Recurrent CRC Progression: Options for Therapy

Tanios Bekaii-Saab, MD, FACP:This is a patient who had adjuvant therapy with FOLFOX, but it was many years ago and one could argue that you could go back to FOLFOX at this point of time. Normally with these patients, on the right side, I’d go with FOLFIRI/bevacizumab as a first choice, FOLFOX/bevacizumab as the second choice, and then regorafenib as the third choice, then possibly introduce an EGFR inhibitor or TAS-102 at that point.

And the evidence for that is for the FOLFOX/bevacizumab, the recurrence was years after exposure to FOLFOX, so the patient is probably still platinum-sensitive. And then the bevacizumab comes from the data from the TML study for bevacizumab beyond progression. And the reason why I wouldn’t move an EGFR inhibitor, although the patient isRASwild-type, into the second-line is because right-sided tumors do not do well with EGFR inhibitors, and that seems to be independent of theRASstatus.

Now most of the right-sided tumors areRASmutated and so, it’s kind of a unique situation. So, with this patient, you could have a discussion about considering introducing an EGFR inhibitor alone. The patient didn’t want chemotherapy other than in pill form, as he expresses it. You could consider single-agent panitumumab or single-agent cetuximab as an option. But this is when we had the discussion about the REVERCE study.

Now albeit that the REVERCE study is a phase II randomized study, it was in a Japanese-only patient population, so I’ll take it with a grain of salt for our Western population, because the data doesn’t necessarily correlate 1:1. But that said, it was very intriguing. This study looked at regorafenib followed by cetuximab, or cetuximab followed by regorafenib, and then the patients switch over at progression. And the data suggested that if you move regorafenib to earlier lines of therapy, even on the left side where you expect EGFR inhibitors to have even a more important effect, that the patients have a longer survival and improved progression-free survival with regorafenib.

Cetuximab, whether you place it before or after, maintains its benefit, which essentially at least tells us that it is possible for some patients to consider moving regorafenib ahead of cetuximab. And so, the discussion took place with the patient, and the patient understood the limitations of the study. I think that certainly helps us, also plays those agents sequentially in a way that’s a little bit more creative because of the REVERCE study. Now mind you that, again, the right-sided component gets in and it tells us perhaps cetuximab should be pushed, or EGFR inhibitors should be pushed, to later and later lines of therapy until we run out of options because of the location.

Then the other option could have been TAS-102. TAS-102 is essentially a cytotoxic agent. It belongs to the super family of fluoropyrimidines. It’s not 5-FU or capecitabine, but it is part of that big family. In fact, it works after you fail the other fluoropyrimidines. And it certainly would be an option. Except if we learn anything, historically, from all the studies that have been published and presented with regorafenib and TAS-102, regorafenib from the CONCUR study, which is an Asian study, tends to work better historically if we move it up the line, and that seems to be confirmed with REVERCE.

On the other hand, with TAS-102, it maintains its activity whether you give it earlier or later, that’s from the TERRA study. Again, an Asian-only study, which also suggests to us that TAS-102 may maintain its activity if you place it after regorafenib. The other way around may not be as well represented. So, for all these reasons, the choice of regorafenib before TAS-102 comes about. Now more importantly in this patient, this patient’s wishes were not to be exposed any more to oxaliplatin, or even initiate irinotecan or the infusional 5-FU. So, naturally, it made sense to proceed with regorafenib.

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