Choices for Upfront Therapy for mCRC

Tanios Bekaii-Saab, MD, FACP:The choice of therapy, assuming this patient wasBRAFwild-type—they didn’t have a mutation in BRAF—I think it’s very appropriate to start the patient on FOLFOX/bevacizumab. An alternative to that would be FOLFIRI/bevacizumab. They’re equivalent. There are some hints that FOLFIRI may be a little bit better, but overall, I think it’s a wash. Whether it’s FOLFOX or FOLFIRI, that’s a chemotherapy backbone that’s acceptable in this patient, especially with aBRAFwild-type tumor.

Now comes the whole issue of sidedness and the decision of how to use biologics. So, we have right-sided tumors and left-sided tumors. We understand that they behave very differently. They’re driven by different genetics. They do have different genetic profiles. And those on the right side generally seem to be nonresponsive to EGFR inhibitors. Those on the left side may have a little bit better outcome with EGFR inhibitors versus VEGF inhibitors.

In this patient, who has a right-sided tumor, it would make a lot of sense to start them on bevacizumab as the biologic plus the chemotherapy backbone. If this patient had a left-sided tumor, I personally would still have started the patient on bevacizumab. However, I would have an earlier onset of use for EGFR inhibitors, meaning second-line rather than the later lines of therapy for the patient with left-sided tumor. So, in all instances on the right side where EGFR inhibitors seems to actually have less activity, it would make tremendous sense to start the patient on a VEGF inhibitor, ie, bevacizumab, with chemotherapy. I think the starting point, again assuming that this was aBRAFwild-type tumor, makes a lot of sense for this patient.

I think the other important question is—and this is a question that arises a lot, of course—we understand that when cancer spreads to the liver only from the colon, it behaves a little bit differently, typically associated with better outcomes overall. But also, we address these recurrences a little bit differently than someone with widely metastatic disease. Why is this important? Because we know that for some patients who have liver limited disease, we can cure them if we are able to get them to surgical resection. Unfortunately, if you take the whole community at-large, there’s only 5% of those patients who will recur just in the liver and with few lesions located in just a few lobes—1 lobe or maybe 2 lobes with isolated lesions. Those patients can go to surgery. They need to be referred to a multidisciplinary program. The surgeon, the medical oncologist, the radiation oncologist, and the intervention radiologist, they all have to come together and decide if this gets optimized. For the majority of the patients with liver-only disease, surgery ends up being not an option. But everyone should be considered for surgery. Everyone with liver-limited disease has to be considered for surgery by a liver-specific surgeon. Like I said, most of them will not go to surgery, but they have to be considered because we know we can cure those patients.

So, other than surgery, there are other liver-directed approaches that we can consider as part of our treatment options. And that essentially includes liver-directed therapies such as SIR-spheres, which certainly have some applications. The question is, when do we consider the application of SIR-spheres in the treatment of metastatic colorectal cancer limited to the liver? There was a large study that looked at the role of adding SIR-spheres earlier on in those patients—similar to this case. It didn’t meet its primary endpoint. In other words, progression-free survival was not much different between the patients who get the SIR-spheres added and those who are not. The only difference was that the disease in the liver got delayed in terms of progression, but we have no clue right now whether this will affect survival or not, which is the ultimate measure. This will be coming. We will understand a little bit more about survival soon. At this point in time, I don’t think I can recommend SIR-spheres in the earlier stages. We leave those typically to second- or third-line if the disease is still limited in the liver, and if we start running out of options.

So, MSI testing, as I alluded to, is now mandatory for all patients with colon cancer, regardless of the stage. In this particular patient, I think it’s a must from the first day you meet the patient. It’s even more of a must when you see the patient with metastatic disease. It’s very important because it tells us about 2 things: 1) it may link us to a family history, and that’s important for the patient and their families, but 2) we know that tumors that have high MSI are exquisitely sensitive to the effects of immune therapies. In other words, when those patients have MSI-high tumors, they tend to have a lot of mutations. They are what we call “hypermutated.” So, they have these antigens that are overexpressed and they make them very inflammatory and very susceptible to the effects of immune therapy.

For those patients, immune therapy becomes very important. Now the question, of course, is if I have this patient coming to me from day 1 with MSI-high tumors, would I consider pembrolizumab or nivolumab in the first-line setting rather than chemotherapy? That question is being answered right now by a clinical trial, a national-international trial, that’s looking at the role of immune therapy first versus chemotherapy. But at some point, that patient will definitely need immune therapy as part of the treatment. In fact, the NCCN guidelines just changed in the refractory setting. The guidelines added that those patients would receive pembrolizumab or nivolumab based on the presence of MSI-high expression.

Now in my own practice, I actually try to individualize. And for many patients, outside of a clinical trial, I would consider bringing immune therapy to the first-line setting. MSI-high status in stage 4 colon cancer is an indicator of that prognosis. So, those patients can actually do very bad very quickly and may never the opportunity to go on immune therapy. I tend to favor bringing immune therapy a little bit closer to either first-line or second-line in those patients. We’ve seen some remarkable responses in our patients. And some patients, who blew through chemotherapy, had just remarkable responses. Not that the depth of response is remarkable on its own, but also the durability of the response is pretty remarkable as well. So, those patients respond and will continue to respond. Unfortunately, there is still a subset of patients who don’t seem to respond at all to immune therapy treatment despite being MSI-high, and we’re figuring out strategies to essentially expand that advantage to most patients.

Transcript edited for clarity.

November 2012

• A 51-year-old man was referred to gastroenterology for screening colonoscopy.
• Family history includes pancreatic cancer on his father’s side and pre-menopausal breast cancer in his aunt.
• Colonoscopy revealed a 3-cm mass, proximal to the hepatic flexure.
• Biopsy confirmed the lesion to be of adenocarcinoma histology.
• At the time, the patient underwent right hemicolectomy revealing a moderately differentiated tumor. Fifteen lymph nodes were removed and tested negative for metastatic disease, denoting stage T3N0M0 colon cancer.
• The patient healed without complications and received no further treatment.

April 2015

• The patient continued to feel well, except for occasional fatigue and diarrhea.
• Routine evaluation showed elevated carcinoembryonic antigen.
• PET/CT scan revealed several small lesions in multiple lobes of the liver that were PET avid
• Biopsy was performed and confirmed the liver lesions to be metastases from colon cancer
• The patient was referred to a local oncologist and started on infusional 5-FU and oxaliplatin (FOLFOX) in combination with bevacizumab.
• CT scan 2 months after starting treatment showed a partial response to therapy; at 4 months the patients tumor continued to shrink
• Oxaliplatin was discontinued; subsequently the patient received maintenance therapy with capecitabine and bevacizumab, resulting in continued disease control

February 27, 2017

• The patient has had stable disease for 22 months and remains on bevacizumab maintenance therapy.
• He appears generally well and free of symptoms.