mCRC: Therapeutic Approach at Progression

Tanios Bekaii-Saab, MD, FACP:The patient does well on FOLFIRI/bevacizumab. Zip through to February 2017, the patient is starting to feel somewhat lousy and not feeling too good. Scans get repeated. The patient has a couple of new nodules in the lungs and also the rest of the disease seems to be progressing. The question is, what do you do now? The patient has failed FOLFOX/bevacizumab in the first-line setting, FOLFIRI/bevacizumab in the second-line setting. This is a right-sided tumor,RASwild-type,BRAFwild-type, microsatellite-stable patient. So, what do you do now? And this discussion goes on every day in our clinics. We have 3 options for this patient on the right side. We can introduce EGFR inhibitors at this point, or we could go to the other 2 oral agents: regorafenib or TAS-102. There are no data that tell us what to do at this point.

The discussion across every line of therapy should always include the option of no treatment. Every patient should be presented with the option of, “This is what treatment helps with, and these are the limitations of the treatment.” So, in clinic, I have my discussion the first day I meet the patient, even before we start first-line therapy, about the importance of maintaining quality of life and supportive care.

And the overwhelming majority of the patients will go through 3 to 4 lines of therapy. So, we have to think about how to optimize the care for those patients. At this point, the discussion goes about EGFR inhibitors, regorafenib, and TAS-102. Since this tumor isRASwild-type, I tend to offer patients the opportunity to go to EGFR inhibitors in the third-line setting, although, again, one could argue that on the right side, there hasn’t been any benefit but it’s mostly being shown in the first- and second-line, not as much in the third-line.

So, the patient would go through EGFR inhibitors, typically continue the irinotecan—so irinotecan plus panitumumab or cetuximab. And following that, then we have 2 options: regorafenib and TAS-102. They’re oral options, so they’re oral pills. And they’re a little bit different. One is a multikinase inhibitor that targets multiple facets of the tumor. The other one, TAS-102, is essentially a cytotoxic agent. It’s a chemotherapy drug that belongs to the super family of fluoropyrimidine. It’s not 5-FU or capecitabine. It’s different and works when the others fail because of its biochemical composition, but it’s a chemotherapy drug.

When we look at the cumulative knowledge with regorafenib or TAS-102, we don’t have any studies that actually compared the 2 head-to-head, so we don’t have that data. Historically from all the studies we have, they seem to derive very similar benefits in terms of survival and progression-free survival. So, this comes from the CORRECT and RECORD studies. Both of them were studies that had patients pre-exposed to all chemotherapy regimens, all biologics as indicated.

There were 2 other studies that give us somewhat of a hint about perhaps the benefit of each one of the agents in less pre-exposed patients. These were Asian studies—CONCUR and TERRA, CONCUR with regorafenib and TERRA with TAS-102. And interestingly in those studies, historically at least when you compare them to the more pre-exposed patients, regorafenib seems to do much better in less pre-exposed patients. TAS-102 doesn’t seem to care.

Additionally, we have only a subgroup analysis in the RECORD study that suggested that if patients were pre-exposed to regorafenib before TAS-102, they do equally well as those that were not. Meaning in other words, pre-exposure to regorafenib did not seem to compromise the chances of TAS-102 to work.

Now these are hints. Ultimately, unless we compare them head-to-head, one cannot make a scientific conclusion. The toxicities are a little bit different—hand-foot syndrome in one; hematologic toxicities in the other one. GI toxicities are about the same, if we believe the 1 study that was published inClinicalColorectal Cancerthat was mostly a retrospective experience with both agents, and fatigue was about the same in 2, which probably speaks to the stage of the disease more than the drug, although both drugs add some level of fatigue. Regorafenib adds fatigue probably quicker than TAS-102, but TAS-102 does induce that.

So, in my clinic, I tend to, for most patients, proceed with regorafenib first, and then leave TAS-102 to later, although there are some select patients—say their liver function tests are a little bit higher than desired and the patient’s performance status is 2 borderlines 2-plus—I probably consider TAS-102. But for most, proceed with regorafenib first.

For this patient, what we’ve done then is we’ve started with FOLFOX/bevacizumab, proceeded with FOLFIRI/bevacizumab, and maintenance regimens in between. Then she went on irinotecan/cetuximab. And after that, she still had a good performance status, we proceeded with regorafenib for 4 months. And after that, the patient decided to proceed to hospice.

Transcript edited for clarity.

November 2015

• A 62-year-old Caucasian female presents with severe crampy right lower quadrant pain
  • 6-month history of occult bleeding and weight loss of 15 pounds in the last 8 months
• PMHx: tonsillectomy at age 23; hysterectomy at age 55
• FHx: Mother diagnosed with colon cancer at age 71
• Laboratory findings: remarkable for Hb, 7.6 g/dL; CEA 5.5 ng/mL
• Colonoscopy reveals a large mass in the ascending colon, measuring approximately 11 cm
• Biopsy results: Invasive, poorly differentiated adenocarcinoma
• Additional pathologic testing
  • KRAS,NRAS, andBRAFwild-type
  • Microsatellite stable
• CT scan revealed widespread lesions in the left lobe of the liver
• Performance status: 0
• Treatment was initiated with FOLFOX + bevacizumab
  • The patient experienced mild neuropathy, significant mucositis, grade 4 neutropenia, and severe diarrhea with the first cycle (suspected DPD deficiency)
  • She subsequently tolerated therapy well with 50% dose reduction of her regimen in addition to dropping the bolus 5-FU and leucovorin.
• Follow-up imaging showed reduction in the size of the liver lesions
• Patient is planned to start maintenance therapy with low-dose capecitabine plus bevacizumab after 8 cycles of FOLFOX

August 2016

• Follow-up CT showed progression in the liver with new lesions
• Performance status: 1
• She began therapy with mFOLFIRI + bevacizumab
• CEA levels stabilized

February 2017

• The patient complained of severe fatigue and additional weight loss. Her performance status remains at 1.
• CT scan revealed progressive disease with 2 new pulmonary nodules in the left lower lobe of the lung and mild progression in the liver.