Subsequent Lines of Therapy and Non-Chemotherapy Options for mCRC


Dr Bekaii-Saab reviews options for subsequent lines of therapy for metastatic colorectal cancer, including non-chemotherapy options.

Tanios Bekaii-Saab, MD, FACP: In a patient with 2 lines of therapy, third or fourth line for some patients, options become limited. We have 2 options in that setting: regorafenib and TAS-102 [tipiracil hydrochloride]. Regorafenib is a multikinase inhibitor. TAS-102 [tipiracil hydrochloride] is a fluoropyrimidine that has backbone, or a piece of that helps with clearance of the fluoropyrimidine, which makes TAS-102 [tipiracil hydrochloride] somewhat active after 5-FU [5-flurouracil] or capecitabine. Both options are available to us. They’re part of our treatment armamentarium in the NCCN [National Cancer Comprehensive Network] Guidelines.

The most important piece is molecular profiling, which has to be done early so we can ensure that the patient has all these potential therapies planned for across lines of therapy. HER2 [human epidermal growth factor receptor 2] amplification is 1 example; it’s present in 2% to 4% of patients. It could change how to treat in the second and even third with HER2-targeted therapies. MSI [microsatellite instability] high will lead us down the path of pembrolizumab in the first line. That can spare 30% to 40% of patients from seeing second-line therapy, chemotherapy, or whatever form of therapy.

For KRAS mutations, G12C is 1 we’re keeping an eye on. There are a number of trials looking at EGFR inhibitors for this, BRAF mutations with the RAF-targeted strategies, and the list goes on. It’s important to have molecular profiling because it changes how we use these therapies across lines. But for most patients, beyond second line, we don’t have any targeted options per se, and we have essentially those 2 agents: regorafenib and TAS-102 [tipiracil hydrochloride].

The decision to proceed with 1 vs the other is based mostly on experience. There aren’t many data comparing the 2, and that’s a limiting factor in terms of sequencing. You have hints here and there that 1 may be better to start with than the other. I’ll touch on that. But overall, if you have a patient who essentially is borderline performance status [PS], these patients may have a little tougher time with regorafenib vs TAS-102 [tipiracil hydrochloride]. I’m talking about those with PS2 [or higher], although those are the patients who typically don’t do too well with treatment. If the patient has a risk of liver toxicity enhanced, then I’d be careful with regorafenib because there are instances where liver dysfunction can be exacerbated. Although if TAS-102 [tipiracil hydrochloride] gets cleared it may not be applicable in that case. That’s something to keep in mind.

One of the advantages of starting with regorafenib is that when we looked at data from Asia, in the CONCUR study, and we looked also at TAS-102 [tipiracil hydrochloride] with data from Asia in a study called TERRA, what becomes clear is that regorafenib does better when used earlier rather than later. When I say earlier that’s as indicated, not first or second line. In the CONCUR study, there were fewer patients pre-exposed to biologics; therefore, regorafenib performed better than expected. TAS-102 [tipiracil hydrochloride] activity didn’t seem to change much, depending where you placed the line of therapy.

Another study, from Japan, called REVERCE, looked at regorafenib followed by cetuximab plus or minus irinotecan, or vice versa. The study had a primary end point of overall survival. It was a phase 2 randomized study. It closed earlier because it couldn’t accrue as well, but it was still close to 100 patients. It’s a relatively a sizable study. It did reach its primary end point with regorafenib being positive when followed by cetuximab followed by the other way around. Regorafenib seemed to do better earlier on. Other data suggest sequencing regorafenib before TAS-102 [tipiracil hydrochloride] may be better.

One of those studies stands out from a network meta-analysis that we published in The Oncologist that did show that if we follow a dose-escalation strategy—I’ll go through that with regorafenib—then you outperform a standard 160 mg regorafenib [per day] or TAS-102 [tipiracil hydrochloride]. This is based on a study called the ReDOS study. The ReDOS study looked at the data from CORRECT, [in which it was] obvious that regorafenib improves outcome over best supportive care. But in clinical practice, we had significant difficulties starting with 160 mg. Everyone started toying around with different dosing strategies.

ReDOS is designed with the thought that we want to go with a dose-escalation strategy on regorafenib from 80 to 120 to 160 mg on a weekly basis. Because most of the toxicities happen within the first 2 weeks, we’re going to figure out the dose best in the first 4 weeks of treatment, before we move on with the best dose beyond cycle 2 vs 160 mg, which was the dose studied on CORRECT. I don’t want to call it standard anymore because the standard is ReDOS and not the 160 mg.

ReDOS had a primary end point that tried to capture the tolerability and efficacy of the strategy. We said we want to see what percentage of patients make it to and start cycle 3. To make it to cycle 3, you must tolerate the drug. To continue beyond cycle 3, you have to respond to the agent. We’re looking for a 15% difference to the advantage of the dose-escalation strategy. We beat that, and it was statistically significant, meaning the study was positive. Interestingly, with a dose-escalation strategy, we’ve shown that we don’t compromise quality of life. You get fewer toxicities, but also it appears to improve survival. This was a secondary end point, but it was interesting to see that survival was extended with the dose-escalation strategy. All these things aligned make it a preferable way to do it.

We just published another paper in The Oncologist that looked at the same randomization we had in the study, and this looked at preemptive steroid cream with clobetasol vs reactive. Preemptive meaning our patients would use clobetasol from day 1 vs those who would use it when they start having hand-and-foot syndrome reactions. This strategy seemed to work for many patients. In the clinic, I’m starting to implement this more, especially for those patients whose support system is a little less developed or they’re a little further out so they can’t come to us frequently. I’ve done that. Ultimately, I’d like to have all my patients on this steroid cream.

Overall, that became the preferred strategy. In fact, it changed the NCCN Guidelines. It’s widely used in Europe and Asia, as well as the United States. In our experience, this has become the preferred line of therapy after 2 prior lines. In the sequencing sense, regorafenib with a dose-escalating strategy is first and then TAS-102 [tipiracil hydrochloride] second, based on experienced data and emerging data.

This transcript has been edited for clarity.

Case:A 65-Year-Old Man With Metastatic Colorectal Cancer

Initial presentation

  • A 65-year-old man reported a 2-month history of constipation, bloating, abdominal pain, and 10-pound unintentional weight loss
  • PMH: Mild hypertension controlled with calcium channel blockers

Clinical workup

  • Labs: Hg 9.4 g/dL, LFTs elevated and CEA 80 ng/mL
  • Colonoscopy revealed a 5-cm completely obstructing mass in sigmoid colon
  • Patient underwent left hemicolectomy with diverting ostomy
  • Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue with5 of 12 resected nodes positive
  • CT scan showed several lesions in both lobes of the liver, measuring up to 15 mm in diameter, and 3 small lesions (<5 mm) in the left lower pulmonary lobe
  • Molecular testing: KRAS mutation in codon 12 of exon 2; microsatellite stable
  • Diagnosis: Stage 4 colorectal cancer
  • ECOG PS is 1


  • The patient received systemic therapy with FOLFOX + bevacizumab in the first line for 4 cycles
  • The patient developed neuropathy and was switched to capecitabine + bevacizumab for 4 months and then unfortunately progressed, residual neuropathy at G1
  • At that time he was switched to FOLFIRI + bevacizumab
  • 6 months later, clinical progression is confirmed when new lung metastases are seen on chest CT
  • The patient was switched to regorafenib
Related Videos
Video 2 - "Setting Expectations + First-Line and Second-Line Treatment of Graft Versus Host Disease"
Video 1 - "Patient Case: Pathology of Graft Versus Host Disease"
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Gary J. Schiller, MD, an expert on MDS
Related Content