Treatment for Chemoresistant mCRC

Tanios Bekaii-Saab, MD, FACP:When we look at the mutational landscape of colon cancer, there are certain things that are important for us. RAS is one that decides or helps us understand the role of EGFR inhibitors versus not, same for sidedness.BRAFV600Emutations are very important because when they’re present, they drive an incredibly bad prognosis. Those tend to be different tumors. In fact, in our clinic, those are the patients we’re treating first-line with Folfoxiri/bevacizumab. But, in second-line, there are rising standards. One is actually on the NCCN [The National Comprehensive Cancer Network] guidelines with irinotecan plus vemurafenib plus cetuximab.

But there is another one that I think is most promising and that’s with encorafenib, binimetinib, and cetuximab, essentially a RAF inhibitor, a MEK inhibitor, and an EGFR inhibitor. But at least in the phase IB study with 30 plus patients, suggested a response rate to close to 50% in patients who are refractory, including those with colorectal cancer. But I think 10% complete responders which in this disease in the refractory setting is amazing by itself. So that’s an emerging standard. The BEACON trial which essentially randomized patients to the triplet versus a doublet versus Folfiri plus cetuximab has completed and should report out hopefully by the end of the year. And we may actually see a new standard for our patients withBRAFV600Emutations. Very important to make sure that these are 600Es because the non-V600E behave completely different. They actually have a very good prognosis, and they respond really well to chemotherapy unlike the V600E.

The other target of interest isHER2. Now, 2 reasons for that.HER2, when amplified, suggests that EGFR inhibitors may not have much of a role. But also we have trials ongoing, one from SWOG study, one from the ACCRU [Academic and Community Cancer Research United] Research Network. The ACCRU Network has a study with tucatinib and trastuzumab. Tucatinib is an oral tyrosine kinase inhibitor [TKI] targeting HER2, very potent, with very low HER2 activity. And the study is about to complete its first stage and hopefully reported on. And then the SWOG study includes trastuzumab and pertuzumab versus standard chemotherapy. It’s also ongoing.

There are also other studies that are looking at the HER2 question, but it all relates back to a study that was done in Europe called HERACLES trial that looked at lapatinib and trastuzumab in the setting of HER2-amplified tumors with a significant amount of responses seen, including some complete responders and very durable responses. Then we’ve talked about NTRK fusions and MSI [microsatellite instable]-high, and hopefully still looking for reintroducing these immune therapy strategies in different shapes or forms into the microsatellite stables.

So there’s a lot of activity in colon cancer. MSI,HER2,BRAF, NTRK,RAS, and then a slew of other lower yield alterations that are being looked at in smaller studies from the FGFR to those who are non-V600E BRAFs, et cetera. So it’s actually becoming a disease that is more than one disease that’s closing down that puzzle. We always thought of colon cancer as one or 2 diseases. Now we think it’s 4 to 6, probably 10 or 15 or more diseases, and hopefully we’ll have a target for each one of these subsets.

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