John is a 66-year-old man with metastatic adenocarcinoma of the colon, which was diagnosed in October 2015 after he presented to his primary care physician (PCP) with symptoms of rectal bleeding and weight loss. A colonoscopy revealed a mass in the descending colon. The biopsy suggested adenocarcinoma consistent with colon primary. The tumor was microsatellite stable (MSS), with wild-type (WT) rat sarcoma viral oncogene homolog (RAS) and B-Raf proto-oncogene (BRAF), and human epidermal growth factor receptor 2 (HER2) nonamplified. Computed tomography (CT) scans of his chest, abdomen, and pelvis revealed widespread metastatic lesions in his lungs and liver. John's laboratory results were within normal limits, except for mild microcytic anemia. His carcinoembryonic antigen (CEA) was 250 ng/mL (normal,<3 ng/mL).
John was started on FOLFIRI plus bevacizumab in November 2015, and he tolerated the treatment well with mild diarrhea. At 2 months, the CT scan shows a partial response (PR). He was continued on treatment for 6 more months. His CEA was 3 ng/mL and his scans showed evidence of a near complete response (CR). John was placed on maintenance therapy with capecitabine and bevacizumab. He had a response until August 2016, when his CEA started rising. A repeat CT scan showed progressive disease (PD) in the liver and lungs. He was restarted on FOLFIRI plus bevacizumab and achieved stable disease (SD) for 6 more months before he showed evidence of progression.
The decision was made to switch John to FOLFOX and panitumumab. He again tolerated his treatment well, with grade 1 rash and mild diarrhea. At 2 months, the CT scan showed a PR. He started to develop grade 1 neuropathy, which he said was tolerable. He was continued on treatment for 2 more months. His CEA was now improved to 12 ng/mL, and his CT scans showed evidence of continuous stable disease. He was placed on maintenance therapy with panitumumab in June 2017. He continued to have stable disease for 3 more months before he showed evidence of progression. At that time, his Eastern Cooperative Oncology Group (ECOG) performance status (PS) remained at a 0; his labs were within normal limits, except for mild microcytic anemia; and his CEA reached 500 ng/mL.
Which of the following would be the most appropriate next option for John?
Regorafenib is the recommended treatment for patients like John with RAS WT metastatic colorectal cancer (mCRC) that has progressed on 5-fluorouracil (5-FU), oxaliplatin, and irinotecan-containing regimens, such as FOLFIRI or FOLFOX; on an anti-epidermal growth factor receptor (EGFR) agent, such as panitumumab; and on an anti-vascular endothelial growth factor (VEGF) biological therapy, such as bevacizumab. Pembrolizumab or nivolumab ± ipilimumab are only indicated for patients with microsatellite instability-high (MSI-H) mCRC or mismatch repair (MMR)-deficient mCRC. Because John was already treated with anti-EGFR and anti-VEGF therapies, further treatment with regimens containing such agents is unlikely to yield a significant response.
Regorafenib is an oral, small molecule inhibitor of multiple
membrane-bound and intracellular kinases involved in normal cellular
functions and in pathologic processes, including oncogenesis, tumor
angiogenesis, metastasis, and tumor immunity.
Kinases targeted include vascular endothelial growth factor receptor
(VEGFR)-1, -2, and -3; platelet-derived growth factor receptor
(PDGFR)-β; fibroblast growth factor receptor (FGFR)-1; tyrosine kinase
with immunoglobulin and epidermal growth factor homology domain 2
(TIE2); KIT proto-oncogene receptor tyrosine kinase (c-KIT); ret
proto-oncogene (RET); Raf-1 proto-oncogene, serine/threonine kinase
(RAF-1); and BRAF.
Regorafenib was approved by the FDA in 2012 based on the efficacy results from the phase 3 CORRECT study, which showed a survival benefit in patients with mCRC that progressed after all standard therapies (Table 1). In the study, 760 patients (median age, 61 years; 60% men) were randomly assigned to best supportive care with placebo (n=255) or regorafenib (n=505). The primary endpoint was overall survival (OS), which was met at a preplanned interim analysis.
|Regorafenib (n=505)||Placebo (n=255)|
|Deaths, n (%)||275 (55)||157 (62)|
|Median OS, months*||6.4||5.0|
|Deaths or progression, n (%)||417 (83)||231 (91)|
|Median PFS, monthsƗ||2.0||1.7|
|ORR, n (%)||5 (1)||1 (0.4)|
Similar efficacy results were seen with regorafenib in the phase 3 CONCUR trial, which was performed in China, Hong Kong, South Korea, Taiwan, and Vietnam to assess regorafenib in a broader population of Asian patients with refractory mCRC; CORRECT included 111 Asian patients, but most were Japanese. CONCUR randomly assigned 204 patients 2:1 to regorafenib (n=136) or placebo (n=68). Of these patients, 40% had not received any prior targeted biological treatment. After a median follow-up of 7.4 months, the primary endpoint of OS was met and was significantly better with regorafenib vs placebo at 8.8 vs 6.3 months, respectively (HR, 0.55; 95% CI: 0.40, 0.77; P <.001).
Regorafenib has only shown activity in patients who have progressed on all standard therapies. Therefore, it is recommended only for patients with mCRC previously treated with all standard therapies, including oxaliplatin-, fluoropyrimidine-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and, in the setting of wild-type RAS, an anti-epidermal growth factor receptor (EGFR) therapy.[1,4]
The decision is made to initiate regorafenib. The oncology team reviewed treatment administration and toxicities with John. John is comfortable with starting treatment.
What is the optimal oral daily dosing for regorafenib?
The ReDOS study found that a strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg daily was superior to the historical starting dose of 160 mg/d, improving tolerability, enabling longer treatment duration, and improving outcomes (OS and PFS).
Because of the toxicities associated with regorafenib, various dosing or interval scheduling have been implemented in clinical practice. The phase 2 ReDOS trial was a dose-optimization study for regorafenib in refractory mCRC that randomized 116 patients 1:1:1:1 to 1 of 4 arms: Arm A1, regorafenib 80 mg daily with weekly dose escalation to 160 mg daily, if tolerated, plus preemptive strategy for palmar-plantar erythrodysesthesia (PPES); arm A2, same dose and escalation strategy as arm A1, but reactive strategy for PPES; arm B1, regorafenib 160 mg daily for 21 days plus preemptive strategy for PPES; or arm B2, same dose as arm B1, but reactive strategy for PPES. The primary endpoint was the proportion of patients in arm A (pooled A1 and A2; N=54) vs arm B (pooled B1 and B2; N=62) who completed 2 cycles of treatment and initiated the third treatment cycle. Patient demographics, including age, sex, ECOG PS scores, and mutation profile, were well balanced between arms.
ReDOS met its primary endpoint, with 43% of patients in arm A initiating the third cycle vs only 25% of patients in arm B (one-sided P value, .028). The secondary endpoints of median OS and PFS were improved in arm A vs arm B, but the difference did not reach statistical significance at 9.0 vs 5.9 months for OS (P =.094) and 2.5 vs 2.0 months for PFS (P =.553). Of note, the median OS in the controls (arm B) is historically comparable to the expected 6.4-month OS observed in the phase 3 CORRECT study.
Overall rates of grade 3/4 toxicity were more favorable for arm A vs arm B, with PPES of 15% vs 16%, hypertension of 7% vs 15%, and fatigue of 13% vs 18%, respectively. Finally, multiple quality of life (QoL) parameters were improved in arm A vs B, as assessed by the Hand-Foot Syndrome-–Specific QoL questionnaire (HFS-14), the Brief Fatigue Inventory (BFI), and the Linear Analogue Self-Assessment (LASA), which were completed on C1D14, C2D1, C2D14, and C2D28. In arm A, dose-escalation from 80 mg to 120 mg to 160 mg was not found to compromise QoL, whereas in arm B, readjustments from the higher standard dose of 160 mg led to decreased QoL.
Based on the ReDOS findings, the National Comprehensive Cancer Network (NCCN) guidelines have been updated to recommend initiating regorafenib at the lower dose of 80 mg daily during week 1, then increasing to 120 mg orally daily for week 2 of cycle 1, and finally increasing to 160 mg orally daily starting week 3 of cycle 1, as tolerated. For subsequent cycles, regorafenib is given at 160 mg orally daily on days 1 to 21, as tolerated, with week 4 providing a break from treatment. Data from the study on preemptive vs reactive strategies for PPES are still undergoing analysis and are anticipated later in 2018
John was started on regorafenib 80 mg orally daily, with a plan to escalate by 40 mg weekly during cycle 1 to reach a goal of 160 mg daily, if tolerated. He was successfully escalated to 160 mg orally daily; however, he developed a grade 2 hand-foot skin reaction (HFSR) and returned to the office.
Which of the following dosing strategies should be used to address John's HFSR?
In patients with a first occurrence of a grade 2 HFSR, the dose should be reduced by 40 mg (1 tablet) but not to<80 mg daily, as 80 mg is the lowest recommended daily dose.1 If there is no improvement after 7 days or the grade 2 HFSR recurs, treatment should be interrupted until ≤grade 1. Patients on 120 mg regorafenib daily with a reoccurrence of grade 2 HFSR should have their dose reduced to 80 mg.
In the CORRECT trial, HFSR (ie, PPES) and rash were the most common reasons for permanent discontinuation of regorafenib. Across clinical trials, adverse skin reactions occurred in 71.9% of patients in the regorafenib arm vs 25.5% of those in the placebo arm. Most commonly, HFSR occurs days to weeks after treatment initiation and is characterized by dysesthesia, erythema, pain, and blisters with hyperkeratosis and surrounding erythema at pressure points. HFSR can be debilitating and impede patients' ability to carry out activities of daily living; thus, it is important for healthcare providers to promptly intervene to minimize the impact of this adverse event (AE) and enable patients to continue on treatment for as long as possible.
Before treatment initiation, a full skin inspection should be undertaken to establish a baseline. Patients should be educated about the risk of HFSR and its symptoms and be advised to contact their healthcare provider as soon as they notice any skin changes, such as rash, pain, blisters, bleeding, or swelling. They should understand that when addressed early, the impact of HFSR and other dermatological problems can be minimized with supportive care measures and that treatment can be continued. They should also be instructed that there are measures they can take to reduce their risk of HFSR. These measures are summarized in Table 2, along with supportive care measures once HFSR occurs.
|Patient Strategies||Provider Strategies|
In addition to supportive care measures, dosage or treatment adjustments are needed in patients who develop ≥grade 2 HFSR. Recommended dosage adjustments are summarized in Table 3.
Table 3. Dosage Adjustment by Grade in Patients With HFSR on Regorafenib 160 mg Daily
|Grade 1||Minimal skin changes or dermatitis (eg, erythema, edema, or hyperkeratosis) without pain)||Continue regorafenib|
|Grade 2||Skin changes (eg, peeling, blisters, bleeding, edema, or hyperkeratosis) with pain, limiting instrumental ADLs||Reduce dose to 120 mg |
Interrupt dose if no improvement 7 days after dose reduction or HFSR recurs
Reduce dose to 80 mg for reoccurrence of grade 2 HFSR at 120-mg dose
Discontinue treatment if 80-mg dose is not tolerated
|Grade ≥3||Ulcerative dermatitis or skin changes with pain interfering with function and limiting self-care ADL||Interrupt therapy for at least 7 days |
After recovery, resume at lower dose of 120 mg
Reduce dose to 80 mg for recurrence of ≥grade 2 HFSR at 120-mg dose
Discontinue treatment if 80-mg dose is not tolerated
John's dose was reduced to 120 mg orally once daily with good
tolerability. He remained on this regimen during cycle 2. His
restaging scans showed evidence of stable disease with cavitation of
his lung lesions, and his CEA dropped to 270 ng/mL. Following
4 additional months of treatment, his disease showed evidence of
progression and his CEA was 450 ng/mL. His ECOG PS was now
TAS-102 is the only option for John because he has been through all other standard treatments. Increasing his dose to regorafenib 160 mg daily is unlikely to provide further benefit. Recycling strategies are not supported by prospective data; however, they may be an option for patients with a great PS who fail all standard therapies, including regorafenib and TAS-102, and in the absence of clinical trials. Although John's disease is progressing, it is premature to refer him to hospice care because he is still well enough to try another treatment strategy
TAS-102, a more traditional cytotoxic therapy, combines the thymidine-based nucleoside analog trifluridine (TFT) with tipiracil
hydrochloride (TPI), improving TFT's bioavailability by inhibiting its catabolism by thymidine phosphorylase. It is given orally in a 1.0:0.5 molar ratio (TFT:TPI).TFT has been shown to bypass resistance pathways for 5-FU and its derivatives (oral tegafur and uracil [UFT], capecitabine).[7,8] In clinical trials, TAS-102 has shown efficacy in patients with 5-FU-refractory mCRC, with results of the pivotal phase 3
RECOURSE trial leading to its approval by the FDA in September 2015.[9,10]
TAS-102 is currently approved for mCRC patients who have previously
received fluoropyrimidine-, oxaliplatin- , and irinotecan-based
chemotherapy; an anti-VEGF biologic product; and, if RAS wild-type, an anti-EGFR monoclonal antibody.
In the RECOURSE trial, 800 mCRC patients who progressed through ≥2 prior
regimens were randomly assigned in a 2:1 ratio to receive TAS-102 or
placebo. The primary endpoint of OS was significantly improved in patients in the TAS-102 arm (7.1 vs 5.3 months; HR, 0.68; 95% CI:
0.58, 0.81; P <.001). The secondary endpoint of PFS was also improved with TAS-102 at 2.0 vs 1.7 months (HR, 0.48; 95% CI: 0.41, 0.57; P <.001). The most common AEs associated with TAS-102 included neutropenia (38%), leukopenia (21%), and febrile neutropenia
(4%). No unexpected safety signals were observed in a postmarketing surveillance study.
TAS-102 may be given before or after regorafenib. In the RECOURSE study, the patients who had been previously exposed to regorafenib had a similar OS benefit as those without
Therefore, the choice to use regorafenib or TAS-102 first in patients
with treatment-refractory mCRC should be guided by
patient characteristics, including performance status, comorbidities,
and tolerability of previous therapies. Two retrospective
analyses from Japan showed that while TAS-102 and regorafenib have
similar efficacy, there are important differences in their
AE profile. Regorafenib led to more HFSR and a greater elevation of
liver enzymes and bilirubin, whereas TAS-102 caused more
neutropenia, febrile neutropenia, leukopenia, and nausea.[13,14] Subsequently, it has been suggested that it might be better to start with regorafenib in patients with pancytopenias from
previous chemotherapy and with TAS-102 in patients with previous HFSR.[15,16]
John was started on TAS-102. He tolerated his treatment well during cycle 1. On day 1 of cycle 2, his absolute neutrophil count (ANC) was 350/mm (normal, 1800 to 7800/mm) with no fever. Treatment was withheld for 1 week. At his return visit, his ANC was back to 2000/mm.
Which of the following represents the most appropriate next step for John?
Patients who develop febrile neutropenia or have their ANC count drop to<500/mm3 within a TAS-102 treatment cycle should have their treatment withheld until their febrile neutropenia resolves or their ANC reaches ≥1500/mm. Upon recovery, treatment should be reinitiated at a lower dose, with the dose reduced by 5 mg/m2 from the previous dose level.
TAS-102 is administered at a dose of 35 mg/m dose orally twice daily on days 1 through 5 and days 8 through 12 of each 28-day cycle, which is followed by a 2-week rest period before the next treatment cycle begins. Ideally, patients should take TAS-102 in the morning and evening within 1 hour of completing their meal, keeping doses 12 hours apart as much as possible, and treatment cycles should start on a Monday to prevent confusion. This enables patients to take TAS-102 between Monday and Friday, providing them with a break over the weekend.
As an oral chemotherapy regimen, patient adherence to TAS-102 is essential, and patients should be advised not to skip or reduce their doses, including if any AEs arise. They should be educated on the AEs associated with TAS-102 and be instructed to call their oncologist as soon as any AEs occur. If a dose is missed, the usual schedule should be maintained, and the patient should not make up doses. For example, if a dose was missed during the day 8 to 12 cycle, that dose should not be made up on day 13.
Although development of neutropenia often means a treatment needs to be
dosed down, early neutropenia after TAS-102 initiation has been shown in
at least 2 studies to be associated with improved outcomes; thus,
dosing down might be counterproductive in this setting. In a
retrospective study of 95 Japanese patients, those with ≥grade 2
during their first TAS-102 treatment cycle had a 52.6% disease control
rate (DCR) vs a 29.2% DCR for those with ≤grade 1 neutropenia (odds
ratio [OR], 2.67; 95% CI: 1.01, 7.24; P =.045).
The median PFS and OS were also improved in patients with ≥grade 2
neutropenia, with a median PFS of 2.7 vs 2.0 months (HR, 0.59; 95% CI:
0.38, 0.91; P =.017) and a median OS of 6.7 vs 5.0 months (HR, 0.68; 95% CI: 0.41, 1.10; P
=.11), though the improved OS did not reach statistical significance.
In a prospective cohort study of 149 US patients with refractory mCRC
who received TAS-102, those who developed ≥grade 2 neutropenia during
their first month of treatment had statistically significant
improvements in median OS (14.0 vs 5.6 months; P <.0001) and median PFS (3.0 vs 2.4 months; P =.0096).
The association between neutropenia and improved outcomes with TAS-102 have yet to be elucidated. However, clinicians should consider that neutropenia might be a predictive biomarker of improved outcomes and follow current prescribing recommendations, which is to maintain the dose within a treatment cycle unless the ANC drops to<500/mm (grade 4), the patient develops febrile neutropenia, or has other severe AEs. When such events occur, the treatment is withheld until ANC recovers to ≥1500/mm, and then reinitiated at a dose 5 mg/m less than the previous dose level.
John resumed TAS-102 with a dose reduction by 5 mg/m. He had no further hematologic toxicities but experienced some mild nausea and diarrhea. His CEA level and restaging scans showed evidence of stable disease. John remained on TAS-102 for 2 more months before showing evidence of disease progression. His performance status remained at 1 and he expressed interest in enrolling in a clinical trial.