Whats Next? Sequencing Later-Line Therapies in Metastatic CRC - Episode 12

Regorafenib vs TAS-102 Salvage Therapy


Fortunato Ciardiello, MD, PhD: It is very important to consider that the more lines of treatment we can offer patients, the better the possibility that these patients will have an extended survival and a better survival. Therefore, third-line treatment is very important for patients with metastatic colorectal cancer. And when all the previous options—including FOLFOX [folinic acid, fluorouracil, oxaliplatin], FOLFIRI [folinic acid, fluorouracil, irinotecan], or the biologic agents used in these patients according to the RAS and RAF status, either antiangiogenic drugs or anti-EGFR monoclonal antibodies—have been used in the first 2 lines, the patient is considered refractory. After the first 2 lines, the best option is to offer patients an alternative drug.

Now we have 2 main options for these patients. The 2 options are either a multikinase antiangiogenic inhibitor, that is regorafenib, or an alternative relative to 5-FU [5- fluorouracil]—an alternative fluoropyrimidine, that is an oral fluoropyrimidine called a TAS-102, or trifluridine-tipiracil hydrochloride. Both regorafenib and TAS-102 have a similar possibility of offering a better survival in this poorly palliative setting as the third line of treatment.

The main question is, what is my choice in terms of which of these 2 drugs to use in the patient after failure of the first 2 lines of therapy. It’s very difficult to answer in a very simplistic and definitive way to this question because both drugs are rather cytostatic than cytotoxic. Both of the drugs work better in patients with that driver, a relatively long metastatic disease that could benefit from 2 previous lines of treatment. In both drugs the best therapeutic efficacy is seen in patients with a relatively well performance status [PS], and therefore patients in PS of 0 or PS 1 will have many more chances of responding to either drug, regorafenib or TAS-120 [trifluridine, tipiracil hydrochloride]. And therefore, it’s very difficult to see if there is a specific profile differentiating the 2 drug choices.

One possibility is to consider the different toxicity and adverse-effect profile. Obviously, TAS-102 [trifluridine, tipiracil hydrochloride] is a chemotherapy agent, and therefore, the main toxicity is bone marrow toxicity with neutropenia and also thrombocytopenia. Whereas because it is an antiangiogenic multikinase inhibitor, regorafenib will usually have adverse effects of antiangiogenic drugs, including potentially hypertension. One specific adverse effect in use of regorafenib for a long time is skin reactions and sometimes asthenia.

Another important question will be, if in the third line I have to choose between TAS-102 [trifluridine, tipiracil hydrochloride] and regorafenib, do I have some evidence that one is better based on what happened with the previous 2 lines? Obviously because TAS-102 [trifluridine, tipiracil hydrochloride] is a cytotoxic chemotherapy agent, if the patient in the 2 previous lines of treatment was heavily pretreated with chemotherapy agents and added bone marrow toxicity, I would prefer to use regorafenib. It has no bone marrow toxicity before TAS-102 [trifluridine, tipiracil hydrochloride]. And then I will use TAS-102 [trifluridine, tipiracil hydrochloride] at progression after regorafenib. On the other hand, if the patient experiences more angiogenic drug-related adverse effects, I prefer to start with TAS-102 [trifluridine, tipiracil hydrochloride] followed by regorafenib. The key point here is whatever we start first, it is really the most beneficial treatment choice for the patient. That we hope to have a sequence of the 2 drugs, one after the other. Actually, we have evidence from a series of clinical experiences from some early clinical trials that regorafenib followed by TAS-102 [trifluridine, tipiracil hydrochloride] or TAS-102 followed by regorafenib are 2 good options for extending the continual care the opportunity of active therapy regimens to these patients.

Certainly, metastatic colorectal cancer is a very heterogeneous disease. We are always looking at understanding this heterogeneity for finding potential biomarkers that can guide us to find the best selected or precision-based medicine treatment options. What we can say in metastatic colorectal cancer is that the first choice has been the knowledge of RAS mutations. Because RAS mutations have been very instrumental to define, for defining those tumors that were resistant to anti-EGFR drugs. And so anti-EGFR drugs to RAS wild-type tumors in patients bearing these tumors.

The second has been BRAF mutations. BRAF mutations are a very bad prognostic factor, but now they are a very important predictive factor for active therapy against the BRAF-mutated access. More importantly we have some older biomarkers that can guide us. One is still in terms of biomarkers linked to the growth factor pathways, and this is amplification of HER2 gene. This is a rare gene alteration because about 4% to 5% of RAS wild-type metastatic colorectal cancer patients have a truly HER2-gene amplified cancer.

But in these patients, we have evidence that a selective anti-HER2 therapy, similar to what we do in HER2-amplified breast cancer patients, could be a very important benefit, at least for chemorefractory patients. More recently, with the introduction of immuno-oncology and immunotherapy drugs, including the immune checkpoint inhibitors, a lot of attention has been given also in metastatic rectal cancer to define the patients who could benefit from immuno-oncology therapy.

Unfortunately, today about 95% of patients have a tumor in which maybe the immune functions could not be restored by treating alone with immune checkpoint inhibitors, such as PD-L1 [programmed death-ligand 1] inhibitor plus or minus anti-CTLA4 Inhibitors. Because these tumors have relatively stable genetic alterations, or that is also reflected by what we call microsatellite stable genotype. Whereas about 5% of tumors, more often for mismatch repair gene deficiency and what we call microsatellite instable [MSI] tumors with high instability, or MSI-high tumors.

In this case we know that we have very strong evidence, at least in second line, but now we are looking for data for first-line treatment. Treatment with PD-L1, PD-1 [programmed cell death protein 1] monoclonal antibodies—such as nivolumab or pembrolizumab or even combination of PD-1 monoclonal, such as nivolumab plus anti-CTLA4 antibody, ipilimumab—could be of great value for these patients. The era of defining better potential biomarkers for metastatic colorectal cancer has just started. We are adding another important piece in this story.

Transcript Edited for Clarity