Treatment for RAS-mutated mCRC

Tanios Bekaii-Saab, MD, FACP:Obviously, this is a patient who isRASwild-type and the discussion about EGFR inhibitors fits as part of the decision tree. To summarize, this is a right-sided tumor and I would continue with bevacizumab from first- to second-line therapy. So, that would be the concept of bevacizumab beyond progression.

On the left side, I would still start with a VEGF inhibitor as a personal preference, although I think that there’s justification to use EGFR inhibitors in the first-line as well, but that’s a personal preference, and that’s also supported by the NCCN guidelines and the studies as well. But I would not wait to introduce the EGFR inhibitors to the third-line. I would actually bring them to the second-line on the left side. If this tumor wasRAS-mutated, that’s a completely different discussion. It’s bevacizumab first-line and bevacizumab second-line whether you’re on the right or the left since EGFR inhibitors are not part of the equation.

The more important discussion in that group of patients, and it also applies to the patients who areRASwild-type, is, what about the other VEGF inhibitors: ziv-aflibercept and ramucirumab? If you look at these today, at the cumulative knowledge, when we look at ziv-aflibercept and ramucirumab, historically, and bevacizumab in the second-line following bevacizumab exposure, they all seem to have the same benefit, although the cost and the toxicities may be a little bit different with the other 2.

So, there’s really no good reason to switch VEGF inhibitors from first- to second-line, and in fact, in the NCCN guidelines, despite that, bevacizumab remains as the preferred VEGF inhibitor beyond progression versus ziv-aflibercept and ramucirumab. In our practices, as of today in colorectal cancer, we do not use ziv-aflibercept or ramucirumab in the second-line setting. It would be bevacizumab. First-line bevacizumab and second-line therapy.

The same principles of maintenance therapy apply in the second-line setting. So, a patient who has a good response after 3 to 4 months and has stabilized their CEA and has stabilized their tumors on scans, we would switch to maintenance therapy. The same exact principle applies across multiple lines of therapy—induction for 3 to 4 months, then maintenance following that as long as the patient is doing well. And I think you have to always think about the concept of maintenance and occasionally chemotherapy holidays for the select patients as we treat those patients now for years.

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.