Choosing Second-Line Therapy for Progression of mCRC

Wells Messersmith, MD:Now we’re in the second-line setting. So, basically, in the first-line setting, we’ve chosen FOLFOX and bevacizumab. They work for about a year, which is about average. You’ll see what are called progression-free survival rates, or times from 10 months, 11 months, 12 months—so, very typical to get roughly a year out of that first-line regimen. But now the patient’s gotten worse, and we need to think about second-line options.

For someone who’s on a FOLFOX-based regimen, we very commonly switch to FOLFIRI or irinotecan. On someone who was on FOLFIRI or irinotecan, we very often switch to FOLFOX. So, it’s really A then B, or B then A. And there have been trials showing it doesn’t really matter which order you do. So, using FOLFIRI as the backbone here in the second-line setting is a very common decision to do.

Then the question becomes, what about the biologic? And really there are 3 different options here. In this case, we’ve continued bevacizumab, which is a very reasonable thing to do. It has level 1 evidence with the bevacizumab beyond progression trial or treatment through multiple lines, where this is a large randomized study that showed a survival benefit to continuing bevacizumab even though the tumor has worsened on first-line therapy. And the hazard ratio there was about 0.8, meaning there’s a 20% improvement in survival.

The other options would be to, for the biologic, switch to ziv-aflibercept, and that’s based on the VALOR trial…also, a hazard ratio of 0.8, or 20% improvement. Ramucirumab—that was in the RAISE trial—also had a 0.8 hazard ratio, or 20% improvement in outcome. So, any one of those 3 options is quite reasonable. And many people pick bevacizumab because they’re familiar with it and it’s cheaper, actually, but it would be also quite reasonable to choose ziv-aflibercept or ramucirumab in the second-line setting.

The treatment goals in the second-line setting remain palliative. And so, in making the decision, I think it’s important to meet with the patient and really clarify what has been their experience with the first line of chemotherapy: Did they do well? Did they not tolerate it? What is their quality of life? Some patients will not want any further chemotherapy, or they’ll want to do a clinical trial or try some immunotherapy trial or something, because they’re just tired. They’ve been coming to clinic, they’ve been getting these side effects for a year. And so, I think it is important to sit down with a patient and really clarify, how did things go at the first chemotherapy? Is your quality of life such that you still want to keep trying this? And I think that can be very helpful in terms of choosing what type of regimen you’re going to use. For patients who tolerate it really well, you might just go ahead and go with FOLFIRI—it’s one of the more aggressive options as your backbone. But for patients who did it, you might start thinking about what are typically third-line options, but you might start thinking about using those a little earlier if they’re really tired of coming in. And so, those are the conversations that you have to have with the patient.

Bevacizumab beyond progression has level 1 evidence to support its use. And basically, you have these other options, including ziv-aflibercept and ramucirumab. But all 3 of them have very similar outcomes, which is a 20% improvement in survival, and typically, they’re very well tolerated. So, most people will continue some type of biologic in that setting. And recall that this is aKRAS-mutated patient. So, again, EGFR antibodies, such as cetuximab and panitumumab, are off the table. And also recall that this is a microsatellite-stable patient or proficient mismatch repair, and so the PD-1 targeting agents are also off the table.

Transcript edited for clarity.

Progression of Left-Sided mCRC

February 2016

• A 66-year-old man reported with constipation, bloating, abdominal pain and weight loss of 12 pounds in 2 months
• PMH: mild hypertension, well-controlled on CCB
• Lab evaluation: Grade 2 anemia (Hb 9.2 g/dL)
• Colonoscopy revealed a7-cm mass in sigmoid colon
• CEA, 80 ng/mL
• The patient underwent sigmoid colectomy
• Pathology: undifferentiated adenocarcinoma tumor invading through muscularis propria and extending into the pericolorectal tissue;
  • Biopsy: 7of 12 resected nodes positive
  • Molecular testing:KRASmutation in codon 12 of exon 2; microsatellite stable
• CT scan showed several lesions in both lobes of the liver, measuring up to 17 mm in diameter, and 3 small lesions (<6 mm) in the left lower pulmonary lobe
• Diagnosis: Stage 4 colorectal cancer
• The patient received systemic therapy with FOLFOX + bevacizumab; therapy was well-tolerated
• The patient was continued on bevacizumab maintenance

February 2017

• One year after starting therapy, the patient complained of nausea and fatigue
• CT of the chest, abdomen, and pelvis showed progression in three of the liver lesions and one lesion in the right pulmonary lobe
• The patient was started on FOLFIRI and continued bevacizumab

January 2018

• Eleven months later, CEA level rose significantly
• Follow-up CT showed progressive disease in the lung and liver
• The patient is interested in knowing his options at this stage