Therapeutic Agents in Relapsed/Refractory mCRC

Fortunato Ciardiello, MD, PhD: It’s important to say that only approved drugs for third- and fourth-line are either regorafenib or TAS-102 [trifluridine, tipiracil hydrochloride]. The ideal sequence is not known, but sequences should be considered equally active or effective. In terms of rechallenge with anti-EGFR monoclonal antibodies in third-line, the question is still very intriguing and open. We have some respective data and some small-size prospective proof-of-concept trials that point out the possibility that in third- or fourth-line, when we re-treat or re-challenge with an anti-EGFR monoclonal antibody, a patient whose tumor was RAS/RAF wild-type and had a very good response to chemotherapy plus anti-EGFR monoclonal antibody in first-line, we will get again an effect in that treatment. Therefore, this is an option we consider but not an option that is standard of care. In my opinion, although this is a valid option, we should still regard them as experimental to explore it in appropriate clinical trials.

Heinz-Josef Lenz, MD, FACP: This is a more interesting discussion because with the development of liquid biopsies, we can monitor the progression of disease based on a molecular makeup. We now know that we have potentially the choice of re-challenging treatment we have used in earlier lines of treatment in this case first-line. Liquid biopsies would be helpful to discuss re-challenging the cetuximab, also TAS-102 and regorafenib. We have learned from many clinical trials that it seems like regorafenib will work better in earlier lines of treatment. This is an important factor. It seems that it works better in younger patients, and it works better in patients who are fit. TAS-102 seems to remain efficacious also in later-lines of treatment, and maybe overall it is a bit better tolerated in patients who have the best performance status. That all goes into the equation of what you want to do. In the third-line, I also consider if there is a tumor burden or tumor symptoms associated with tumor progression that I could re-challenge with chemotherapy. For example, when I gave FOLFOX [5-fluororacil, leucovorin calcium, oxaliplatin] in the first-line and then switched to FOLFIRI [5-fluororacil, leucovorin calcium, irinotecan] for a significant time of treatment, I would consider FOLFOX if they need tumor shrinkage, because reintroduction of FOLFOX has shown that you can have response rate from 10% to 20%, which is very difficult to reach with the single-agent TAS-102 or single-agent regorafenib. Here you can reintroduce cetuximab combination with the FOLFOX depending on your previous use of this treatment. Today, with introduction of liquid biopsy and better understanding than mechanism resistance, we have a choice to revisit treatments we have given in earlier-lines of treatment, along the new approved medications such as TAS-102 and regorafenib.

Fortunato Ciardiello, MD, PhD: Anticancer agents are given either intravenously or orally, some of them also subcutaneously. For all drugs that are not given orally, usually for a short access to the hospital, that we in Europe call day hospital access, are administered to patients. In terms of fourth-line, both TAS-102 and regorafenib could be provided as oral drugs. This is good and could add to the compliance of the patients but requires very close monitoring of the patient to be sure that the patient is taking the right amount of pills, the right days, with the right day off or rest periods. More important, when we treat patients with TAS-102 or regorafenib, we should frequently see the patient in ambulatory care during treatment to be sure that we can control, as early as possible, potential adverse effects and check if therapy is being active and effective. Usually in our practice, when patients are put in third- or fourth- line with the regorafenib or TAS-102, patients obviously have therapy at home but they come every week to the hospital for ambulatory care. This is not very easy everywhere. Before the COVID-19 pandemic, this was normal in most Italian hospitals. With the COVID-19 pandemic, the situation has been different region by region in Italy and Europe. I still think it is important that the patients who are treated with anticancer drugs given at home orally should be closely monitored by an expert nurse or by a medical oncologist.

Heinz-Josef Lenz, MD, FACP: We have continued to do chemotherapy, and we did not adjust or make decisions or step down on our chemotherapy. Patients in second- and third-line are dependent on the efficacy of treatment, and a significant delay or undertreatment may not be in their benefit. It has to be all risk and benefits, and for us, the benefits of chemotherapy outweighed in almost all patients. That led to the decision that we continue with the treatment we think is the best without making adjustments for COVID-19.

Transcript Edited for Clarity