Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Axel Grothey, MD: We want to move patients from first-line to second- and hopefully third-line treatment to optimize the exposure to all active agents. The choice of second-line therapy depends on what we did in first line. For instance, if we start with FOLFOX [leucovorin calcium, fluorouracil, oxaliplatin]–based therapy, we normally go to a FOLFIRI [folinic acid and irinotecan]–based treatment and second-line treatment, or vice versa. And if we start with bevacizumab based on the fact that we had a RAS-mutant or right-sided cancer, I think the best data recommend continuing a VEGF inhibition beyond progression, and not necessarily even using an EGF receptor antibody in the second line. Unless there’s a need for, let’s say, a higher response rate that we can achieve when we add panitumumab, for instance, during a irinotecan-based regimen.
Of course, the experience that patients had with in terms of toxicities in frontline treatment plays a role. And we would, for instance, not re-expose patients to an oxaliplatin-based therapy after maintenance period if patients had a neurotoxicity or perhaps even persistent neurotoxicity after prior adjuvant therapy. How did they tolerate the fluoropyrimidine that they likely had in their treatment? These factors play a role in the selection of the chemotherapy and biological agents.
There are emerging data regarding especially BRAF V600E–mutant tumors, which are in about 8% to 10% of patients with metastatic disease. We have clear data that those patients might actually benefit more from a targeted approach with a combination of a BRAF inhibitor, EGF receptor inhibitor, and potentially even a MEK inhibitor. There are very intriguing data that came from randomized cooperative group studies and now from a randomized company-sponsored study, that those treatment approaches might be better for patients in second- and third-line treatment than standard chemotherapy, which we previously did. These 10% of patients’ BRAF mutations need to be treated differently. Similarly, likely in second-line or third-line treatment, MSI [microsatellite instability]–high tumors could be exposed to pembrolizumab or nivolumab-based therapies.
Fortunato Ciardiello, MD, PhD: Second-line treatment is an important component of treatment in metastatic colorectal cancer, because the continual care of subsequent lines of therapy is essential for prolonging survival, giving a relatively better quality of life to each patient with metastatic colorectal cancer. In this sequence, even the possibility of doing surgical removal of liver metastasis can play a role, either in the curative intention or for prolonging progression-free survival. In this scenario, the second-line options depend a lot on the first-line options. In terms of chemotherapy backbone, usually patients who in first line are treated with FOLFIRI receive second-line FOLFOX. So from irinotecan to oxaliplatin. Whereas the reverse is a situation when first line is FOLFOX followed by FOLFIRI.
In terms of biological agents, in patients whose disease is RAS mutated, obviously we cannot use anti-EGFR drugs, and usually in second line the strategy is sequencing chemotherapy by switching irinotecan to oxaliplatin or vice versa, and keeping antiangiogenic drugs—either continuing bevacizumab during progression or replacing the bevacizumab with other antiangiogenic drugs such as aflibercept or ramucirumab. Although the data with ramucirumab and aflibercept are only with FOLFIRI, and therefore we can use this option for second line only if we did FOLFOX–OXALOX in first line.
For patients with the RAS or RAF wild-type disease, in first line we use the chemotherapy backbone plus bevacizumab. In second line usually patients have 2 options: either to continue bevacizumab beyond progression by continuing this in combination with alternative chemotherapy, or—and this happens more often in several countries to switch to the alternate chemotherapy plus an anti-EGFR monoclonal—either cetuximab or panitumumab.
Tanios Bekaii-Saab, MD: We think about our patients’ treatment options as a long-term plan, not a short-term plan. The way I think about it is I want to take those patients through a marathon rather than through a sprint where I exhaust options and exhaust the patients too, and then lose the capacity to continue building up options for them. Whatever we do in the first line is important and should not be disconnected from our line of thinking about what should be done in the second, third, or fourth line.
If we have a right-sided tumor and you use VEGF—so bevacizumab in the first line—typically in the second line you will switch to chemo and go to bevacizumab. On the left-sided, with a left-sided tumor, that’s again RAS wild type, BRAF wild type, HER2 nonamplified. And assuming again microsatellite stable for that patient, if we went with an EGFR inhibitor in the first line, then naturally we’ll progress to a VEGF inhibitor, bevacizumab in the second line. If you started with FOLFIRI plus, say, cetuximab in the first line, you can actually continue the FOLFIRI. I’m sorry, you switch to FOLFOX and then switch the biology to bevacizumab. If you started with a FOLFOX–panitumumab in the first line, then in second line you have FOLFIRI plus bevacizumab.
On the other hand, if you start with bevacizumab and FOLFIRI, you can actually continue the FOLFIRI and just add the EGFR inhibitor. If you started with FOLFOX plus bevacizumab in the first line, then you switch to chemotherapy, to FOLFIRI, and then you go with EGFR inhibitor. The reason I don’t continue bevacizumab from first line to second line in that patient who is perfect for EGFR inhibitors is because I really don’t want to wait too long before we introduce the effects of the EGFR inhibition. Some may argue that EGFR inhibitors keep their activity across lines of therapy regardless of line of therapy, and perhaps you could still push it further down.
I think the data from CALGB 80405 and FIRE-3 are intriguing enough to actually convince me that I cannot wait beyond second line to use an EGFR inhibitor, and I prefer not to in terms of planning for overall survival. For most of my patients, though, the preferred first line remains chemotherapy plus bevacizumab, and usually FOLFIRI plus bevacizumab because I like to keep that backbone and then introduce the EGFR inhibitor in the second line.