Optimized Dosing of Regorafenib in Patients With Metastatic Colorectal Cancer: A Practical Guide for Oncologists, Advanced Practice Providers, and Pharmacists.

REGORAFENIB DOSING AND THE RATIONALE FOR ReDOS
In CORRECT, CONCUR, and CONSIGN, the regorafenib starting dose was 160 mg/day for the first 3 weeks of each 4-week cycle (Grothey et al., 2013b; Li et al., 2015; Van Cutsem et al., 2019). The dose could be reduced (to 80 mg), interrupted, or permanently discontinued to manage treatment-related toxicities, with reescalation up to 160 mg after TEAEs resolved. Treatment was discontinued permanently if TEAEs did not resolve following treatment delay or dose reductions. Across the three trials, TEAEs led to regorafenib treatment modifications in > 60% of patients, including 38% to 46% of patients who had a TEAE leading to a dose reduction (Grothey et al., 2013b; Li et al., 2015; Van Cutsem et al., 2019). In CONCUR and CONSIGN, fewer patients (14% to 25%) discontinued treatment due to TEAEs, suggesting that dose modifications allowed some patients to remain on therapy (Li et al., 2015; Van Cutsem et al., 2019). Similarly, clinical studies of regorafenib in gastrointestinal stromal tumors or hepatocellular carcinoma (HCC) show that regorafenib-associated TEAEs were largely managed with dose modifications or interruptions (Bruix et al., 2017; Demetri et al., 2013).
In real-world practice, the dose of regorafenib is often modified or interrupted in response to TEAEs, consistent with clinical trial protocols and current prescribing information (Bayer AG, 2023; Bayer HealthCare Pharmaceuticals, 2020; Grothey et al., 2013b). However, different dosing strategies are being used without the support of prospective clinical trial evidence. Many physicians reported starting regorafenib below the approved dose (i.e., 80 or 120 mg/day) in cycle 1 and then up-titrating to improve tolerability (Grothey, 2015; Tabchi & Ghosn, 2015). Evidence from real-world studies shows that over one-third of patients start regorafenib below the approved dosage (Ducreux et al., 2019; Yamaguchi et al., 2019). The frequent need for dose reductions when starting regorafenib at 160 mg/day, coupled with the use of proactive dose-titration strategies in real-world practice, motivated the design of ReDOS (Bekaii-Saab et al., 2019b). The structured dose-escalation strategy used during cycle 1 was based on exploratory analyses of CORRECT and CONSIGN, showing that the most common regorafenib-related TEAEs, such as fatigue and HFSR, usually occur early and are noncumulative (Grothey et al., 2013a; Van Cutsem et al., 2019). These observations are consistent with the results of a phase III study of regorafenib in HCC (Merle et al., 2017) and with the time course of HFSR related to treatment with other tyrosine kinase inhibitors, including sorafenib (Nexavar) and sunitinib (Sutent), in patients with HCC, renal cell carcinoma, or differentiated thyroid carcinoma (Lacouture et al., 2008; Worden et al., 2015).
Initiating regorafenib below the standard dose would allow the dose to be individualized according to how well the drug is tolerated during cycle 1. ReDOS included an extensive evaluation of quality of life (QOL). In clinical practice, patients with mCRC often receive regorafenib as a third or fourth line of treatment, at a stage where QOL is paramount.

ReDOS FIRST-CYCLE DOSE-ESCALATION STRATEGY
ReDOS was a randomized phase II study in patients with refractory mCRC and Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 (Bekaii-Saab et al., 2019b). Patients were randomly assigned to initiate regorafenib at the standard daily dose (n = 62) or at a reduced dose (80 mg), increasing by 40 mg weekly, over 2 weeks, to reach 160 mg/day if tolerated (n = 54; Figure 1).
The primary endpoint was the proportion of patients in each group who completed two cycles of treatment and initiated the third cycle and, therefore, encompassed safety and efficacy parameters. Patients were only allowed to begin cycle 3 if they had tolerated treatment (may have experienced mild-to-moderate, but not significant/debilitating, drug-related toxicities despite dose modification) and had stable disease on the first scan after two treatment cycles (8 weeks). The primary endpoint was achieved, with more patients starting cycle 3 in the dose-escalation group (43%) vs. the standard-dose group (26%; p = .043; Bekaii-Saab et al., 2019b).
Weekly dosing for all patients is summarized in Figure 2. Patients in the dose-escalation group received a lower percentage of the planned dose in cycle 1 vs. the standard-dose group (77% vs. 83%, respectively) and a higher percentage in cycle 2 (93% vs. 73%, respectively). Dose modifications in the dose-escalation group and standard-dose group occurred in 24% and 21% of patients in cycle 1, respectively, and in 22% and 32% of patients in cycle 2, respectively. Collectively, the mean dose received was similar in both groups by the end of cycle 2; however, it was individualized in response to tolerability.
The safety profile of regorafenib was consistent with reports from previous clinical trials, and there were no marked differences between the two dosing strategies. However, the incidence of grade 3 TEAEs commonly associated with regorafenib (fatigue, HFSR, hypertension, diarrhea) was generally lower in the dose-escalation group vs. the standard-dose group during both cycles. The most common grade 3/4 TEAEs (dose escalation vs. standard dose) were fatigue (13% vs. 18%), HFSR (15% vs. 16%), abdominal pain (17% vs. 6%), and hypertension (7% vs. 15%). Additionally, a prespecified analysis of cycle 1 showed that the rate of grade 2/3 HFSR was lower in the dose-escalation group vs. the standard-dose group (Bekaii-Saab et al., 2019b).
Secondary efficacy endpoints showed that the dose-escalation strategy did not negatively impact regorafenib activity; median PFS was 2.8 (dose escalation) vs. 2.0 (standard dose) months (HR, 0.84; log-rank p = .38). Median OS was numerically longer in the dose-escalation group (9.8 vs. 6.0 months; HR, 0.72; log-rank p = .12).

QUALITY OF LIFE
Quality of life was assessed by applicable instruments (HFSR-specific Hand–Foot Syndrome 14 [HFS-14]; Brief Fatigue Inventory [BFI]; Linear Analogue Self-Assessment [LASA]; Bretscher et al., 1999; Mendoza et al., 1999; Niska et al., 2017; Sibaud et al., 2011) at baseline and at the end of weeks 2, 4, 6, and 8 (Table 1; Bekaii-Saab et al., 2019b). At baseline, LASA and BFI scores were similar between the dosing strategies. At week 2, the mean BFI scores were significantly higher in the dose-escalation group for current fatigue, general activity interference, mood interference, walking ability interference, and normal work interference (Table 1). There were no significant differences between the dosing strategies at weeks 4, 6, and 8. Although overall scores on the HFS-14 and LASA questionnaires were slightly higher in the dose-escalation group, the differences were not significant. A sensitivity analysis, in which missing values were imputed to the worst possible value for the given measure, supported the QOL results (Bekaii-Saab et al., 2019b). Observed improvements in fatigue and other QOL scores at week 2 in the dose-escalation group vs. the standard-dose group suggest that the dose-escalation strategy may be advantageous when standard dosing appears to compromise QOL.
Application of clobetasol before the development of HFSR (pre-emptive use) during the first two cycles of regorafenib treatment significantly reduced the incidence of HFSR and was associated with better QOL compared with application of clobetasol after development of HFSR (reactive use; Jatoi et al., 2021). Over the first two cycles, no evidence of HFSR was observed in 30% of patients who received pre-emptive clobetasol (n = 61) vs. 13% of patients who received reactive clobetasol (n = 55, p = .03).

IMPLICATIONS FOR CLINICAL PRACTICE

The Oncologist's Perspective
Oncologists have been using regorafenib in clinical practice since 2012, and this experience has provided insights to help patients derive the maximum benefit from treatment. For example, in both interventional trials and real-world studies, the primary effect of regorafenib is exerted through disease stabilization (Ducreux et al., 2019; Grothey et al., 2013b; Li et al., 2015). Therefore, optimizing therapy requires maximizing treatment duration. Regorafenib-related AEs should be managed with a goal of keeping patients on treatment for as long as possible. ReDOS showed that a dose-escalation strategy in the first cycle allowed significantly more patients to remain on treatment through to cycle 3 compared with standard dosing (Bekaii-Saab et al., 2019b). The dose-escalation strategy was designed to minimize early AEs, to allow patients to reach the maximum tolerated dose within the first cycle, and to derive maximum treatment benefit. Oncologists can employ this strategy as some regorafenib-related AEs occur early and are noncumulative. This strategy cannot be used with traditional agents with cumulative toxicities (e.g., oxaliplatin- and irinotecan-based chemotherapy; Braun & Seymour, 2011; Kelly & Goldberg, 2005).
ReDOS enrolled “clinically fit” (ECOG PS 0–1), adult patients (aged ≥ 18 years) who had progressed on standard systemic treatments for mCRC (Bekaii-Saab et al., 2019b). For patients who are frailer than those included in clinical trials (i.e., ECOG PS > 1, presence of significant comorbidities and/or geriatric features, or those who have received multiple lines of prior systemic therapy for metastatic disease leading to cumulative toxicity), starting regorafenib below 160 mg/day might be a reasonable alternative to starting at the standard dose. The dose can then be escalated over the first 1–2 cycles to reach a target of 160 mg/day, if tolerated.

The Advanced Practice Provider's Perspective
Advanced practice registered nurses (APRNs) and physician assistants (collectively known as APPs in the United States), as well as registered nurses (RNs), are crucial to the interdisciplinary care of patients with cancer. Most APRNs are nurse practitioners; other APRNs practicing in oncology include certified registered nurse anesthetists and clinical nurse specialists (Nevidjon et al., 2010; Reynolds & McCoy, 2016).
Advanced practice providers are part of the interdisciplinary team developing a care plan, providing supportive care, patient monitoring, and therapeutic management (including drug-related AEs) with the active engagement and direction of oncologists. Advanced practice providers play vital roles in ensuring that patients and/or caregivers have a solid understanding of potential AEs related to oncology treatments and strategies for their management/mitigation. As regorafenib is an oral therapy, it is self-administered at home, which heightens the importance of patient education at the start of treatment and communication with patients between office visits. Patients with mCRC who are prescribed regorafenib have usually received two or more prior lines of systemic therapy; therefore, maintaining QOL becomes a key goal (Arnold et al., 2018; Bayer AG, 2023; Bayer HealthCare Pharmaceuticals, 2020). Providing APPs with education, including information on how to distinguish between the patient's disease trajectory and common regorafenib-related AEs, provides them with the knowledge to ensure that patients obtain the maximum benefit from this therapy through education and support. Advanced practice providers counsel patients to take regorafenib tablets at the same time each day. Ideally, the tablets are swallowed whole with water after a low-fat meal containing < 600 calories and < 30% fat (Bayer AG, 2023). A suitable low-fat meal that comprises 520 calories and 2 g of fat would include cereal (approximately 30 g), skimmed milk, a slice of toast with jam, a glass of apple juice, and a cup of coffee or tea (Bayer AG, 2023).
Adverse events commonly associated with regorafenib include HFSR, rash, oral mucositis, diarrhea, hypertension, abnormalities of liver enzymes, and fatigue (Table 2; Ducreux et al., 2019; Grothey et al., 2013b; Li et al., 2015; Van Cutsem et al., 2019; Yamaguchi et al., 2019). The most commonly observed AE is fatigue, which is one of the most distressing and activity-limiting symptoms that patients with cancer endure, especially during the final disease stages, and can have a significant impact on QOL (De Wit et al., 2014; Hofman et al., 2007). Regorafenib-related fatigue can be difficult to manage and is often difficult to distinguish from general fatigue related to the disease and/or previous treatments. One of the recommended strategies to combat fatigue is encouraging physical activity (De Wit et al., 2014). Prior to treatment, the patient's level of activity can be assessed using the BFI, which should be monitored weekly during the first two cycles and twice monthly thereafter (Hofheinz et al., 2015; Mendoza et al., 1999). Additionally, documenting fatigue-related symptoms daily using a patient-recorded diary allows APPs to continually track and advise patients on effective management/mitigation strategies.
In our experience, a substantial subset of patients are prescribed regorafenib using the first-cycle dose-escalation strategy defined in ReDOS (Bekaii-Saab et al., 2019b). The advantages of using this strategy include fewer and/or less severe AEs, predictability in the onset of any TEAEs, better treatment adherence, and improved patient QOL/wellbeing, all of which increase the likelihood of patients remaining on treatment for longer, thus improving outcomes (Bekaii-Saab et al., 2019b).

The Pharmacist's Perspective
The role of oncology pharmacists has evolved in recent decades, extending beyond dispensing to provide direct evidence-based care (Hematology/Oncology Pharmacy Association, 2024; Holle et al., 2020). Clinical pharmacists who are integrated within the MDT (typically board-certified oncology pharmacists) are usually responsible for providing in-person initial education to both the patient and caregiver, ensuring that prescriptions are sent to the appropriate pharmacy in a timely manner, obtaining prior authorization and addressing insurance issues and/or copay assistance, closely monitoring the patient for treatment-related AEs, and either recommending or implementing dose adjustments. Pharmacists who practice in this capacity develop pharmaceutical care plans, which include treatment strategies and supportive care management, such as recommending and/or prescribing symptom-relieving treatments.
Patient education prior to starting and communication during therapy are key roles of the pharmacist and are important for patients receiving oral treatments, such as regorafenib. Prior to treatment, pharmacists provide patients with the necessary resources, including online information regarding their treatment (see Resources for Patients). Patients are advised how to use treatment calendars, pill boxes, and treatment kits. Additionally, the pharmacist explains the dosing schedule and educates the patient on how to manage TEAEs, both proactively and during therapy. The patient is counseled to use moisturizers, and address hyperkeratoses and calluses before initiating treatment to minimize the risk of developing HFSR. The pharmacist also explains how the patient should report TEAEs, either to the pharmacist or an APP. When a patient reports an AE that may require a dose modification, the physician or APP is notified, and a decision is taken within the team. A new prescription request is sent electronically to the pharmacist for patient collection. The pharmacist may provide advice by e-mail or telephone to assist with any prescription-related enquiries. Depending on their level of responsibility, the pharmacist may even be involved at the forefront of clinical decision-making, including adjusting dose schedules, which are always communicated beforehand with the patient. The pharmacist is also responsible for managing the patients' expectations related to drug supply, and for notifying them of any potential delays arising from mail order pharmacy protocols and insurance approvals.
Clinics that do not have clinical pharmacists rely on the dispensing pharmacist to ensure that the patient has an uninterrupted supply of medication at the correct dose and schedule. Good communication between the pharmacist and the patient and/or caregiver is crucial to ensure that the dose-adjustment strategy is understood. Managing the supply of regorafenib tablets is a challenge, whether an oncologist prescribes regorafenib at the standard dose or uses the ReDOS dose-escalation strategy in cycle 1. With standard dosing, the prescriber reactively adjusts the dose after the patient experiences AEs. When the dose is reduced, there is a discrepancy between the quantity of tablets needed to complete the cycle and the quantity in the patient's possession. This can lead to confusion, may result in dosing errors, and can affect patient safety. Patient education is important to ensure that the patient understands the revised dosing schedule and is not surprised to have extra tablets at the end of the cycle.
Alternatively, with the ReDOS dose-escalation strategy, the dose may change weekly during cycle 1. To minimize confusion and dosing errors, the prescription should clearly describe the first-cycle dose-escalation strategy so that any dose adjustments are clear for the pharmacist, patient, and payer. Ambiguity in the prescription may cause delays in dispensing and result in treatment interruptions, especially if the prescriber and/or payer must be contacted by the pharmacist. The time required to obtain clarification from the prescriber and seek approval from the patient's insurance provider can cause prescription delays. To avoid such delays, a comprehensive written instruction and/or a calendar indicating the time of planned dose escalations should be included in the prescription and provided to the patient.

RESOURCES

Resources for Health-Care Professionals
Advanced practice providers and pharmacists who are informed about strategies available to manage regorafenib-related AEs are best positioned to assist their patients. Suitable resources include journal articles providing information related to the prevention and management of AEs, including regorafenib-related HFSR, for example the article on the prevention and management of adverse events related to regorafenib (De Wit et al., 2014; McLellan et al., 2015) and websites of organizations such as the National Community Oncology Dispensing Association (NCODA; National Community Oncology Dispensing Association, 2021) and the Hematology/Oncology Pharmacy Association (HOPA; Hematology/Oncology Pharmacy Association, 2024), which include information for pharmacists on monitoring patients receiving regorafenib.

Resources for Patients
Patient education is crucial for patients to benefit from regorafenib. During a consultation, patients are informed about its mechanism of action and route of administration. Educating the patient about common AEs prior to therapy, along with how they can be effectively managed, is important with respect to compliance and, consequently, clinical outcomes. Additionally, APPs and pharmacists advise patients to inform their assigned healthcare team upon the onset of any symptoms, as early detection can prevent symptoms from worsening. Several resources are available for patients. APPs or pharmacists can provide patients with a regorafenib starter kit that contains a patient brochure with information about how regorafenib works, how it should be administered, managing common AEs, and services available to assist with the cost of treatment; a caregiver brochure with information on regorafenib and strategies for caring for patients and for themselves; a digital thermometer; and pill boxes for organizing regorafenib tablets for each cycle. Health-care providers are encouraged to distribute free patient education sheets (PES), developed by the NCODA and its partners, which contain easy-to-understand information about oral cancer drugs, including regorafenib, and to refer patients to the PES website (Patient Education Sheets [Formerly IVE and OCE Sheets], 2025). A universally accessible website is available to assist patients with meal planning (U.S. Department of Agriculture, 2020).

CONCLUSION
The ReDOS trial provides an evidence-based guide for health-care professionals to optimize regorafenib dosing in patients with mCRC, without compromising outcomes. The dose-escalation strategy improved tolerability and QOL parameters that included fatigue and activity/mood interference during the first two cycles of treatment, without reducing overall drug exposure, vs. standard regorafenib dosing. In our experience, the advantages of using a dose-escalation approach with regorafenib include better management of associated AEs and improved patient adherence, which helps patients to stay on treatment and improves outcomes. Furthermore, the ReDOS dose-escalation strategy may be a valid dose-optimization approach for frail patients, in whom tolerability and QOL is paramount. Patient education and support provided by APPs and pharmacists is vital to ensure continuity of care and that patients with mCRC derive the maximum benefit from treatment.