mCRC: Options for Third-Line Therapy and Beyond

Wells Messersmith, MD:So, now we come to the third line in treating this patient. We started with FOLFOX/bevacizumab. We then had FOLFIRI/bevacizumab, and each line of therapy that you give the response rates tend to go down, and the amount of time the patient benefits tends to go down—which makes sense if you think about how these cancer cells are getting hit by this chemotherapy and the ones that are resistant tend to survive. The ones that are sensitive tend to die. And so, each time you’re using a different line of therapy, you’re taking on a tougher opponent. I think if we were forced into the boxing ring, I would rather take on someone who’s 0 and 0 versus 2 and 0, basically. But we’re in the third-line setting, and there are a couple of FDA-approved therapies that have a survival benefit, even though it’s an incremental survival benefit.

The treatment goals in the third-line setting remain the same as in the first-line or second-line settings, which is to improve survival of the patient and also try to maintain quality of life by keeping growth of the tumor in check.

There are 2 FDA-approved therapies that we tend to use in the third-line setting forKRAS-mutated metastatic colorectal cancer. One is called TAS-102. And this is basically a 5-FU—type of drug—although it has different activity than 5-FU does, it is similar in structure—that was actually synthesized quite some time ago. It has a very short half-life and so they basically formulated it with a metabolism inhibitor.

And this trial was tested in the third-line setting, which is exactly where we are now in a large randomized trial basically showing that it improved survival, although it’s incremental and modest—but nonetheless, it improved survival. And, of course, it’s important to remember that that is on average. Some patients will actually get no benefit, and some patients can actually go for quite a long time on these.

And these are pills, so it’s easier than carrying around a pump. You don’t have to come into the infusion center all the time. So, many patients, even though they’ve had 2 lines of chemotherapy, they’re probably a little tired of all this, but many of them are able and willing and interested in trying them.

With TAS-102, the most common side effect is the key, and so that’s something to warn patients about. You also often have low blood counts, so those have to be monitored. If the patient’s bone marrow has been hit for 2 years with all this standard chemotherapy, frequently, the low counts can be an issue with this drug. So, those are the 2 main aspects there.

The other option would be regorafenib. This is a multitargeted tyrosine kinase inhibitor—also a pill—and it also has a modest survival benefit in this setting. Again, some people get no benefits, some people get a very good benefit, and the side effect profile is a little different. It tends to cause more in the way of hand-foot syndrome, or rash on the hands and feet. And I found it has a little bit more diarrhea, although not everyone has found that. It can also cause mouth sores. It tends to cause less in the way of low blood counts. And so, these 2-pill drugs have somewhat different toxicities. It’s important to flush that out with the patient in terms of what has been a dominant toxicity before and what’s the toxicity they most want to avoid in this setting, and that can kind of help you make a decision one way or the other.

Transcript edited for clarity.

Progression of Left-Sided mCRC

February 2016

• A 66-year-old man reported with constipation, bloating, abdominal pain and weight loss of 12 pounds in 2 months
• PMH: mild hypertension, well-controlled on CCB
• Lab evaluation: Grade 2 anemia (Hb 9.2 g/dL)
• Colonoscopy revealed a7-cm mass in sigmoid colon
• CEA, 80 ng/mL
• The patient underwent sigmoid colectomy
• Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue;
  • Biopsy: 7of 12 resected nodes positive
  • Molecular testing:KRASmutation in codon 12 of exon 2; microsatellite stable
• CT scan showed several lesions in both lobes of the liver, measuring up to 17 mm in diameter, and 3 small lesions (<6 mm) in the left lower pulmonary lobe
• Diagnosis: Stage 4 colorectal cancer
• The patient received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• The patient was continued on bevacizumab maintenance

February 2017

• One year after starting therapy, the patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed progression in three of the liver lesions and one lesion in the right pulmonary lobe
• The patient was started on FOLFIRI and continued bevacizumab

January 2018

• Eleven months later, CEA level rose significantly
• Follow-up CT showed progressive disease in the lung and liver
• The patient is interested in knowing his options at this stage