Options for Third-line Therapy in Metastatic CRC

Tanios Bekaii-Saab, MD, FACP:So, in January 2017, the patient presents to her oncologist with, again, more symptoms of weight loss, nausea, and fatigue. And so, she gets referred back for another CT scan, which showed even further progression in the lungs, a little progression in the liver, and now the patient has a couple of boney lesions that are nonthreatening. The patient essentially shows evidence of progressive disease, and her CA levels are rising significantly. The patient, after discussion with her oncologist, expresses motivation to continue with therapy. Her performance status is 1. She’s doing great, she’s still doing her house chores. She’s a little bit more fatigued, limited, but overall, she’s still very functional and she wants to continue on further therapy. There are no clinical trials that she would be eligible for. There was a discussion between herself and her medical oncologist regarding the 2 oral agents that are available for refractory disease: regorafenib and TAS102. The decision was to proceed with regorafenib.

So, now the patient progressed through FOLFIRI/cetuximab, CapeOx/bevacizumab—2 lines of therapy—and the question is, what do you next? What would be done next is essentially a couple of options that are now made available to us. Again, as a reminder, this patient is microsatellite stable, so immune therapy outside clinical trials is not an option for this patient. Our 2 options are TAS102 and regorafenib. There are differences between the two. TAS102 is your traditional cytotoxic agent, and that essentially is fluoropyrimidine or part of that fluoropyrimidine super family. It’s not 5-FU, it’s not capecitabine. It actually has functions within it that will allow it to work when 5-FU and capecitabine fail. And so, in that sense, it’s a little different although it belongs to that super family. But it’s a cytotoxic agent.

Regorafenib, on the other hand, is what we call a multi-kinase inhibitor. It has multiple targets. It’s not your traditional cytotoxic agent; it’s a targeted agent. It has a lot of targets on the cancer cells and in the environment, including VEGF. This agent essentially is what we call a dirty drug; promiscuous, essentially, with all these targets. So, they’re different. And these agents have never been compared head-to-head. Actually, each one of these agents had 2 large phase III studies, and regorafenib, in addition, had an observational study called CONSIGN. We have CONCUR and we have CORRECT, and CORRECT is the larger study that essentially led to the approval of the agent, regorafenib. CONCUR is an Asia-only study, and CONSIGN is essentially an observational study, which I think collected more than 2000 patients.

On the other hand, we have TAS102 in the RECOURSE study, which was the large study that led to its approval versus placebo; so, similar design to the CORRECT trial. Then, TERRA is very similar to CONCUR. Again, it was the drug versus placebo and was in Asia only, similar to CONCUR. We have these studies on hand that are similar, but like I said, we don’t have any comparative data looking at TAS102 versus regorafenib to help us with a decision. So, we really have to rely on historical controls, personal experience, and other factors as well.

When we look at regorafenib, and between CORRECT and CONCUR, CONCUR had patients who were less pre-exposed to treatment. In other words, in Asia and certain Asian countries where there is less availability of VEGF and EGFR inhibitors, those patients will get regorafenib a little earlier on. Historically, when we looked at CORRECT and CONCUR, it does seem that regorafenib may have a further benefit if moved up the line. When we look at TAS102, we have, as I said, RECOURSE and TERRA, and when we look at very similar populations again, RECOURSE patients had to fail all standard therapies similar to CORRECT. And in fact, with the TAS102 study, the RECOURSE, about 20% of the patients had prior regorafenib. Prior regorafenib did not seem to affect the benefit that you see with TAS102. So, whether you had regorafenib or not, you still derived benefit, which is good news. At least we have that little hint there.

TERRA, on the other hand, is a study that is like CONCUR. It had less pre-exposed patients. Interestingly, TAS102, as it moves up the line, didn’t seem to have a larger delta, meaning the benefit is maintained regardless of where you place it in the line of therapy. And maybe one of our hints that, perhaps, in terms of sequencing regorafenib, there are some patients whose performance status is borderline PS 2 or the liver is quite dysfunctional—not too dysfunctional, of course, because you can’t give either drug, but dysfunctional enough to worry about regorafenib, and we would give TAS102 first. On the other hand, in patients who clearly had issues with their bone marrow, you want to avoid TAS102. Their toxicity profiles are different. CONSIGN just confirms a lot of the observations with CONCUR and CORRECT.

Transcript edited for clarity.

October 2015

• A 64-year-old woman underwent left hemicolectomy for an obstructing mass at the rectosigmoid junction
  • CEA were elevated, 23.3 ng/mL
  • Pathology showed an undifferentiated adenocarcinoma, invading through the muscularis mucosae up to the pericolic fat; 14 nodes were biopsied, 10 of which were metastatic
  • Imaging with PET/CT showed several lung lesions, three measuring up to 3.0 cm in size
  • Mutational status was both RAS and BRAF wild-type
  • Microsatellite stable
  • Diagnosis; high grade colorectal adenocarcinoma, stage T4N2M1
• PMH includes arterial hypertension, well-controlled on an ACE inhibitor and coronary angioplasty with stent placement 4 years ago
• The patient received systemic therapy with FOLFIRI + cetuximab; grade 1 rash and grade 2 thrombocytopenia were managed with dose adjustment of FOLFIRI
• Follow-up imaging at 2 months and 4 months showed significant response in the lung lesions
• The patient was continued on maintenance therapy with cetuximab

August 2016

• The patient complains of weight loss, nausea and fatigue
• CT of the chest, abdomen, and pelvis showed marked progression in 2 of the lung lesions and development of new liver lesions
• The patient was switched to CAPEOX with bevacizumab. Her blood pressure was closely monitored and remained stable
• Follow up imaging at 2 months and at 4 months showed stable disease in the lung and liver lesions and improvement of her symptoms
• At 4 months, oxaliplatin was discontinued; maintenance therapy with capecitabine and bevacizumab was continued

January 2017

• At 5 months, the patient reports having reappearance of her symptoms, although she continues her normal physical activity
• CEA level is rising significantly
• Follow up CT showed further progressive disease in the lung and the appearance of several small boney lesions
• The patient is motivated to try another therapy and has opted for regorafenib