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Using Regorafenib and TAS-102
How I Use Regorafenib and TAS-102 in My Patients With Metastatic CRC

Released: April 24, 2019

Expiration: April 22, 2020

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For patients with metastatic colorectal cancer (CRC), the dramatic improvement that has occurred over the past couple of decades in median survival from less than 12 months to more than 30 months has been driven primarily by the development of multiple lines of effective therapies. We are now seeing—and planning for—many patients receiving 3 or more lines of therapy. In this commentary, I will focus on supportive data and clinical considerations in later-line treatment of patients with microsatellite stable CRC tumors that are BRAF wild type, HER2 nonamplified, and lack NTRK fusion. Optimal treatment for these patients includes regorafenib and trifluridine‑tipiracil hydrochloride (TAS‑102), both of which are approved for use in this setting.

Regorafenib
Regorafenib is a molecularly targeted multikinase inhibitor. The approval of regorafenib for patients with metastatic CRC who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy (and, if RAS wild type, an anti-EGFR therapy) was based on the phase III CORRECT trial, which compared regorafenib with placebo in 753 patients with previously treated, progressive metastatic CRC. Median survival was significantly improved by nearly 2 months with regorafenib, thereby establishing this agent as a standard of care in the refractory setting. Further results showing a survival improvement greater than 2 months with regorafenib vs placebo came from the phase III CONCUR study, which enrolled 204 Asian patients. The historically larger improvement in outcome likely stems from the fact that many patients included in this study had less prior exposure to VEGF and EGFR inhibitors, thus emphasizing the importance of earlier exposure to regorafenib.  

The randomized phase II REVERCE trial examined sequencing of regorafenib and cetuximab in 101 Japanese patients. Although this trial did not meet its accrual goal, exposing patients to regorafenib prior to cetuximab significantly improved the primary endpoint of OS by more than 5 months vs the reverse sequence with cetuximab exposure prior to regorafenib.

TAS-102
TAS-102 is a new generation oral fluoropyrimidine cytotoxic agent. TAS-102 was approved in the same setting as regorafenib based on results from the phase III RECOURSE trial, which showed a significant improvement in OS and PFS with TAS‑102 vs placebo for patients with metastatic CRC and ≥ 2 previous lines of treatment (N = 800). The magnitude of improvement was historically comparable to that reported in the CORRECT trial. Interestingly, TAS-102 appeared to maintain relative benefit in the 20% of patients previously exposed to regorafenib. Notably, the phase III TERRA trial (conducted in a setting similar to that of CONCUR) suggested that TAS‑102 improved survival vs placebo in an Asian population, with a magnitude historically similar to that observed in RECOURSE.

Sequencing
We currently lack randomized, late-phase studies comparing these 2 agents in the refractory setting. In making decisions regarding sequencing, factors such as historical data, toxicity profiles, and patient preferences should be taken in account. For example, data from CONCUR and REVERCE suggest that (at least historically) regorafenib should be considered for earlier use as indicated. TAS‑102 appears to maintain its benefit regardless of prior exposure, whether to regorafenib (RECOURSE) or other biologics (TERRA). In our collective practice, we tend to generally administer regorafenib first in the sequence of agents prior to TAS‑102. Exceptions include patients who may have experienced severe hand–foot skin reaction (HFSR) with capecitabine; we also avoid administering regorafenib to those with significant elevations in liver function tests. In addition, we consider regorafenib to be administered prior to cetuximab in patients with RAS/BRAF wild type, right-sided tumors.

If you are considering TAS‑102 first, caution with patients who experienced myelosuppression during previous lines of chemotherapy should be exercised. A key adverse event associated with TAS‑102 is neutropenia, with approximately 3% of patients experiencing febrile neutropenia.

Dosing and Toxicities
A major challenge with both regorafenib and TAS-102 is how to optimize the dose and schedule for these oral agents. Difficult schedules with TAS-102 (administered 5 days on, 2 days off for 2 weeks every four weeks) may prove challenging for many older patients. Fatigue and gastrointestinal toxicities occur at similar rates with TAS-102 and regorafenib. With regorafenib, the biggest challenge is HFSR, which typically occurs in the first 2-3 weeks of administration and can lead to early discontinuation and loss of benefit.

The standard dosing regimen for regorafenib is 160 mg daily administered 3 weeks on, 1 week off; unfortunately, this standard approach often leads to early toxicity and discontinuation. In practice, many physicians start patients at either 80 mg or 120 mg daily to avoid toxicities—leading to concerns that patients may be incorrectly dosed. To help understand how to best optimize the dose of regorafenib, we conducted the phase II ReDOS trial, which randomized patients to the standard of care dosing vs starting regorafenib at 80 mg and then stepping up by 40 mg weekly to 160 mg daily, as tolerated. The study met its primary endpoint, showing that 43% of patients on the dose-escalation arm (vs 25% on the standard-of-care arm) initiated treatment cycle 3. Surprisingly, survival was numerically improved from nearly 6 months with standard of care (consistent with CORRECT) to 10 months with the dose-escalation approach. Additionally, toxicities were improved and quality of life was maintained in the dose-escalation arm. Interestingly, and regardless of treatment arm approach, patients who continued beyond cycle 3 had a median survival of approximately 1 year in this refractory setting. The results of ReDOS have led to a change in national guidelines and, in my opinion, this dose-escalation strategy should be the standard of care for regorafenib for all patients with refractory mCRC when this agent is considered for use.

Your Thoughts?
How do you sequence regorafenib and TAS-102 for your patients with metastatic CRC? Please answer the polling question on your screen and share your thoughts in the comments box.

To see what 5 experts would recommend for patients with metastatic CRC in different clinical scenarios, visit the Interactive Decision Support Tool: Treatment of Metastatic CRC; bookmark this link and check back for an updated CRC tool coming soon!

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