Regorafenib offers a unique challenge in terms of AE management. AEs with regorafenib have been reported across several clinical trials, and more recently, a clinical case study demonstrated the utility of regorafenib in a "real world" scenario, adding further insight.
Ronald Tang, MD
The standard treatment for patients with metastatic colorectal cancer (mCRC) includes multiple lines of therapy, with the ultimate goal of extending survival while maintaining quality of life. Distinct challenges are faced with each new line of therapy, specifically in regard to managing adverse events (AEs).
The need for early AE management is particularly important in the setting of refractory mCRC. In this setting, patients have experienced disease progression on first- and second-line therapy but may still have a good performance status. In most cases, these patients are still amenable to further life-prolonging treatments, such as regorafenib (Stivarga), which was approved by the FDA in September 2012.
As with each new line of therapy, regorafenib offers a unique challenge in terms of AE management. AEs associated with regorafenib have been reported across several clinical trials, including the pivotal CORRECT trial, the Asian CONCUR study, and the phase IIIb CONSIGN trial. More recently, a clinical case study demonstrated the utility of regorafenib in a “real world” scenario, adding further insight into the agent’s use.1
“These patients are heavily pretreated and have progressed on 5-FU, oxaliplatin, irinotecan, anti-VEGF therapy, and if KRAS wild-type, an anti-EGFR. Patients are more fragile in terms of count recovery and are mostly predisposed to hand-foot syndrome due to prior capecitabine therapy,” the authors of the case study Ronald Tang, MD, from the LA Cancer Network, and Tara Seery, MD, from the University of California, Irvine, toldTargeted Oncologyvia email.
“We recommend seeing the patients weekly for the first cycle,” they continued. “It is important to recognize and treat side effects early, so patients will be able to remain on therapy. The ultimate goal is to preserve quality of life with minimal adverse events.”
Results From Clinical Trials
Approval of regorafenib was based on results from the phase III CORRECT trial,2which showed a significant benefit in overall survival (OS), progression-free survival (PFS), and disease control rate for patients randomized to best supportive care (BSC) plus regorafenib compared with BSC plus placebo.
In this study, median OS was 6.4 months with regorafenib versus 5.0 months with placebo (HR, 0.77; 95% CI, 0.64-0.94). Median PFS was 2.0 months with regorafenib versus 1.7 months with placebo (HR, 0.49; 95% CI, 0.42-0.58).
Safety findings from the CORRECT trial identified hand-foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation as the most important treatment-related AEs of grade 3 or higher. AEs leading to dose reduction or interruption occurred in 67% of patients treated with regorafenib, with 38% and 61% of patients having their dose reduced or interrupted, respectively.
“From our experience, the side effects [of regorafenib] present early, sometimes within the first week of therapy. The side effects are more common in the first cycle and decrease in subsequent cycles,” said Seery and Tang. “For this reason, we like to see our patients weekly when starting regorafenib.”
A second randomized phase III trial, known as CONCUR, evaluated the impact of regorafenib in an Asian mCRC population who had been treated with at least 2 prior lines of theapy.3CONCUR demonstrated a significant OS benefit for regorafenib over BSC. In the study, median OS was 8.8 months for patients who received regorafenib versus 6.3 months for patients who received placebo (HR, 0.55; 95% CI, 0.40-0.77;P= .00016).
In this study, safety findings were generally consistent with CORRECT, with HFSR, hypertension, hyperbilirubinemia, hypophosphatemia, ALT and AST increases, lipase increases, and maculopapular rash emerging as the most important grade 3 or higher AEs.
Findings from a large expanded access program, known as CONSIGN,4added to the robust dataset for regorafenib. This study was initiated to assess the safety of regorafenib in a larger cohort of patients (N = 2872). The estimated PFS in the study was 2.8 months with regorafenib.
The overall safety findings of this trial showed a similar profile for regorafenib-related AEs as in CORRECT and CONCUR. In this study, grade ≥3 AEs occurred in 80% of patients, with 57% considered to be related to regorafenib. Serious AEs related to regorafenib occurred in 9% of patients. There was one non-fatal case of severe drug-induced liver injury and grade 5 AEs were documented in 13 patients (<1%).
“It is very important to emphasize that, although this is an oral pill, providers cannot administer regorafenib and have patients return in a month for follow up,” Seery and Tang said. “This could lead to early discontinuation of a very effective line of therapy, and cause the patient unnecessary morbidity.”
Specific guidance for regorafenib dose modifications is outlined in the prescribing information. Overall, dose reductions, if necessary for AEs are recommended in 40 mg increments, beginning at 160 mg and down to a minimum of 80 mg.5Several recent reviews have also focused on how HFSR, hypertension, rash, diarrhea, fatigue can be effectively managed, allowing patients to continue treatment over an extended period.
“From our experience, we do not start patients on full dose regorafenib (160mg) due to the adverse events. We start patients at 120mg, and monitor patients weekly,” said Seery and Tang. “If they are able to tolerate the medication, we titrate the dose up to 160mg.”
Once therapy with regorafenib is initiated, regular communication between the patient and healthcare provider is an integral part of these management strategies, so that specific AEs can be recognized and addressed. Additionally, judicious management of treatment associated AEs can aid in promoting a patient’s adherence to their treatment, which can be particularly challenging in the context of a heavily pretreated patient population in mCRC.
“The hand-foot syndrome is typically seen by the second week of therapy. We have not had a patient with hypertensive urgency or emergency, but noticed an elevation of blood pressure by the second week,” said Seery and Tang. “We also advise patients to take their blood pressure at home on a daily basis during the first two weeks of therapy.”
Managing AEs in Clinical Practice
In Seery and Tang’s case study,1the patient had progressed through several lines of therapy for mCRC, beginning in 2011 with capecitabine, oxaliplatin, and bevacizumab. This was followed by second-line therapy in 2012 with cetuximab and FOLFIRI. In September 2013, the patient began regorafenib.
“The patient progressed on 5-FU, oxaliplatin, irinotecan, bevacizumab, and cetuximab. She remained very active, with a good performance status and wanted to travel, but wanted to continue therapy,” said Seery and Tang. “With this in mind, regorafenib was her only option, as it is an orally administered therapy.”
In the case study, the patient started regorafenib at the full 160 mg daily dose. Quickly after beginning therapy, she underwent a treatment interruption followed by dose reductions, in order to resolve hypertension. After restarting at a lower dose (120 mg/day), she developed grade 3 fatigue. After further treatment interruption and a second dose reduction to 80 mg/day, the patient’s AEs were stabilized.
Importantly, the successful management of these AEs ultimately allowed the patient to remain on therapy for 11 months, with symptom palliation and minimal side effects.
“We monitored the patient very closely at the beginning, with dose modifications due to hypertension, and were able to find the appropriate dose to preserve her function, keep her cancer stable, which in turn palliated her symptoms,” Tang and Seery concluded.