Later Lines of Therapy for mCRC

Fortunato Ciardiello, MD, PhD: For the continuum of care of medical treatment for patients with metastatic colorectal cancer, to offer them all the opportunities to extend lifespan, we must offer all the appropriate therapeutic options, also beyond second line. Therefore, after the first 2 lines, basically incorporate FOLFIRI [folinic acid, fluorouracil, irinotecan] and/or FOLFOX [folinic acid, fluorouracil, oxaliplatin] in either sequence and incorporate all the potential biologic agents. This includes anti-EGFR monoclonal antibodies and antiangiogenic drugs, as well as including the combination of BRAF inhibitor and anti-EGFR therapy in patients with a BRAF mutation.

In third-line treatment, unless patients are entered in an early phase clinical trial with investigational drugs for specific mutations, patients are candidates for treatments that are not based on any molecular selections. We have basically 2 options that are completely different from each other, but can be used in sequence. The drug regorafenib, the multikinase, mostly antiangiogenic small molecule that is an oral drug, and another oral drug, TAS-102 [trifluridine/tipiracil]. Obviously, TAS-102 [trifluridine/tipiracil] is a chemotherapy drug and has mostly chemotherapy [adverse] effects, including bone marrow toxicity. Whereas, regorafenib has only specific [adverse] effects that are typical of small molecules of that class of agents and oral antiangiogenic agents. Therefore, especially for patients in the first lines of treatment who have been treated with very aggressive chemotherapy regimens, for example, with triplet chemotherapy or for long periods, I would like to spare them from further bone marrow toxicity by chemotherapy. I prefer to use the regorafenib first, and then eventually at progression, TAS-102 [trifluridine/tipiracil]. For some patients in which the angiogenic drugs have been toxic in the previous lines of treatment, or the antiangiogenic treatment has been very short because of rapid progression, maybe TAS-102 [trifluridine/tipiracil] would be a better option before going to regorafenib. I will say that, in general, we have no evidence that TAS-102 [trifluridine/tipiracil] is better than regorafenib, or vice versa. We have no evidence that sequencing the regorafenib followed by TAS-102 [trifluridine/tipiracil], or vice versa, is a preferred option. What we know is that we should use both agents in sequence in third and fourth line and that in most cases in practice, when patients have been treated intensively with chemotherapy in the first lines, regorafenib will be, for the mechanism of action and for the adverse effects, the best potential option.

An important question is how many patients after failing second line will go to third line? I would say that between 30% and 60% of patients after we start with the first line, will end up starting an appropriate third line of treatment. Among those patients that start a third line, about half of them will start a following fourth line of therapy.

Heinz-Josef Lenz, MD, FACP:When you look at the official data, it's always shocking how low they are. In my practice, maybe because it's a referral center, basically almost 100% go to a third-line treatment. Very few don’t go to third line, when they are BRAF mutated, have very aggressive extensive disease, are elderly, or have a significant issue with liver function. But the vast majority goes into third line. In fact, I think our dilemma is we don't have enough treatment after third and fourth line because these patients are still in relatively good shape, and with increasing effectiveness of our first- and second-line treatments, this patient population moving to higher lines of therapy may get bigger.

Axel Grothey, MD: As patients move from line to line to line of therapy throughout the continuum of care, the more limited our treatment options will become, eventually, the more potentially affecting the patient's performance status, overall health, and they might be fatigued from just getting a lot of treatments; their health outcome and their health perspective has completely changed. When we look at later lines of therapy, we're not talking about the immunogenic tumors where we have great treatment options with immune therapies. We’re talking about the garden variety, 95% of patients, who have no new, let’s say, immune checkpoint inhibitor option, and are linked to regorafenib and TAS-102 [trifluridine/tipiracil] as treatment options.

The goal of therapy has changed. We're not looking at shrinkage of the tumor, long-term progression-free survival, and maintenance therapies, etc. Our goal is instead to control the disease and maintain quality of life for patients. I think that's a critical point. When patients initially come to see me in first line, everyone wants to be cured, and we all know that this is not possible. The longer patients stay on therapy, the more they realize that this is not possible, and that goals of care are changing. My goal is really to have them live as long as possible and as well as possible, and we talk about this in patient interaction. When I introduce, a third- or fourth-line setting based on progression of disease, if the patient has good performance status, willing to continue therapy, then I introduce the goal of care, which is that I want to control the cancer as long as possible and I want you to have good quality of life. Patients are intrigued by the idea of getting oral agents, which make them more independent, but you need to be quite aware of the toxicities of these oral agents, with the idea that we don't want to compromise quality of life.

Fortunato Ciardiello, MD, PhD: It is very important to talk to the patient before we start first line and explain to them that we have a series of therapeutic options that we are trying to use in the best sequential way that we know, according to clinical practice, based on evidence-based medicine. Therefore, when we start the first line, we try to explain to the patient that we will try to make their disease as chronic as possible and try to control the disease for as long as possible. Therefore, any passage from one line to another for us is not seen as a failure but as a possibility or an opportunity to explore another combination or another therapy with a different mechanism of action that we hope will be effective. What we say to the patients before starting third line is that with either regorafenib or TAS-102 [trifluridine/tipiracil], whichever one we pick, we explain the adverse effects, and we hope that at least 1 or 2 of them will get a good advantage in terms of progression-free survival. Especially for regorafenib, I could say to the patient that a subgroup of them, maybe 1 out of 5, or 1 out of 6 could experience a very prolonged control of disease progression that could last even several months.

Heinz-Josef Lenz, MD, FACP: I think the treatment goal depends on the extent of disease and organ involvement. If you have organ-limited disease, like liver or lung, I see if there is a chance that the treatment goal could be cure or curative resections. If this is a widespread disease, the treatment goal would be palliative, and it's very clear why we do chemotherapy. It's very important to share that with the patients, that the treatment goal is to extend their life, but also guaranteeing that quality of life. It's not only extending life but also preventing complications that can be caused by the tumor, like obstruction, and bleeding, and pain. I think that is often not really discussed in detail enough that patients understand that it's not only about living longer, but also living better.

Axel Grothey, MD: Later-line therapy in colorectal cancer, in patients with too much progression on 5-FU [fluorouracil], oxaliplatin, irinotecan, bevacizumab, so the VEGF inhibitors, and if they are RAS wild type, EGFR antibodies, the drugs that we have available are 2 oral agents as standard of care. It is regorafenib, which is a multikinase inhibitor, not chemotherapy, and TAS-102 [trifluridine/tipiracil], which is a combination of fluorothymidine, and a degradation inhibitor of trifluridine. These 2 drugs are available, and they have very similar efficacy in phase 3 trials. These drugs were developed in the later-line setting, 2:1 randomization against placebo, and studied in the Western population and Asian population.

Development of these agents was much the same. Both have clear demonstration of overall survival benefit, both agents do not induce response to a large degree, and the response rates we see are around 1% or lower. The emphasis of both agents is disease control rate, so we can control the disease in about 45% to 50% of patients. In those patients, we have data on regorafenib, patients have control of disease after 2 months from when we get the first scan. If they don't have progression of disease, they have a 50% chance to be alive 12 months from now, which I think is a meaningful parameter for patients.

Transcript Edited for Clarity