Anti-EGFR/Chemo Combos Allow for Tailored Approach in mCRC

Ardaman Shergill, MD

EGFR inhibitors play a prominent role in the treatment of patients with metastatic colorectal cancer (mCRC), but their impact is more pronounced with the addition of triplet chemotherapy, explained Ardaman Shergill, MD. She added that the availability of oxaliplatin and irinotecan allowed for tailored approaches based on underlying neuropathy and liver dysfunction.

“If a patient has underlying neuropathy, for example, we’ll probably shy away from oxaliplatin, assuming everything else is equal, and maybe start with irinotecan. If the patient has significant liver dysfunction, we might start with oxaliplatin rather than irinotecan, or if they have known toxicity or low counts, we might start with oxaliplatin,” said Shergill.

In an interview with OncLive®, Shergill, an assistant professor of medicine at the University of Chicago Medicine, discussed the use of EGFR inhibitors in mCRC and advantages of expanded dosing indications.

OncLive®: Which patients with mCRC should receive treatment with an EGFR inhibitor?

Shergil: We use anti-EGFR therapy in patients who are RAS wild-type and who do not have HER2 amplification or overexpression. In patients who have HER2 amplification or overexpression, EGFR-directed therapy does not work quite as well. In patients who have RAS mutations, EGFR-directed therapy doesn’t work because there’s constitutive activation of that pathway. In addition, our preference for left-sided tumors if they are RAS wild-type is to use anti-EGFR therapy earlier on, if possible, because there’s improved outcomes using the therapy early on.

Do you tend to use EGFR inhibitors in combination with chemotherapy?

We have 3 options in that setting. We have 5-flourouracil [5-FU]/irinotecan-based regimens, we have 5-FU/oxaliplatin-based regimens, and then we have combination 5-FU/oxaliplatin and irinotecan, something called FOLFOXIRI or modified FOLFOXIRI regimens. In patients where I really want a response, I tend to use the 3-drug regimen along with the [EGFR] antibody. Additionally, in patients where I have time to get a response or there’s not an impending organ failure, patients who are not quite as symptomatic, or [patients in whom] I’m [trying to get them to] surgery and really want a response to see if [the patient] can go for surgery––that’s where I’m picking 3-drug regimens as well.

[That’s] especially true for left-sided colon cancers. A meta-analysis presented at the 2020 ASCO Annual Meeting showed that there is an overall survival benefit with 3 drugs, but when you break it down, it was mostly seen in RAS wild-type right-sided colon cancer. My preference there is, if we can, to use the 3 drugs.

Now, if other things are equal between FOLFOX and FOLFIRI, there’s not really a preference of one or the other as far as efficacy is concerned. Both have been shown to be equally efficacious. It’s up to patient factors then whether we can use CAPOX with capecitabine and oxaliplatin. Capecitabine with irinotecan is very toxic, so we tend to use 5-FU/irinotecan in that setting. For 5-FU, you need a port, so it’s a matter of whether the patient wants that. We talk about adverse effects for irinotecan and oxaliplatin.

Will we see EGFR inhibitors move into the neoadjuvant setting?

Some of those studies have been done, and the antibody didn’t make a big difference. We don’t use cetuximab alone, for example, in early-stage resectable colon cancers. One of the challenges in earliest-stage colon cancers is we don’t know the staging because they’re pathologically staged. We look at the nodes and everything pathologically to stage colon cancers. It’s also harder to appropriately stage colon cancer before surgery. Having said that, it is done for window-of-opportunity studies in certain settings, such as microsatellite instability–high, but not so far in the EGFR space.

On April 6, 2021, the FDA approved a new dosing regimen for cetuximab in the treatment of patients with KRAS wild-type, EGFR-expressing CRC. What are your thoughts on the newly approved biweekly dosing regimen?

We can now dose cetuximab every 2 weeks. We used to give [cetuximab in] a loading dose and then every week [thereafter]. [The dosing update] is great and was used in other diseases. Now we have an indication also in colon cancer. Especially in this environment, where we are not bringing patients to medical centers quite as much if we don’t need to, it’s an excellent update.

We were using [that dose] a little bit off-label for the appropriate patient, especially because the FOLFOX and FOLFIRI regimens are given every 2 weeks. In that way, patients can stay on that 2-week schedule, and you’re minimizing between visits. It’s a really great thing, and now more patients can benefit from this schedule. The time where we might still consider weekly dosing is if there’s toxicity concerns. If you’re seeing that a patient has toxicity, and you want to be able to control when you take the drug off, that’s where you might consider weekly dosing still.

Are there any toxicity concerns with the biweekly dosing regimen for cetuximab?

I’m not concerned about toxicity. We had been using [the biweekly dosing] before, and it’s done in other diseases, so it makes sense. We have experience. It doesn’t necessarily increase toxicity, but in a patient who is already having toxicity, if you want to have control, and it makes sense to, for the appropriate patient, [you can] continue weekly dosing, so that you can stop it if it’s quite toxic for them. Other than that, I don’t have concerns about doing every 2-week dosing, I fully support it, and we do it already, so it’s all positive change for the patients.

Is the effect of the expanded dosing indication going to be felt in community practices as well?

Absolutely. Most patients are treated in community practices rather than academic practices. Their decreased visits and decreased interaction with the health care system, hopefully, decreases their risk of other diseases. Of course, in this environment, we’re worried about COVID-19, but also anything else that could be acquired from part of our health care system.

Should non–prospective data be used to guide regulatory indications?

If [the data are] in favor of the patient, which most of the time [these analyses] are, then it’s great. [These types of data sets are] contributing to continued learning and advancing the field in favor of patients and [increasing] access to care, so it’s great.