Therapy in the Salvage Setting of mCRC

John Marshall, MD:When one gets to third-line therapy—you’ve had oxaliplatin-based therapy, you’ve had irinotecan-based therapy—you have a menu of things, and we spell this out for patients, “Here’s what you can do from here on.” You’ve got 2 approved drugs: regorafenib and TAS-102. You’ve got clinical trials that are out there, and these patients often go on to clinical trials because they’re still in pretty good shape. Their performance status is pretty good. And then you’ve got recycling of chemotherapy—drugs that you stopped, usually this is oxaliplatin, not because it wasn’t working, but because you were trying to avoid neurotoxicity. You have a pretty good menu of choices. And doctors and patients all bring to the table expectations, values, and discussions about what they should do at that point.

Where I have evolved over the last several years is to value the oral therapies, the TAS-102 and the regorafenib, and their survival advantage that they bring to patients. I’m a big clinical trials guy, don’t get me wrong. We’re always looking for new things. But I also don’t want to ignore the fact that these 2 medicines have survival advantage. I also want to emphasize that if you wait too long, then these drugs don’t really work as well. So, to me, this good performance status—patient in the third-line setting is really an ideal patient to start on the approved drug approaches and then push off the clinical trial piece until the next one.

For third-line metastatic cancer, patients were randomized in this clinical trial between placebo and regorafenib—at a full dose, 160 mg daily—in a 2:1 randomization. And the clinical trial was positive, thus the approval. So, it improved overall survival and progression-free survival. The toxicity was acceptable, so it was brought forward. And it’s really fascinating that this drug works because we don’t really know how it works. It has a bunch of different targets—maybe as many as 19—one of which is a VEGF angiogenesis target, but there are others as well. And we’ve been looking very hard for a biomarker to figure out who benefits and who doesn’t. But despite lots of investment time and effort, we haven’t figured that out yet. And so, all-comers—RAS, MSI—they’re eligible for this kind of treatment. Based on the randomized clinical trial, there is a survival advantage and a progression-free advantage.

Dosing regorafenib is a hot-debated topic out there. The standard dose is 160 mg, 4 pills once a day. A lot of people are dose modifying right from the beginning. I think the most common pattern is to start at 120 mg, 3 pills a day, and then watch them weekly. Some will start at 80 mg and escalate, some will start at 160 mg and come down. So, I don’t really care how you do it. I just think you need to recognize the need for monitoring.

When regorafenib, oral chemotherapy, first came out, we thought you could sort them, see them a month later, and that was the right thing to do. And that turns out not to be really the best way to go. You need to monitor these people, maybe more closely than you’re used to even with chemotherapy. So, most of us pick a dose—80 mg, 120 mg, 160 mg—and watch them a week later; go ahead, make sure you see them, do some labs on them, and look at their liver functions. See them 1 week after that because often it’s in that window that hand-foot syndrome will all of a sudden arise and come on fairly suddenly. And just the process of seeing them is reassuring to the patient. It also emphasizes the need for them to be good stewards of their own toxicities, compliance, all of those things that you need to monitor with patients. Once you get to a dosing schedule, you can then opt out and see them once a month or so. So, you can get there, but the first cycle, the first month, you want to really see them 3 weeks in a row—draw labs, look at their hands, modify any doses, hold for 1 or 2 days, etc.

In terms of managing the toxicities, there’s not a lot here, other than the dose, that we figured out. You can use good hand creams. Urea-based hand creams help. It’s a good time for a manicure/pedicure, even for a podiatrist to remove calluses. Some people argue that that’s a good idea. And you have to remember, the majority of your patients will tolerate 160 mg pretty well. But there are ones who really don’t, who come in their house slippers 2 weeks later and say that you need to modify these doses. Liver function abnormalities are rare, but we watch and monitor for them in all patients. So, get them through that initial time. Figure out if they’re in the half that benefits from initial therapy, and get them on a dose that you can continue long term.

I think a drug like regorafenib, to clinicians, has taken us a while to figure out its value. We want responses and CEAs dropping. And stable disease is okay, but we want more than that. I think our patients want more than that, too. Over time, as my experience has increased with the medicine, there are clearly patients who have long-term benefit. There’s clearly a tail on the curve for some patients who have 6 to 12 months of stabilization, and it’s very hard to predict who that patient is going to be. So, I’ve seen it with big tumor burden and small tumor burden, young and old. What we need is that biomarker to figure out who that’s going to be. But until such time, we really, I think, are obligated to ask, for our patients, “Are you one of these people on the curve where you’re going to have long-term benefit? Find those patients and treat them.

This patient has had oxaliplatin-based therapy and irinotecan-based therapy now, has had regorafenib therapy and progressed on that. Many, many of these patients will still have good performance status, still be eligible for more treatments. It’s, in essence, the same menu we talked about before of, now you’ve got TAS-102 as an approved drug, you’ve got clinical trials—which are out there—and you’ve got recycling of oxaliplatin. And I think you make your decision at this point based on the overall needs of the patient, how the disease is doing, eligibility for clinical trials, and the like. Don’t forget that TAS-102 is out there. Survival advantage is well with that. It’s more of a myelosuppressive kind of drug, but one that can help patients as well.

We do have, in the refractory setting, 2 drugs approved: regorafenib and TAS-102. And because TAS-102 came second, we actually have, in the clinical trial, patients who’d had regorafenib first. And so, if you look at the subgroup analysis of the patients who’d had regorafenib first, there was still benefit from TAS-102 as a fourth-line, if you will, therapy. So, we at least have that experience that one after the other is still a positive for patients.

Transcript edited for clarity.

February 2013

• A 53-year old Caucasian man presented to his gastroenterologist complaining of rectal bleeding and abdominal tenderness
• PMH includes hypertension, well-controlled on a beta-blocker
• Family history; mother died from breast cancer
• He underwent colonoscopy with biopsy
  • Pathology results confirmed poorly-differentiated adenocarcinoma
  • Genetic testing was positive forKRASexon 2 codon 12 mutation
• CT scan of the abdomen, pelvis, and chest showed multiple liver lesions and a large nodule in the right lower pulmonary lobe.
• Diagnosis: Adenocarcinoma of the colon; staging, T4N0M1
• The patient was started on FOLFOX and bevacizumab, therapy is well-tolerated
• The second follow-up scan showed a marked decrease in volume of the primary tumor, two of the liver lesions, and the lung lesion.

March 2014

• The patient complains of intermittent shortness of breath but continues his normal activities
• Imaging shows slow but steady progression in the plural lesion
• Bevacizumab therapy was continued; the patient was also started on FOLFIRI
• Follow-up imaging shows continued regression of the lung lesion; patient continues to tolerate therapy with management of gastrointestinal distress

February 2017

• The patient complains of abdominal fullness, nausea, and constipation
• He continues to work full-time but feels sluggish
• MRI indicated diffuse metastatic disease in the peritoneum, consistent with carcinomatosis
• The patient was started on regorafenib 80 mg, with a plan to gradually increase to 160 mg if tolerated