Impact of Clinical Data on Sequencing in Recurrent CRC

Tanios Bekaii-Saab, MD, FACP:So, overall, what did we learn about all this data that have been presented and published over the past couple of years, because that informs us a lot about how to treat a patient such as Mr. Smith? If the tumor is on the right side, which is the case here, what we’ve learned is that EGFR inhibitors may not have a role, or if they do, it’s usually a role that we keep to the end of the line, especially if they’reRASwild-type. If they’re not, if they’reRASmutated, then it’s a no-brainer, there’s no role for EGFR inhibitors, period. But for those withRASwild-type right-sided tumors, EGFR inhibitors have fallen out of favor because those patients just don’t do well. In fact, the way I look at the data is that there may even be a detriment for those patients on the right side, especially if you use the EGFR inhibitors in earlier lines of therapy. So, we have to be very careful, and that teaches us about that.

Then the next question is, of course, how do we treat those patients? It’s usually chemotherapy plus bevacizumab in the first-line—FOLFIRI or FOLFOX. My preference is FOLFIRI, but FOLFOX is equally acceptable. And then the second-line usually, whatever they didn’t have in the first-line therapy is the second-line therapy. So, if they start with FOLFIRI, it’s FOLFOX. If they started with FOLFOX, it’s FOLFIRI, and they continue with the bevacizumab as long as the patients are willing to continue with chemotherapy. This particular patient decided he doesn’t want to deal with chemotherapy anymore, that’s why we jumped to one of the oral agents.

So, if we go with chemotherapy/bevacizumab, then the third-line on the right side is typically the regorafenib or TAS-102. Now, one may argue you still consider EGFR inhibitors in theRASwild-type here, but my bias, seeing the REVERCE and essentially looking at the data with EGFR inhibitors on the right side, probably avoid at that point EGFR inhibitors until we drop 1 line of therapy. So, regorafenib comes first in my clinic, and then, for the reasons I discussed, TAS-102, and then ultimately an EGFR inhibitor. Although the discussion will continue with the patient all the way through about the pluses and minuses of each one of those approaches.

And if we choose regorafenib, typically now since we presented the data at ASCOGI, I typically now use a dose-escalation strategy from 80 mg to 120 mg to 160 mg with a dose escalation on a weekly basis until the patients reach their essentially tolerated dose that they can continue with. Then if the tumor is on the left side, which is not this particular patient, things get a little bit more tricky. The options are a little bit more and the discussion is a little bit more in-depth. Because this is where EGFR inhibitors have been shown to perhaps have a slight edge in the first-line setting versus bevacizumab. And I say perhaps because I’m still not certain that that’s the case. But what I believe is that both are at least equally good. There may be a little bit edge for the EGFR inhibitors.

But our knowledge for this comes from 2 negative studies. And I don’t know how much inference you can make from negative studies. CALGB 0405 was negative. FIRE3 was negative. We’re making a lot of inferences into clinical practice from 2 negative trials. But nonetheless, they do inform us that at least on the left side, the strategy is very valid to use a VEGF inhibitor, bevacizumab, or an EGFR inhibitor, cetuximab or, arguably, panitumumab.

Now, second-line therapy, what do we do if the patient was exposed to a VEGF inhibitor? We usually move the EGFR inhibitor to the second line. So, that has been my practice. I do FOLFIRI/bevacizumab in the first line. You can do FOLFOX/bevacizumab. Your second-line therapy is typically irinotecan or FOLFIRI plus the EGFR inhibitor of choice, either panitumumab or cetuximab.

And then you get to the third-line setting and then your options are either regorafenib or TAS-102. And for the reasons I discussed—and the understanding of the data and the role of regorafenib perhaps being a little bit more active when you move it up the line—my preference would be to start with the regorafenib with a dose escalation strategy and then followed by TAS-102.

And of course, there’s a lot of nuances. Whether there is a microsatellite-unstable phenotype then, of course, PD-1 inhibitors would enter the field—pembrolizumab or nivolumab—and I try to move them up the line of therapy, typically in first-line for most patients. For some, certainly wait until the second- or third-line setting. Then there’s also the HER2-amplified tumors. These tend not to respond well to EGFR inhibitors. They tend to be on the left side. They tend to beRASwild-type, but they don’t respond as well to EGFR inhibitors. We have a study but I would try to first to get HER2-targeted therapy. And there are then nuances across the board of targets. But overall, the 30,000 view of how we treat colon cancer has shifted to that level.

Transcript edited for clarity.

January 2017

A 62-year-old African-American man presented with recurrent CRC

• Diagnosed at age 55 with stage 3 CRC, treated with surgery and adjuvant FOLFOX
• He underwent colonoscopy with biopsy
  • 6-cm ulcerated non-obstructive mass noted in the right colon
  • Pathology confirmed poorly-differentiated adenocarcinoma
  • Staging; T3N1M0
• History
  • Former smoker, 1 pack a day; quit 20 years ago
  • Obese, BMI = 30.2 kg/m²
  • Mother had inflammatory bowel disease, died at age 70
  • Other medications: metoprolol for hypertension, omeprazole, regular NSAID use
• PET/CT scan showed recurrent disease with multiple metastases in liver
  • CEA, 28.4 ng/mL
  • Biopsy of liver lesions suggests poorly-differentiated with colon primary
  • Mutation analysis;KRASandNRAS,WT;BRAF-wild-type; microsatellite-stable
• He was started on FOLFIRI with bevacizumab and achieved partial response

January 2018

• The patient reports feeling short of breath.
• PET/CT showed progressive disease in the liver and multiple metastases in both lung fields
• Therapy options were discussed with the patient; he preferred an oral therapy
• He was started on regorafenib, 80 mg once daily
  • He experienced grade 2 dermatologic toxicity on his hands and feet (palmar-plantar erythrodysesthesia syndrome [PPES]), which was managed with dose escalation from 80 mg to 120 mg to 160 mg. With recovery, he resumed regorafenib at 120 mg/day
  • At present,he remains on regorafenib 120 mg/day with evidence of stable disease at 6-month follow-up