The Challenges in Determining Second-Line Therapy for mCRC

Tanios Bekaii-Saab, MD, FACP:Unfortunately, with the right-sided tumors, we know that these tumors have a very poor prognosis regardless of their genetic profile. And so they tend to progress early. Most patients will start with a doublet, usually Folfiri or Folfox plus bevacizumab. And then when they fail, their second-line would be the other regimen. So, if they started with Folfiri, they go to Folfox. If they started with Folfox, they go to Folfiri and we continue the bevacizumab. In this patient we chose to go with Folfoxiri plus bevacizumab because of the high tumor burden and symptom burden. And so we needed a higher response rate, and we went with Folfoxiri/bevacizumab. So, technically, when you fail Folfoxiri/bevacizumab, then your next option would be either regorafenib, or TAS-102 [trifluridine/tipiracil], or an EGFR inhibitor. If you went with say Folfiri/bevacizumab in the first-line, your second-line would be Folfox/bevacizumab. Then your third-line, you assess the same options.

Now, how do you choose between all these—regorafenib, TAS-102, and EGFR inhibitors. Now, again, we’re focusing on the right-sided tumors. If this was a left-sided tumor, and I started with bevacizumab in the first-line, then my second-line is going to be an EGFR inhibitor. If I started with an EGFR inhibitor, my second-line would be bevacizumab. On the right-sided tumor, as we discussed, those EGFR inhibitors have to fall down the line of therapies.

And so the question, do you introduce it in the second, third, fourth-line? Where exactly is the right point? Remembering that this was a RAS wild-type, BRAF wild-type tumor. Most of these areRASmutated or many of them areRASmutated, and therefore this would not even be a discussion. But, specifically in the RAS wild-type, BRAF wild-type right-sided tumors, where do we introduce these EGFR inhibitors, whether it’s cetuximab or panitumumab? The answer is frankly not clear because most of our knowledge is really in the first-line, to a lesser degree in the second-line.

There are some hints that in the refractory settings, there may still be some benefit from EGFR inhibitors. There’s an interesting study that was presented and now about to be published called REVERCE study which essentially looked at a sequencing question. Start with regorafenib followed by cetuximab, start with cetuximab followed by regorafenib—so REGO/CETUX or the reverse, CETUX/REGO. The primary endpoint of the study was survival. This was a Japanese study, so in some ways it may not apply to what we do in the United States or may not apply to our patient population but, nonetheless, gave us very intriguing finding. And that finding was that if you actually start with regorafenib followed by cetuximab, the survival benefit is a few months higher than if you start with cetuximab followed by regorafenib, regardless, by the way, of side, whether you are right or left.

So, on the right side where there is a big question mark about the role of EGFR inhibitors, I take this study a little bit more seriously. Although, again, I think it needs to be reproduced at a larger level in the US, and it’s in the works. So we will have more answers hopefully in the next couple of years on this. But, at this point of time, I just look at this, I look at the data say from CONCUR that suggest that regorafenib may actually have a little bit more of a benefit in patients who are less pre-exposed to biologics, i.e., VEGF and EGFR inhibitors.

And you put all this knowledge into works and from my standpoint, it would make sense to start with the regorafenib and push cetuximab, panitumumab to later lines, in fact I would say even after TAS-102. So my sequence in my colonic would be regorafenib followed by TAS-102. And then EGFR inhibitors would still be used, but I’d use them in much later lines of therapy, just because, again, on the right side, there are big question marks about the value of these inhibitors.

Once patients go through multiple lines of therapy to one or 2 lines of extensive therapy, so in this patient, Folfoxiri/bevacizumab or sequentially Folfiri, Folfox, bevacizumab, those patients, as they get to the third, fourth-line, so the more refractory setting, they’re pretty fatigued. They’re tired of their chemotherapy. Their cancer burden continues to grow on them and makes it much more difficult for them to tolerate further chemotherapy. So they start off with a very difficult journey, perhaps much more difficult than they’ve had it in the first and second-line which makes treatment challenging. If we look across the board, whether it’s regorafenib, TAS-102, whether it’s Folfiri, Folfox in second-line and beyond, for most of these patients the benefit at the median is small.

Although for the patients who benefit, they tend to benefit for a meaningful amount of time. But, for most patients, the benefit is actually small, and that’s because they start coming from behind because of essentially what they had to deal with from the prior chemotherapy. But mostly, because as we get through multiple lines of therapy, the cancer burden and I call the level of aggression become much more noticeable, and those patients have a harder time overall to withstand any type of treatment.

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