Options for Second-Line Therapy in mCRC

Tanios Bekaii-Saab, MD, FACP:August 2016, the patient comes to the clinic feeling a little bit more tired. The scan at the time shows evidence of progressive disease. So, now the patient has progressed on capecitabine and bevacizumab. There was a discussion with the physician: Do we reintroduce oxaliplatin or do we shift to the other regimen, FOLFIRI? Is this now the time to bring the EGFR inhibitors or can we continue with bevacizumab? And so, the decision at the time was to proceed with switching the chemotherapy backbone from FOLFOX—which she was exposed to primarily—to FOLFIRI and continue the bevacizumab.

The discussion when the patient comes in with progressive disease after a prolonged period of exposure to maintenance therapy is whether we introduce the oxaliplatin, in which we know there are data from OPTIMOX. We know that we may get about 20% likelihood of response. At the same time, these responses tend to be short-lived, and whether that makes more sense versus switching gears to FOLFIRI, you can go both ways. Some folks would argue about placing the oxaliplatin first and then switch to FOLFIRI. I tend to think that at this point of time—since they’re equivalent and the patient in some ways progressed on one, we can always reintroduce it much later down the line when needed—to make the complete switch to combination FOLFIRI.

The other point is whether this would be the right time to introduce EGFR inhibitors. And the answer is since this was a right-sided tumor—although most of the data that we have are with EGFR inhibitors not having any benefit in the first-line setting—we don’t know much about the second-line setting, and we have hints that it probably also applies to the second-line setting. I try to avoid EGFR inhibitors even in thisRASwild-type tumor in the second-line because of the right-sided element, and leave the consideration for EGFR inhibitors, like cetuximab and panitumumab, to third-line therapy.

There’s a study that looked at cetuximab versus best supportive care that eventually was reanalyzed introducing the left versus right concept. Interestingly, that study suggested no PFS benefit on the right. But there was a slight overall survival benefit on the right. So, I think that EGFR inhibitors may still have a place on the right side, but I do believe that it’s not the first- or the second-line therapy, it’s likely going to be the third-line therapy and beyond until we have more data.

If this patient had the left-sided tumor, then the question is, if we started with a VEGF inhibitor, do we now introduce the EGFR inhibitors in the second-line versus continuing with the bevacizumab beyond progression, although we know there are data that suggest that bevacizumab beyond progression improves outcomes?

I think because of the data we have on left-sided tumors and the really good benefit with EGFR inhibitors, my tendency is to introduce those EGFR inhibitors in the second-line rather than continue with bevacizumab, rather than wait until the third-line—again, because of the benefit on the left side. So, I tend to do chemotherapy plus bevacizumab in the first-line on the left side followed by chemotherapy plus the EGFR inhibitor, so panitumumab or cetuximab. We tend to use more of the panitumumab than cetuximab for historical reasons, but either would be a fit there.

Transcript edited for clarity.

November 2015

• A 62-year-old Caucasian female presents with severe crampy right lower quadrant pain
  • 6-month history of occult bleeding and weight loss of 15 pounds in the last 8 months
• PMHx: tonsillectomy at age 23; hysterectomy at age 55
• FHx: Mother diagnosed with colon cancer at age 71
• Laboratory findings: remarkable for Hb, 7.6 g/dL; CEA 5.5 ng/mL
• Colonoscopy reveals a large mass in the ascending colon, measuring approximately 11 cm
• Biopsy results: Invasive, poorly differentiated adenocarcinoma
• Additional pathologic testing
  • KRAS,NRAS, andBRAFwild-type
  • Microsatellite stable
• CT scan revealed widespread lesions in the left lobe of the liver
• Performance status: 0
• Treatment was initiated with FOLFOX + bevacizumab
  • The patient experienced mild neuropathy, significant mucositis, grade 4 neutropenia, and severe diarrhea with the first cycle (suspected DPD deficiency)
  • She subsequently tolerated therapy well with 50% dose reduction of her regimen in addition to dropping the bolus 5-FU and leucovorin.
• Follow-up imaging showed reduction in the size of the liver lesions
• Patient is planned to start maintenance therapy with low-dose capecitabine plus bevacizumab after 8 cycles of FOLFOX

August 2016

• Follow-up CT showed progression in the liver with new lesions
• Performance status: 1
• She began therapy with mFOLFIRI + bevacizumab
• CEA levels stabilized

February 2017

• The patient complained of severe fatigue and additional weight loss. Her performance status remains at 1.
• CT scan revealed progressive disease with 2 new pulmonary nodules in the left lower lobe of the lung and mild progression in the liver.