mCRC: Options for Third-Line Therapy

Tanios Bekaii-Saab, MD:At 5 months on cetuximab, the patient starts experiencing symptoms that were concerning for progressive disease: fatigue, some nausea. A CT scan performed did indeed confirm that the patient is progressing. MCA was 89. She continues to have a good performance status, and her desire is to proceed with further therapy at this time.

Here’s a patient who was exposed to FOLFOX, FOLFIRI, bevacizumab, and cetuximab—so, essentially, went through 2 lines of therapy. She’s microsatellite stable, so no options for immune therapy. She’s BRAF wild-type, so no options for BRAF-targeted therapies. She’s HER2 nonamplified, so no options to go on a HER2-targeted therapy, at least on a clinical trial. Her standard of care options are regorafenib and TAS-102.

Performance status is an important factor in determining who should (1) proceed with treatment and (2) what treatment would be optimal. In all frankness, any patient beyond performance status of 2 should not be treated at this stage. That’s a patient where we have a discussion for no therapy. The patient here is still performing and desires to have additional therapy. So, the options are regorafenib and TAS-102, understanding that there’s no difference between the 2 options—at least, we don’t know of any differences, since they haven’t been compared head-to-head.

My preference would be to start the patient on regorafenib first, followed by TAS-102. That’s the sequence I typically apply in my clinic. And the primary reason for that comes essentially from an attempt to understand the data that are or have been presented and published in the last few years, any emerging data from ASCOGI 2018. And the understanding is that with regorafenib, we do have the RECOURSE study, which was TAS-102 versus placebo and had a subset of patients, about 20%, who had prior regorafenib exposure. And prior regorafenib exposure did not seem to affect the performance of TAS-102.

So, we have that subset analysis. Again, it’s certainly not a randomized way to think about therapy or therapeutic options, but it’s a hint that regorafenib at least placed ahead of TAS-102 does not affect outcome.

The other study is the CONCUR study from Asia, where patients are typically less preexposed to treatments, and that suggests that regorafenib has a wider or a more steep benefit when patients are less exposed and they see regorafenib a little bit earlier in the line. This was confirmed in a different way by the Japanese study that was presented in ASCO GI, the REVERCE trial, that suggested that if you place regorafenib ahead of cetuximab versus the reverse—so cetuximab followed by regorafenib—patients do tend to have a much better survival, which was a quite statistically significant 6-month difference. And there was also an improvement in progression-free survival. So, that study suggests or confirms that regorafenib perhaps placed earlier makes more sense.

In terms of how we dose for regorafenib, we had the regorafenib dose optimization study that suggested that the strategy with going from 80 mg to 120 mg to 160 mg in the first cycle—so, dose optimization strategy may be the preferred way to treat patients with regorafenib than going just straight with 160 mg. We found an improvement in the primary end point of the study, which was how many patients would be able to go through 2 cycles, get a scan, and intend to go to the third cycle, an improvement in overall survival—a slight improvement in PFS, and there may be also a little advantage with the quality of life.

Transcript edited for clarity.

Metastatic Colorectal Cancer Originating on the Left Side

October 2016

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
  • PMH: atrial fibrillation, moderately controlled on a beta- blocker; patient is also on warfarin
  • CEA elevated; 23.3 ng/mL
• Pathology:
  • Undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 were involved
  • Molecular testing:RASandBRAFwild-type, microsatellite stable
• Imaging with PET/CT showed multiple lung lesions bilaterally, three measuring approximately 3.0 cm
• Diagnosis: grade 3 colorectal adenocarcinoma, stage T4N2M1
• The patient preferred to avoid rash and received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
• The patient was continued on bevacizumab maintenance

August 2017

• The patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in two of the lung lesions and development of 3 small liver lesions
• The patient was switched to FOLFIRI and cetuximab; her heart rhythm was closely monitored and remained stable
• Follow-up imaging at 2 months and 4 months showed stable disease in the lung and liver lesions; her symptoms improved
• At 4 months, the patient complained of severe fatigue and was changed to maintenance therapy

January 2018

• At 5 months, the patient reports reappearance of symptoms and states she requires frequent rest because of fatigue
• CEA, 89.8 ng/mL
• CT shows progressive disease in the lung and presence of several small boney lesions
• The patient is motivated to try another therapy