Whats Next? Sequencing Later-Line Therapies in Metastatic CRC - Episode 1

Changing Realities in Treating mCRC


Axel Grothey, MD: When we look at the advances in the treatment of metastatic colorectal cancer over the last years, there are several things that actually happened. First, we have more drugs available for treatment. We went beyond chemotherapy agents, irinotecan, oxaliplatin, and 5-FU [5-fluorouracil] to incorporate biological agents routinely in our treatment. We got new agents like regorafenib and TAS-102. The more agents we have, the more treatment options we have for our patients, and the longer we can keep them alive.

Second, we saw the emergence of molecular profiling as 1 of the standard features in the management of patients. We routinely identify a patient with MSI [microsatellite instability]—high mismatch repair-deficient cancers. We check for BRAF and RAS mutations to really select patients for a specific treatment.

Newly on the horizon is HER2, which is another marker you can use to target using HER2-targeting agents like trastuzumab, pertuzumab, and breast cancer agents more or less. There is this emergence of new treatment options in reassignment of treatments based on molecular profiling of patients. And both have enhanced treatment options and outcomes for patients.

By utilizing all these different treatment options, we’re seeing group of patients who are candidates for immunotherapy, for instance, having extremely long survival in metastatic colorectal cancer now, which we don’t even know exactly how to capture because we’ve just started using these agents. Those patients might have years and years of overall survival on immunotherapy, the patients mismatch repair-deficient cancers, which unfortunately make up only about 5% of patients with metastatic disease. Otherwise, we’ve seen movement of overall survival in clinical trials from the era before biological agents, which had about 20-month median survival, to now routinely approaching 3 years in median overall survival, with the incorporation of biologics and sequential use of these agents.

Tanios Bekaii-Saab, MD: Over the last couple of decades, a number of agents have become available to our patients, and that certainly has complicated, in a good way, how we think about sequence. Time after time, what we’ve been seeing and observing, the studies have been showing exposure to multiple lines of therapy, effective therapies, which seem to continue to stretch the survival of patients. And now, at least in the KRAS or the RAS wild-type patients, we’re talking about survival that’s close to 40 months, again close to the 4-year mark at the median, which essentially means a lot of patients now are surviving beyond 5 years, obtaining even 10 years with metastatic disease. That’s important to keep in mind. If we look at the whole landscape of studies that have led to this improvement, each 1 of them has contributed a little bit. The first line is usually the major contributor, although again, it’s a relatively small delta. But then you look at every line of therapy, there’s about a couple of months of improvement. And all this has taken us from 5-FU alone, with survival of about a year or a little bit less, to close to 3 or 4 years.

When we think about choosing and sequencing therapies, there’s still quite a bit for us to learn. We think that there are at least multiple options that are available. We’re not very clear about how to choose best. We have ideas about if we have, and we should have, at least RAS, BRAF, HER2, MSI, and one could argue even NTRK fusions available from the get-go because they help us somewhat in the long-term planning as well as the short-term and the sidedness of the tumor. Then age comes into play, whether it’s resectable or not, and then patients’ preferences, right versus left. A lot of things essentially enter into that equation and the discussion with the patient.

There are a number of guidelines about how to consider doing it. There are still some questions that are pending. It has become clear to us that regardless of RAS status, meaning a RAS wild-type, BRAF wild-type tumor on the right does not seem to benefit from EGFR inhibitors. We know that in addition to the biomarker, the side matters. On the left side, it’s a little different when we’re talking about the first line; it is whether we use EGFR or VEGF inhibition. There are trends that may favor a little more the EGFR inhibitors, but that does come also at a level of toxicities and perhaps even a little dent into the quality of life.

We have to think about all these things as we choose. It’s just not a number but a number of things that go into the equation. I think overall we have some level of comfort about what makes sense and what may not, but there is no very rigid line—this is what you get first line, second line, and third line, depending on this number or this number. There are essentially a lot of things that go into this equation, including the discussion between the patient and the physician.

Transcript Edited for Clarity