mCRC: Rationale for EGFR Therapy

Wells Messersmith, MD:The rationale for EGFR therapy after bevacizumab is the fact that it has shown survival benefit. Now, we have to go back and remember the particular aspects of this case. First of all, this patient was left-sided. That’s critical because, as it turns out, in the right-sided tumors, there is no benefit so far, from what we can tell, from anEGFR-targeting monoclonal antibody. Well, you could argue, “Well, wait a minute. That was from the 80405 trial; that’s a first-line trial.” We don’t have all the data from the second- and third-line trials, and that’s true, but the data that are coming out suggest that no matter what line of therapy—here we’re in the third-line setting—right-sided patients don’t benefit from anEGFR-targeting monoclonal antibody. So, if this patient had a right-sided tumor, I would not be advocating for that.

Secondly, this patient isRASwild-type,KRASwild-type, andNRASwild-type, and this was done through NGS, so we know that we’ve checked not just codons 12 and 13, but we’ve checked other ones, such as 61, 45, etc. So, because they’reRASwild-type, that’s the subpopulation of patients who can benefit. Now, you have to be really careful because you have to remember, most of the trials where these kinds of combinations are used didn’t haveRAStesting and they didn’t have sidedness. So, a lot of the patients in the trials shouldn’t have been on the arm that they got. You had right-sided patients who wereRAS-mutated who got cetuximab in some of those studies where these drugs were first being given. So, it gets a little tricky. If you go back to the literature and start looking up studies, you have to be very careful about extrapolating data from theRAS-ignorant, sidedness-ignorant older studies to what we know now, which is you really want to give those drugs to left-sided andRASwild-type patients. I think there will be more and more data coming out with more contemporary patient data sets.

But surprisingly, despite the fact that all these patients were misassigned really, all these right-sided andRAS-mutated patients were getting this stuff. Now, they still showed survival benefit, so again, there’s level 1 evidence and there are FDA-approved package inserts to say this is the setting where an EGFR inhibitor should be used. By the way, we could have used it in the first-line setting. In fact, the FIRE-3 trial out of Germany suggested that maybe there’s some benefit to using it first.

Biologically what’s going on when you take bevacizumab first and then take cetuximab later versus vice versa, that is not very well understood. There have been some laboratory-based papers suggesting maybe there’s some benefit, but depending on how you order those things. But that’s all very theoretical at this point. I just stick to what the clinical trial showed, which said there is survival benefit in the first-line, second-line, and third-line setting, so it’s a very reasonable option.

For this patient, in terms of what treatment to choose, there are many different options here. In a 71-year-old who has gotten over a year of chemotherapy, I’m not sure I would continue the irinotecan. But again, if the patient looks good, good performance status, tolerated it well, you definitely could use it. But often times, in this third-line setting, I’m starting to see patients get beat up. I’m starting to see them get sick of coming to the infusion center, feeling nauseous, or whatever their side effects are. So, I often would turn to a singlet in this case.

You could use panitumumab or cetuximab alone, and you could also start to think about switching over to the 2-pill drugs we have in colorectal cancer. I guess there’s 3 if you consider capecitabine, that’s oral 5-FU, but we have TAS-102 and we also have regorafenib. And both of those would be reasonable choices. Both of them are labeled for the third-line setting and above. And so, as I said, with the first- and second-line, you have options. There are many different things you can do, depending on how your patient is doing. Sometimes insurance coverage makes a difference because these pills come out of a prescription plan, and 20% of a lot of money is still a lot of money. And often patients are having financial issues as it is. There are some studies actually looking at what we call “financial toxicity.” So, there’s a whole host of things that would go into that decision. But I must say, in the third-line setting in a 71-year-old patient, am I using a cytotoxic-like irinotecan? Not as much.

Transcript edited for clarity.

September 2015

• A 71-year-old Caucasian male presented with severe left lower quadrant pain
  • He sought medical treatment after experiencing bloody diarrhea
• PMH: hypertension, managed with benazepril
• He is active and can perform daily activities without restrictions
• Laboratory findings: remarkable for CEA, 6.0 ng/mL
• Colonoscopy showed a mass in the descending colon which was biopsied
  • Pathological findings: Moderately differentiated adenocarcinoma
• NGS mutation testing results wereNRAS, KRAS, HRAS, HER2,andBRAFwild-type
  • Microsatellite stable
• CT of the chest, abdominal, and pelvis showed an 8-cm mass in the sigmoid colon
  • a 2-cm mass in the right lobe of the liver, and a 5-cm in the left lobe adjacent to the left hepatic vein
  • Impression: metastatic disease, borderline resectable
• Treatment was initiated with FOLFIRI + bevacizumab
• Imaging at 3 and 6 months showed decreased size of the liver nodules, but was not resectable

July 2016

• The patient complained of increased fatigue, requiring the need for frequent rest
• CT scan showed increasing size of the liver nodule (3 cm) and appearance of 3 new small liver lesions (<2 cm)
• He began therapy with FOLFOX + bevacizumab

February 2017

• The patient reported weight loss, increasing fatigue, and shortness of breath
• CT scan revealed progressive disease with no improvement in the primary and metastatic lesion size and/or number
• A new pulmonary nodule was seen in the right lung
• He was switched to irinotecan + cetuximab
• PET/CT at 3 months showed stable disease
• At 6 months, he reported moderate improvement in fatigue