Whats Next? Sequencing Later-Line Therapies in Metastatic CRC - Episode 10
Transcript:Fortunato Ciardiello, MD, PhD: There have been a lot of gigantic new discoveries in the treatment of metastatic colorectal cancer [mCRC] in the past 20 years. And, step by step, these discoveries have included a new chemotherapy, a better chemotherapy combination, the addition of biologic agents, the blockade of specific receptors or angiogenesis, the continual care of different lines of treatment, the introduction of third-line drugs like regorafenib or TAS-102 [trifluridine and tipiracil hydrochloride], and the introduction of surgical metastatic sites as a strategy for the disease. All these together have brought a much better prognosis for most mCRC patients. However, there are still a lot of patients that are suffering with disease that is rapidly exploding.
Who are these patients? Mostly they are the patients who do not respond well to first-line treatment. Mostly these are the patients whose tumors are located more on the right side of the colon, for an anatomic reason because usually the diagnosis is much later when the stage is much more advanced and also for biologic reasons because there are some genetic alterations that are more common with a worse prognosis in the right versus left colon. One of these is the mutation of the BRAF gene. About 5% to 10% of mCRC patients have a tumor that harbors this mutation and especially the activating mutation called the V600E is a very bad prognostic indicator. Now, do we have specific therapies for BRAF-mutant tumors? The answer until very recently has been, “no,” although we have had good news in the past couple of years and at least we can start to treat these patients in a more selective way.
I think that the treatment of mCRC is a rapidly evolving field that step by step is changing the landscape of disease and offering more opportunities to patients. The more we have a characterization of the genotype and the phenotype of the tumor, acknowledging the heterogeneity of the disease and acknowledging that we can subdivide the disease into different more homogenous groups, the more we have opportunities to define prognostic indicators or, more importantly, predictive factors that can guide us in therapeutic choices. And then learning that the tumor characteristics can evolve in a dynamic way is part of it.
This has been really accelerated by the fact that now we know that, for example, after treatment without the EGFR inhibitors, when the tumor becomes resistant to therapy, some of these patients, in about let’s say one-third to 50% of cases, have a tumor with RAS mutations. But what we know is that if we do a subsequent line of treatment without anti-EGFR monoclonal antibodies, these mutations that are not needed by the tumor any longer can disappear, usually with an average half-life of about 4 to 5 months.
Therefore, these have brought the concept that rechallenge therapy in third- or fourth-line treatment of patients with a metastatic disease whose tumor originally was RAF, RAS wild-type and responded well in the first line to chemotherapy anti-EGFR antibody could be a suitable third- or fourth-line therapeutic choice for patients with a tumor with the RAS wild-type genotype. And we have evidence about it. Earlier this year, 2 clinical trials have been presented, but this evidence has become more and more relevant.
Another important question in the chemorefractory setting of mCRC treatment choice is which is the best sequence. We have the possibility of rechallenge with anti-EGFR. We have regorafenib with TAS-102. So the question is which is the best sequence. It’s very difficult to make an answer that fits for all patients, and what I will say is that it is very important that all patients have all available therapeutic opportunities. More than the sequence, it’s important that patients can be offered all the therapeutic options. If a patient didn’t do an anti-EGFR monoclonal antibody in first or second line, so a patient is to be exposed for the first time to an anti-EGFR monoclonal antibody, the question will be should we use regorafenib or TAS and then the anti-EGFR antibody or vice versa. We don’t have clear evidence.
There is a study that was done again by a Japanese colleague called REVERCE, recently published, in which in patients never exposed to anti-EGFR therapy in first or second line, at the time of third line in RAS wild-type patient populations, they were randomized to receive regorafenib followed by cetuximab anti-EGFR monoclonal antibody or the REVERCE sequence. And there is some evidence that, at least within the limitations of this study, that is a randomized phase II study, maybe regorafenib followed by cetuximab is better than anti-EGFR monoclonal antibody followed by the multikinase antiangiogenic drug.
Is this affecting my practice? I will say I don’t know or maybe, also because, at least in Europe, we use an anti-EGFR monoclonal antibody in patients with RAS, RAF wild-type tumors, mostly in first line or in second line. And, therefore, the conditions of the REVERCE study are not existing any longer, at least in Europe. And, therefore, the question in Europe would be more, should I do a rechallenge with anti-EGFR antibody in patients who have responded in first line or not? Should I use regorafenib as first choice for third line or should I use TAS-102 as a choice for third line? In any case, I would like to outline and make a very strong case that the sequence does not matter too much. What matters is that we can offer to the patient all available drugs.
And this is also an extension of what was earlier found when chemotherapy was the only available type of therapy for mCRC. It was clearly shown in patients receiving a fluoropyrimidine, irinotecan, and oxaliplati combination that patients who receive the sequence will be better off in terms of survival as compared to patients who didn’t receive, let’s say, irinotecan or oxaliplatin and were treated only with 5FU [fluorouracil].
The bottom line here is that, since the beginning of metastatic disease, based on all the molecular determinants we can know, including MSS or MSI-high [MSI-H] status, HER2 gene amplification, RAS status, RAF status, and even tumor location and primary tumor location, we can define a strategy in which we can define if there is a possibility of resection of liver metastases or not. And this applies only, unfortunately, to patients with liver-limited metastatic disease which is the best way to do chemotherapy in first line, even intensifying chemotherapy by doing, for short time, FOLFOXIRI [irinotecan, oxaliplatin, fluorouracil, and folinate (leucovorin calcium)], or which is the best biologic agent to put together with chemotherapy doublet, according to this, to decide what happens second line.
And according to this to define how the patient responded, adverse effects to do regorafenib, to do TAS-102, to do the best sequence of them in some selected patients with RAS wild-type tumors, to do rechallenge with anti-EGFR. And obviously for patients with MSI-high tumor, to do as early as possible, immunotherapy for patients with HER2 amplified tumors. I have had the opportunity to do therapy in the chemorefractory setting. And more importantly, there is evidence more and more that BRAF and MEK can have important role plus EGFR blockade in patients with BRAF-mutant tumors after first line failure.
Transcript Edited for Clarity