Optimal Treatment of Chemoresistant mCRC - Episode 3

Determining First-Line Therapy for mCRC

March 13, 2019

Tanios Bekaii-Saab, MD, FACP:There are multiple factors that go into the equation when thinking about our patients with metastatic colorectal cancer, specifically for first-line but also beyond first-line. One is, is the tumor left-sided or right-sided, age of the patient, comorbidities, genomic factors,RASmutation,BRAF, HER2 amplification, microsatellite stability [MSI]. And there are other factors: patient preference and physician preference. Overall, we know that left-sided tumors, and RAS wild-type, BRAF wild-type,HER2, and nonamplified may actually do a little bit better with an EGFR inhibitor versus bevacizumab versus an anti-VEGF inhibitor.

On the right side, it does appear that regardless of the mutational status, but specifically the RAS wild-type, BRAF wild-type, tumors do not seem to respond well—at least from the CALGB 80405 abstract—well to EGFR inhibitors. So we know that in this particular group of patients like this gentleman, despite the fact that they had a RAS wild-type, BRAF wild-type tumor, his likelihood of responding to the EGFR inhibitors is not only low, probably inexistent, but at least from the CALGB 80405 abstract, there were signs that we actually may induce some detriment. Now, again, this was not a randomized question, so we have to be careful about how to look at this. But the survival was actually the lowest we’ve seen in colorectal cancer for the last decade.

So a word of caution about this. The other things we look at, of course, especially on the left side of the tumor, is this patient RAS wild-type, BRAF wild-type, and HER2 nonamplified. I think these are important. RAS wild-type, BRAF wild-type tend to respond well to EGFR inhibitors. If HER2 is amplified, then there’s much more likelihood of responding to EGFR inhibitors. That’s why I think it’s very important to check thatHER2along with a panel, butHER2also opens up other doors for us. We’ll discuss those later.

The other important element is microsatellite instability. The presence of microsatellite instability at high levels would predict favorable outcomes with immune therapies, and so that also completes the picture. Of course, age and comorbidities, so let’s say someone has a recent history of a myocardial infarction, or has angina, or had a stroke 3 months prior or 6 months prior, then you would avoid a VEGF inhibitor. You may favor, in the right patient, an EGFR inhibitor. There’s, of course, patient preferences. Some patients would rather not have the rash. Actually, most patients don’t like the rash. It’s an offender to the quality of life of patients. It increases the risk of diarrhea.

Now, the other thing that was important in these patients to think about is this patient was getting very symptomatic very quickly, was losing weight, was having a lot of pain, and you needed a response. Now, on the left side, let’s say this was a left-sided tumor, RAS, BRAF wild-type, HER2 nonamplified, one could certainly consider an EGFR inhibitor plus chemotherapy. There may be a little bit of an improvement in response. My personal choice would still be Folfoxiri plus bevacizumab for many reasons in these patients. 1) very high response rate, probably higher than what you get with chemotherapy doublet plus EGFR inhibitors, 2) You would get your best response in the first 2 to 3 months of therapy and you can deescalate maintenance or to Folfiri/bevacizumab such as happened in this patient.

Now, on the right side, you don’t have a choice. EGFR inhibitors are not an option on the right side, regardless of the genomic profile. The right-sided tumors don’t respond to them, and so naturally you would be either a doublet or a triplet plus bevacizumab. In a younger patient that’s very symptomatic, I think a triplet makes sense. Those patients have a worse prognosis overall. Thus, the choice in this patient to proceed with Folfoxiri plus bevacizumab. As I said, within 3 months, you should reach your maximum response, and that’s why this patient was exposed to 3 months of the regimen.

Transcript edited for clarity.

Case: A 60-Year-Old Male With mCRC

Initial presentation

April 2015

  • A 60-year—old man was referred to gastroenterology after complaining of general malaise and alternating constipation with bloody diarrhea.
  • PE: Showed left-sided lower abdominal pain
  • Carcinoembryonic antigen (CEA); 8.1 mg/L
  • Colonoscopy revealed a left-sided adenocarcinoma of the colon
  • Surgery: left hemicolectomy
  • Pathology: well-differentiated adenocarcinoma
  • PET/CT: 15/15 lymph nodes tested negative
  • Staging: IIIA
  • ECOG PS 0
  • Patient received adjuvant mFOLFOX4

April 2018

  • 24 months later, the patient complained of mild abdominal distension and his stools were pencil-shaped with some presence of blood
  • PET/CT scan showed widespread small liver lesions
  • CEA; 14.7 mg/L
  • Biopsy was CK2-positive
  • Molecular testing; allRAS&BRAFWT
  • ECOG PS 1
  • Patient began treatment with FOLFIRI + bevacizumab

February 2019

  • PET/CT scan showed evidence of new liver lesions and a 2-cm mass in the right lung
  • CEA; 31.7 mg/L
  • Patient started on regorafenib 80 mg/day