)	2.0 (1.8, 3.5)	2.6 (2.3, 2.8)	2.8 (2.6, 3.0)	
<160 mg starting daily dose	NR	NR	1.7 (1.2, 2.6)	
160 mg starting daily dose	2.0 (1.8, 3.5)	2.6 (2.3, 2.8)	2.9 (2.7, 3.4)	
Objective response rate, n (% [95% CI])	2 (3.4 [0.4, 11.9])	NR	6 (4.2 [1.6, 8.9])	
Complete response, n (% [95% CI])	0 (0.0 [0.0, 5.0])	NR	0	
Partial response, n (% [95% CI])	2 (3.4 [0.4, 11.9])	NR	6 (4.2 [1.6, 8.9])	
Stable disease, n (% [95% CI])	23 (39.7 [27.0, 53.4])	NR	17 (11.9 [7.1, 18.4])	
Disease control rate, n (% [95% CI])†	25 (43.1 [30.2, 56.8])	NR	23 (16.1 [10.5, 23.2])	
<160 mg starting daily dose	25 (43.1 [30.2, 56.8])	NR	4 (16.7 [4.7, 37.4])	
160 mg starting daily dose	NR	NR	19 (16.0 [9.9, 23.8])	
Tumor response was assessed according to RECIST v1.1 (or by clinical assessment if a patient could not have a radiological examination) in CORRECT, using methods that complied with each institution's best standard of care in CONSIGN and according to the treating physician's routine practice in CORRELATE.

† In CORRECT, disease control rate was defined as proportion of patients with a best response of complete or partial response or stable disease (assessment of stable disease had to be made at least 6 weeks after randomization); in CORRELATE, disease control rate was calculated as the percentage of patients with complete or partial response or stable disease lasting at least 6 weeks.

NR: Not reported; RECIST: Response Evaluation Criteria in Solid Tumor.

Median OS was 5.6 months (95% CI: 4.2, 8.3) in CORRECT and 7.7 months (95% CI: 6.2, 9.1) in CORRELATE (Figure 1). In the real-world CORRELATE study, median OS was 7.9 months (95% CI: 6.5, 9.5) in the 119 patients starting regorafenib at 160 mg/day, and 5.2 months (95% CI: 2.9, 14.5) in the 24 patients starting regorafenib at lower doses. Additionally, in CORRELATE, subgroup analyses revealed a numerical improvement in OS for patients with a lower ECOG PS (ECOG 0 vs ECOG PS 1 vs ECOG >1: 10.1 months (95% CI: 7.4, 12.7) vs 6.6 months (95% CI: 5.3, 7.9) vs 5.0 months (95% CI: 0.6; p = 0.078). OS at 12 months was not estimable due to censored data in CORRECT, and 29.1% (95% CI not reported) in CORRELATE.

Figure 1. Kaplan–Meier analyses of overall survival in the CORRECT (A) and CORRELATE (B) studies, and of progression-free survival in the CORRECT (C) CONSIGN (D) and CORRELATE (E) studies.

OS: Overall survival; PFS: Progression-free survival.

Median PFS was consistent across the three studies: 2.0 months (95% CI: 1.8, 3.5) in CORRECT, 2.6 months (95% CI: 2.3, 2.8) in CONSIGN and 2.8 months (95% CI: 2.6, 3.0) in CORRELATE (Figure 1). In the real-world CORRELATE study, median PFS was 2.9 months (95% CI: 2.7, 3.4) in the 119 patients starting regorafenib at 160 mg/day and 1.7 months (95% CI: 1.2, 2.6) in the 24 patients starting regorafenib at lower doses. PFS at 6 months was 10.0% (95% CI: 0.8, 19.2) in CORRECT, 17.8% (95% CI: 13, 23) in CONSIGN and 16.5% (95% CI not reported) in CORRELATE. PFS at 12 months was not estimable due to censored data in CORRECT, 4.3% (95% CI: 2, 7) in CONSIGN and 3.6% (95% CI not reported) in CORRELATE.

The best objective response in both CORRECT and CORRELATE was stable disease: 23 patients (39.7%; 95% CI: 27.0, 53.4) in CORRECT and 17 patients (11.9%; 95% CI: 7.1, 18.4) in CORRELATE. Disease control rate in CORRECT, which was defined as the proportion of patients with a best response of complete response, partial response or stable disease (assessment of stable disease had to be made at least 6 weeks after randomization), was achieved by 25 patients (43.1% [95% CI: 30.2, 56.8]). In CORRELATE, disease control rate was calculated as the percentage of patients with complete response, partial response or stable disease lasting at least 6 weeks, and this was achieved by 23 patients (16.1% [95% CI: 10.5, 23.2]).

4. Discussion

In this analysis, we present data for the Spanish cohorts of three prospective studies that investigated safety, efficacy and effectiveness, and use of regorafenib in patients with previously treated mCRC, including data from an RCT (CORRECT), a single-arm clinical trial (CONSIGN) and a real-world study (CORRELATE). The Spanish cohorts represented 10.7–13.8% of the corresponding global cohorts. Overall, efficacy and safety in the Spanish cohorts reflect the findings from the corresponding global cohorts, with evidence of a flexible dosing approach being adopted in routine clinical practice since initial regorafenib approval.

Baseline patient characteristics were generally similar across the global and Spanish cohorts of the three studies. Patients enrolled in the real-world CORRELATE study in Spain had a slightly higher median age compared with the clinical trials, and three patients (2.1%) had ECOG PS ≥2. This is due to the fact that, whereas the clinical trials included patients with ECOG PS 0 or 1, the real-world CORRELATE study also included patients with higher ECOG PS at the discretion of the treating physicians [13].

In Spain, a lower proportion of patients in the real-world CORRELATE study received four or more lines of prior systemic therapy on or after diagnosis of metastatic disease compared with the CORRECT and CONSIGN trials. All patients had received prior therapy according to standard practices. A published study of treatment patterns for mCRC in Spain (STREAM) was based on the evaluation of adherence to then current ESMO clinical practice guidelines for the treatment of mCRC between 2012 and 2016 [15]. This study indicated that in a representative sample of Spanish patients at the time of the CORRELATE study, treatment with chemotherapy (most frequently FOLFOX, CAPOX and FOLFIRI) was in accordance with ESMO guidelines, however KRAS and BRAF mutation testing and the use of targeted therapy was not fully consistent with the guidelines [15]. Another analysis of data collected during 2009 from a random sample of adults with mCRC from France (n = 515), Germany (n = 862), Italy (n = 656) and Spain (n = 649) showed that treatment practices were generally consistent with guidelines published at the time. However, the study also highlighted differences among the countries in treatment patterns, which the authors suggested related to local treatment and reimbursement practices [16].

In the current study, a higher proportion of Spanish patients initiated regorafenib in less than 18 months from diagnosis of metastatic disease in CORRELATE (CORRECT: 13.8%; CONSIGN: 20.5%; CORRELATE: 30.8%), which was also observed in the global cohorts (CORRECT: 18.0%; CONSIGN: 17.9%; CORRELATE: 30.3%). It should be noted that, based on global cohort data, a lower proportion of patients in CORRELATE (86.4%) received prior anti-VEGF therapy compared with patients in CORRECT and CONSIGN (100 and 95.9%, respectively).

The Spanish cohort of CORRECT included slightly more patients with KRAS mutation compared with CONSIGN, CORRELATE and the global study population of CORRECT (58.6 vs 54.1%). In an exploratory analysis of the global cohort of CORRECT, the frequency of the KRAS genetic mutation (58.6% in archival tumor tissue and 69.4% in plasma DNA) was higher than previously reported in the COSMIC study in CRC (36.0%), potentially due to overrepresentation of patients eligible for fewer treatment options; in contrast, the low BRAF frequency in the global cohort of CORRECT (1.5% in archival tumor tissue and 3.4% in plasma DNA) compared with COSMIC (10.7%) may have been due to underrepresentation of patients with poor prognoses associated with this mutation [17,18].

Treatment with regorafenib was initiated at the approved 160 mg/day dose in all patients enrolled in CORRECT and CONSIGN, whereas in CORRELATE the initial dose was selected at the discretion of the prescribing physician. Accordingly, a proportion of the Spanish cohort of CORRELATE initiated treatment at a dose lower than 160 mg/day, with 9.1% of patients starting at 120 mg/day and 7.7% starting at 80 mg/day. Furthermore, the proportion of patients initiating regorafenib at reduced starting doses was lower in the Spanish cohort compared with the global cohort of CORRELATE (120 mg/day: 9.1 vs 30.4%; 80 mg/day: 7.7 vs 12.3%), with a higher proportion of patients initiating treatment at the approved 160 mg/day dose (83.2 vs 57.0%). Although regorafenib confers survival benefit, it can be poorly tolerated by some patients, and is associated with TEAEs that often require dose reductions or interruptions and occasionally lead to permanent treatment discontinuation, thereby limiting the use of regorafenib in some circumstances. Dose modifications (defined as reductions, interruptions/delays, escalations and re-escalations) to manage toxicity were protocol-defined in CORRECT and CONSIGN, whereas dosing was adjusted at the physician's discretion in the real-world CORRELATE study. In the Spanish cohort of CORRELATE, 67.8% of patients required dose modifications for any reason, which included TEAEs, fewer than in both CORRECT and CONSIGN (75.9 and 87.3%, respectively). This suggests that flexible dosing in real-world clinical practice may allow physicians to adapt the initial dose to individual patients, potentially reducing the need for dose reductions because of adverse events, thereby increasing tolerability and allowing patients to remain on treatment.

The safety profile of regorafenib in patients with previously treated mCRC from the Spanish cohorts was consistent across studies and with the known safety profile for regorafenib. The most frequently reported TEAEs in the Spanish cohorts across the three studies were fatigue, HFSR, diarrhea, hypertension, rash/desquamation and voice changes. The most common grade ≥3 drug-related TEAEs across studies were fatigue, HFSR, hypertension and diarrhea. The prevention and management of these well-known regorafenib-related adverse events has been described in detail in previously published reviews [19,20]. The percentage of drug-related TEAEs requiring dose modifications was consistent across the three trials and ranged from 51.7% in CORRECT to 59.0% in CONSIGN. In line with findings from the global cohorts, rates of some of the most frequently reported drug-related TEAEs were lower in the Spanish cohort of CORRELATE compared with CORRECT and CONSIGN. This may be due to a combination of under-reporting, better management of adverse events in clinical practice following several years of experience with the drug and a flexible dosing approach in routine clinical practice with physicians prescribing regorafenib at a starting dose lower than the approved 160 mg/day dose. Indeed, there are previous reports of physicians optimizing treatment by starting patients on regorafenib at reduced doses and increasing as tolerated [21–23]. The ReDOS phase II trial reported comparable activity and lower incidence of adverse events with a dose-escalation strategy (starting dose 80 mg/day orally with weekly escalation, per 40 mg increment, to 160 mg/day in cycle 1 and highest tolerated dose from cycle 1 in any subsequent cycles) compared with the approved 160 mg/day dose [24]. Although the REARRANGE trial in Spain did not meet the primary end point of improving global tolerability with either a reduced dose (120 mg/day 3 weeks on/1 week off) or an intermittent dose (160 mg/day 1 week on/1 week off), there was a numerical improvement in the most clinically relevant adverse events in the intermittent dose arm compared with the control arm (160 mg 3 weeks on/1 week off) without jeopardizing efficacy [23]. Another real-world study evaluating dosing patterns in patients with mCRC in Spain is ongoing (the RE-SEARCH study, NCT04920422) [25]. Beyond mCRC, a recent retrospective real-world study in Italian patients with metastatic gastrointestinal stromal tumors found that personalized regorafenib dosing schedules were commonly adopted in routine clinical practice, and these correlated with significant improvement of therapeutic outcomes [26].

Median OS in the Spanish cohort of the real-world CORRELATE study was longer compared with the Spanish cohort of the CORRECT trial (7.7 vs 5.6 months), while median PFS was similar in both studies, consistent with the global cohorts. A meta-analysis of 702 mCRC patients in retrospective studies of regorafenib reported a median OS of 7.3 months [27], which is in line with findings from CORRELATE (global and Spanish cohorts). However, median OS in the Spanish cohort of CORRECT was shorter compared with the corresponding global cohort (5.6 vs 6.4 months). The REBECCA real-world study conducted retrospectively across 136 institutions in France highlighted the importance of patient selection and identified patients deriving maximum benefit from regorafenib using a model with potential predictive/prognostic value (based on performance status, time from initial diagnosis of metastases to the start of regorafenib, initial regorafenib dose, number of metastatic sites, presence of liver metastases and KRAS mutations). The study reported a median OS of 5.6 months in 654 patients with refractory mCRC treated with regorafenib [28]. A similar approach to patient selection was used in a real-world study of 130 patients with refractory mCRC treated with regorafenib across seven hospitals in Galicia; a median OS of 6.7 months and a median PFS of 2.9 months were reported [29]. In the subset of patients from the full analysis set with characteristics similar to CORRECT (FAS-CORRECT), OS FAS-CORRECT prognostic subgroups 0–3/4 and 5/6+ were 9.2 vs 6.9 vs 5.3 months, respectively; OS Tabernero subgroups best prognostic characteristics (BPC)/good prognostic characteristics (GPC)/poor prognostic characteristics (PPC) were 10.5 vs 6.9 vs 5.2 months, respectively [28–30].

More recent retrospective studies have reported longer median OS and PFS. A recent retrospective study in a population of 100 Italian patients with refractory mCRC reaching an OS ≥6 months with regorafenib administered as per indication reported considerably longer median OS (11.5 months) and median PFS (4.2 months) in this selected group of patients [6]. Similarly, Novakova-Jiresova et al. evaluated a Czech registry-based cohort of 555 patients with mCRC treated with regorafenib (an extension of the cohort previously investigated by Kopeckova et al. [31]) and reported a median OS of 9.3 months and median PFS of 3.5 months [32]. Both studies speculate that the better outcomes may be attributable to better patient selection [6,32], but it is also possible that both clinical and real-world evidence with regorafenib is guiding treatment optimization as more experience with this agent is gained over time, resulting in better survival outcomes. Moreover, regorafenib may have greater benefit when used earlier in the course of metastatic disease, in less heavily pre-treated patients [31–33]. Longer median OS (8.5 months) was also reported by Eng et al. in the IMblaze370 phase III trial of atezolizumab plus cobimetinib or atezolizumab monotherapy vs regorafenib in the third-line setting [33].

In the real-world CORRELATE study, 24 patients started regorafenib at doses lower than 160 mg/day. In these patients, median OS was 5.2 months (95% CI: 2.9, 14.5) compared with 7.9 months (95% CI: 6.5, 9.5) in patients starting regorafenib at 160 mg/day. Importantly, efficacy in CORRELATE was found to be in the range observed in the clinical trials despite evidence of flexible dosing, although this may also be due to selection bias, with lower starting doses potentially implemented more frequently in frail patients [11]. Further research evaluating the potential impact of a flexible dosing approach on survival outcomes is warranted.

The strengths and limitations of each of the three studies have been discussed in detail in the global publications (CORRECT [7], CONSIGN [10] and CORRELATE [11]). RCTs are considered the ‘gold standard’ when evaluating the efficacy of new therapies before their adoption in the clinical practice. However, the strict protocols adopted and the population enrolled often do not represent real-world clinical practices and populations living with a disease, which are the major limitation of such studies and strengths of real-world studies [34–37]. Patients included in real-world studies are not screened and may have a higher burden of disease (i.e., more comorbidities) than compared with those included in RCTs, and the dosing regimen may not reflect the approved label for a drug. Accordingly, the real-world CORRELATE study included patients with ECOG PS ≥2 and showed that physicians sometimes prescribe regorafenib at a starting dose lower than the approved 160 mg/day [11]. Limitations of real-world studies include the lack of defined intervals for patient visits, which can impact reporting and data collection for dosing, safety and efficacy outcomes. A specific limitation of the current study is that the findings presented are based on the experience of a single country. As such, it is not possible to extrapolate the results to the rest of the world or to evaluate potential regional differences in practice patterns at the time the three clinical studies were done.

5. Conclusion

The CORRECT, CONSIGN and CORRELATE studies discussed here are separated by time, design and sample size and cannot be directly compared. Nonetheless, they provide useful insights into the use of regorafenib in Spain, from the initial clinical trials to current routine clinical practice. Key findings include a consistent safety profile across the CORRECT and CONSIGN clinical trials with prospectively defined starting dose, and evidence of a flexible dosing approach in routine clinical practice in both the Spanish and global cohorts of CORRELATE. Real-world studies are conducted in everyday clinical practice which may not be uniform from site to site and country to country, highlighting the importance of conducting country-specific studies. Based on findings from the CORRELATE study, regorafenib use in patients with mCRC has evolved in the real-world setting, emphasizing the need for further research evaluating dosing patterns that can optimize clinical outcomes in these patients.

Acknowledgments

The authors thank the participating patients and staff at each of the study centers.

Author contributions

All authors made substantial contributions to the conception or design of the work or to the acquisition, analysis or interpretation of data for the work. All authors were involved in drafting the work or revising it critically for important intellectual content. All authors provided final approval of the version to be published. All authors provided agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Financial disclosure

This study was funded by Bayer. The CORRECT, CONSIGN and CORRELATE studies were supported by Bayer HealthCare Pharmaceuticals. A Carral: advisory role honoraria and speaker honoraria from Amgen, Bayer, Bristol Myers Squibb (BMS), Eisai, Eli Lilly, Grunenthal, Kyowa Kirin, Merck, MSD, Novartis, Pierre Fabre, Roche, Sanofi and Servier. A Cervantes: institutional research funding from Astellas, Bayer, BeiGene, BMS, Eli Lilly, FibroGen, Genentech, Merck Serono, MSD, Novartis, Roche, Servier and Takeda; and advisory board or speaker fees from Amgen, Bayer, Merck Serono, Pierre Fabre, Roche and Servier in the last 5 years. BG Paredes: advisory role honoraria and speaker honoraria from Advanced Accelerator Applications (a Novartis company), Amgen, Bayer Hispania, Eisai, Eli Lilly, Ipsen, Merck, MSD, Novartis, Roche Farma, Sanofi-Aventis and Servier. C Guillén-Ponce: contracts for clinical trials from AstraZeneca, Boston Scientific, ERYTECH, IPSEN and QED Therapeutics; and support for attending meetings and/or travel from AstraZeneca, General Electric, Merck Serono and Sanofi-Aventis. J Feliu: has received consulting and advisory honoraria from Amgen, Eisai, Ipsen, Merck, Novartis, Organon, Roche, Sirtex and Viatris; and research funding from Amgen and MSD. J Sastre: scientific consultancy role for Amgen, Bayer, BMS, Celgene, Ipsen, Merck, Roche, Sanofi and Servier; speaker honoraria from Eli Lilly, Ipsen, Merck, MSD, Pfizer, Roche, Servier and Shire. J Tabernero: personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, HalioDx SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Menarini, Merck Serono, Merus, Mirati, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, SOTIO Biotech, Taiho, Tessa Therapeutics and TheraMyc; stocks: Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource. R Garcia-Carbonero: provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, Boehringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pierre Fabre, Roche, Servier and Sanofi; and has received research support from BMS, MSD and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

This study was funded by Bayer. Medical writing and editorial support were provided by S Pregnolato and M Reynolds of OPEN Health Communications, London, UK, with financial support from Bayer.

Ethical conduct of research

The CORRECT, CONSIGN and CORRELATE studies were approved by the independent ethics committee or institutional review board at each site where required, and were conducted in accordance with applicable international and local laws and regulations. All participants provided written informed consent.

Data availability statement

The authors certify that this manuscript reports original clinical trial data. Availability of the data underlying this publication will be determined according to Bayer's commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing”. This pertains to scope, time point and process of data access.

As such, Bayer commits to sharing, upon request from qualified scientific and medical researchers, patient-level clinical trial data, study-level clinical trial data and protocols from clinical trials in patients for medicines and indications approved in the United States (US) and European Union (EU) as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 1, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct further research that can help advance medical science or improve patient care. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is not involved in the decisions made by the independent review panel. Bayer will take all necessary measures to ensure that patient privacy is safeguarded.
==== Refs
References

Papers of special note have been highlighted as: • of interest; •• of considerable interest

1. World Health Organization; International Agency for Research on Cancer. Globocan 2020 Spain cancer fact sheet. 2020. [accessed 2023 August 21]. Available at: https://gco.iarc.fr/today/data/factsheets/populations/724-spain-fact-sheets.pdf
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71 (1 ):7–33. doi:10.3322/caac.21654 33433946
3. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325 (7 ):669–685. doi:10.1001/jama.2021.0106 33591350
4. Tampellini M, Di Maio M, Baratelli C, et al. Treatment of patients with metastatic colorectal cancer in a real-world scenario: probability of receiving second and further lines of therapy and description of clinical benefit. Clin Colorectal Cancer. 2017;16 (4 ):372–376. doi:10.1016/j.clcc.2017.03.019 28465170
5. Bekaii-Saab T, Kim R, Kim TW, et al. Third- or later-line therapy for metastatic colorectal cancer: reviewing best practice. Clin Colorectal Cancer. 2019;18 (1 ):e117–e129. doi:10.1016/j.clcc.2018.11.002 30598357
6. Lai E, Puzzoni M, Ziranu P, et al. Long term survival with regorafenib: REALITY (Real Life in Italy) trial – a GISCAD study. Clin Colorectal Cancer. 2021;20 (4 ):e253–e262. doi:10.1016/j.clcc.2021.07.008 34429245
7. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, Phase III trial. Lancet. 2013;381 (9863 ):303–312. doi:10.1016/S0140-6736(12)61900-X 23177514
•• International, multicenter, randomized, placebo-controlled, phase III trial evaluating the efficacy and safety of regorafenib in previously treated patients with metastatic colorectal cancer (mCRC) and subsequently leading to its approval in 2012.

8. European Medicines Agency. Stivarga (regorafenib) 40 mg film-coated tablets. Summary of product characteristics. 2023. [accessed 2023 August 21]. Available at: www.ema.europa.eu/en/documents/product-information/stivarga-epar-product-information_en.pdf
9. Bayer Healthcare Pharmaceuticals Inc. Stivarga(R) (regorafenib) US Prescribing Information. 2021. [accessed 2023 August 21]. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2020/203085s011lbl.pdf
10. Van Cutsem E, Martinelli E, Cascinu S, et al. Regorafenib for patients with metastatic colorectal cancer who progressed after standard therapy: results of the large, single-arm, open-label phase IIIb CONSIGN study. Oncologist. 2019;24 (2 ):185–192. doi:10.1634/theoncologist.2018-0072 30190299
•• International, multicenter, single-arm, open-label phase IIIb trial of regorafenib reporting a consistent safety and efficacy profile with the CORRECT trial in a large population of previously treated patients with mCRC.

11. Ducreux M, Petersen LN, Öhler L, et al. Safety and effectiveness of regorafenib in patients with metastatic colorectal cancer in routine clinical practice in the prospective, observational CORRELATE study. Eur J Cancer. 2019;123 :146–154. doi:10.1016/j.ejca.2019.09.015 31698328
•• International, prospective, observational study of regorafenib in previously treated patients with mCRC reporting consistent safety and effectiveness with the CORRECT and CONSIGN trials, as well as evidence of a flexible dosing approach in real-world practice.

12. Choi HCW, Lam K-O, Pang HHM, Tsang SKC, Ngan RKC, Lee AWM. Global comparison of cancer outcomes: standardization and correlation with healthcare expenditures. BMC Public Health. 2019;19 (1 ):1065. doi:10.1186/s12889-019-7384-y 31391013
13. Metges JP, Genet D, Tougeron D, et al. Real-world safety and effectiveness of regorafenib in metastatic colorectal cancer: the French CORRELATE cohort. Future Oncol. 2021;17 (25 ):3343–3353. doi:10.2217/fon-2021-0266 34011165
• Data analysis from the French cohort of the real-world CORRELATE study reporting consistent safety and effectiveness of regorafenib with the CORRECT and CONSIGN trials and the global cohort of the real-world CORRELATE study.

14. Yeh KH, Yang TS, Hsu TC, et al. Real-world evidence of the safety and effectiveness of regorafenib in Taiwanese patients with metastatic colorectal cancer: CORRELATE Taiwan. J Formos Med Assoc. 2021;120 (11 ):2023–2031. doi:10.1016/j.jfma.2020.12.015 33422398
15. Aranda E, Polo E, Camps C, et al. Treatment patterns for metastatic colorectal cancer in Spain. Clin Transl Oncol. 2020;22 (9 ):1455–1462. doi:10.1007/s12094-019-02279-5 31974819
16. Zhao Z, Pelletier E, Barber B, et al. Patterns of treatment with chemotherapy and monoclonal antibodies for metastatic colorectal cancer in Western Europe. Curr Med Res Opin. 2012;28 (2 ):221–229. doi:10.1185/03007995.2011.650503 22171947
17. Tabernero J, Lenz H-J, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol. 2015;16 (8 ):937–948. doi:10.1016/S1470-2045(15)00138-2 26184520
18. Forbes SA, Bindal N, Bamford S, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39 (Database issue ):D945–D950. doi:10.1093/nar/gkq929 20952405
19. De Wit M, Boers-Doets CB, Saettini A, et al. Prevention and management of adverse events related to regorafenib. Support Care Cancer. 2014;22 (3 ):837–846. doi:10.1007/s00520-013-2085-z 24337717
20. Mclellan B, Ciardiello F, Lacouture ME, Segaert S, Van Cutsem E. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol. 2015;26 (10 ):2017–2026. doi:10.1093/annonc/mdv244 26034039
21. Grothey A. Regorafenib in metastatic colorectal cancer: optimal dosing and patient selection recommendations. Clin Adv Hematol Oncol. 2015;13 (8 ):514–517. doi:10.1371/journal.pone.0190497 26351814
22. Tabchi S, Ghosn M. Regorafenib: start low and go slow. Target Oncol. 2015;10 (3 ):445–447. doi:10.1007/s11523-014-0352-7 25548130
23. Argilés G, Mulet N, Valladares-Ayerbes M, et al. A randomised Phase II study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial). Eur J Cancer. 2022;177 :154–163. doi:10.1016/j.ejca.2022.09.037 36335783
• Randomized phase II trial in Spain reporting a numerical improvement in the most clinically relevant adverse events with an intermittent dose of regorafenib (160 mg/day 1 week on/1 week off) compared with the control arm (160 mg 3 weeks on/1 week off) without jeopardizing efficacy.

24. Bekaii-Saab TS, Ou F-S, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, Phase II study. Lancet Oncol. 2019;20 (8 ):1070–1082. doi:10.1016/S1470-2045(19)30272-4 31262657
• Randomized, multicenter, open-label phase II trial in the USA reporting comparable activity and lower incidence of adverse events with a first cycle dose-escalation strategy of regorafenib compared with the approved 160 mg/day dose.

25. U.S. National Library of Medicine. RE-SEARCH study: a study to learn how and in which amount regorafenib is given in usual practice to patients in Spain: a study looking back at cases that have already happened when the study begins. 2021. [accessed 2022 November 9]. Available at: https://clinicaltrials.gov/ct2/show/NCT04920422
26. Nannini M, Rizzo A, Nigro MC, et al. Standard versus personalized schedule of regorafenib in metastatic gastrointestinal stromal tumors: a retrospective, multicenter, real-world study. ESMO Open. 2021;6 (4 ):100222. doi:10.1016/j.esmoop.2021.100222 34352702
27. Mercier J, Voutsadakis IA. A systematic review and meta-analysis of retrospective series of regorafenib for treatment of metastatic colorectal cancer. Anticancer Res. 2017;37 (11 ):5925–5934. doi:10.21873/anticanres.12039 29061771
28. Adenis A, De La Fouchardiere C, Paule B, et al. Survival, safety, and prognostic factors for outcome with regorafenib in patients with metastatic colorectal cancer refractory to standard therapies: results from a multicenter study (REBECCA) nested within a compassionate use program. BMC Cancer. 2016;16 :412. doi:10.1186/s12885-016-2440-9 27389564
29. Martínez-Lago N, Carnero Lopez B, De La Cámara Gómez J, et al. P-63 efficacy, safety and prognostic subgroups for outcome with regorafenib in patients with refractory metastatic colorectal cancer in the real-world setting: the CORE study. Ann Oncol. 2022;33 (Suppl. 4 ):S269–S270. doi:10.1016/j.annonc.2022.04.153
30. Tabernero J, Argiles G, Sobrero AF, et al. Effect of trifluridine/tipiracil in patients treated in RECOURSE by prognostic factors at baseline: an exploratory analysis. ESMO Open. 2020;5 (4 ):e000752. doi:10.1136/esmoopen-2020-000752 32817131
31. Kopeckova K, Buchler T, Bortlicek Z, et al. Regorafenib in the real-life clinical practice: data from the Czech registry. Target Oncol. 2017;12 (1 ):89–95. doi:10.1007/s11523-016-0458-1 27638381
32. Novakova-Jiresova A, Kopeckova K, Boublikova L, et al. Regorafenib for metastatic colorectal cancer: an analysis of a registry-based cohort of 555 patients. Cancer Manag Res. 2020;12 :5365–5372. doi:10.2147/CMAR.S255332 32753954
33. Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, Phase III, randomised, controlled trial. Lancet Oncol. 2019;20 (6 ):849–861. doi:10.1016/S1470-2045(19)30027-0 31003911
34. Booth CM, Tannock IF. Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. Br J Cancer. 2014;110 (3 ):551–555. doi:10.1038/bjc.2013.725 24495873
35. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real-world evidence – what is it and what can it tell us? N Engl J Med. 2016;375 (23 ):2293–2297. doi:10.1056/NEJMsb1609216 27959688
36. Batra A, Cheung WY. Role of real-world evidence in informing cancer care: lessons from colorectal cancer. Curr Oncol. 2019;26 (Suppl. 1 ):S53–S56. doi:10.3747/co.26.5625 31819710
37. Di Maio M, Perrone F, Conte P. Real-world evidence in oncology: opportunities and limitations. Oncologist. 2020;25 (5 ):e746–e752. doi:10.1634/theoncologist.2019-0647 31872939
