Going back to Cathy, what do you think about the whole concept of rechallenging patients with a previous agent versus changing therapy at those touchpoints?

 Many of us have rechallenged when we want to provide the most treatment options to the patients to prolong their overall survival, especially when it comes to trials not available. But I am hesitant depending on the degree of neuropathy. Anybody with grade 2 or greater neuropathy would not restart oxaliplatin-based therapy.

There’s always the case about the oxaliplatin hypersensitivity that you may see on some records. You have to discuss it with the patient. Some of it’s very serious, and I would never rechallenge the patient. Sometimes it’s just a light redness or some pruritis of the hands, and then you can prolong the infusion time, in actuality, then they can be rechallenged. So it depends upon the scenario.

Raghav, rechallenging with anti-EGFR therapy, a concept that is emerging, any thoughts about it? Does it have a role in the clinic, or should we wait on John’s study to teach us a little more about the role of EGFR rechallenge?

 I would always say we should wait for John’s study. But in the meantime, that’s more rational than most cases, where we rechallenge with chemotherapy at the back end. Often those rechallenges are more like reintroductions rather than true rechallenges if you had significant progression.

With anti-EGFR, it’s an evolving field. The schools of thought are if you have a sufficient amount of time that has passed between your last EGFR, and you did have a good response to it, and then acquired resistance to it. That’s the more likely one because they are the ones that develop that resistance through the 

 clones, which tend to go away, usually at about 6 to 8 months, on average.

Fortunately, we have better tools nowadays, such as ctDNA [circulating tumor DNA], which can be used to detect those clones. Either you use that time duration, the further out you are the better it is, but if you don’t exactly have that, at least do a ctDNA to confirm that those mutant clones are not present before rechallenging the patient. Preferably, these patients should be entered into clinical trials, whether they are rechallenge trials or in combination with MEK inhibitors and other trials.

John, you’ve done quite a bit of initial work on this, along with other colleagues. Any thoughts?

I agree with everything Raghav said. We know that when we give people anti-EGFR therapies, almost all patients will experience progression. We also know from doing large-scale circulating tumor DNA studies on these patients, that we can identify the drivers of resistance: 

 active domain mutations. All of these can be detected through these blood assays.

As Raghav pointed out, over time, when you withhold that anti-EGFR therapy, those resistant clones are less fit and will go away. It does provide a therapeutic opportunity, and that’s already been shown by some very interesting work out of Italy, showing benefit from an anti-EGFR rechallenge approach.

We still don’t have that prospective data with molecularly selected patients, showing that patients benefit from the approach. I do encourage clinical trial participation. It’s something that will be evolving in the years to come and something that will be part of our management practice if these newer generation studies are positive.

Is that a place where liquid biopsies play an important role?

 Absolutely. The only way we are able to detect these alterations easily is through obtaining 1 to 2 tubes of blood and sending that off for molecular testing. What we’ve found is that just rebiopsying a tumor lesion, maybe a liver lesion, you might miss some of those resistance alterations. It’s really where the liquid biopsy performs at its best, particularly in comparison to a more conventional tumor tissue biopsy.

Joleen, when do you consider a liquid biopsy, assessing for circulating tumor DNA?

 I generally will do that after progression on first- and second-line therapy because I want to try to identify any new mutations for which we may have a clinical trial to identity any resistance mechanisms. That’s when I’m using those platforms, ctDNA, to try to figure out what the potential options are. Is there a clinical trial out there? That’s one of the best ways to identify the clinical trials.

 Are we talking about looking for minimal residual disease?

No, circulating tumor DNA, to assess targets, basically.

 Up front, as soon as I meet the patient if it hasn’t already been done, it has to be done, if I don’t have access to tissue. Honestly nowadays, I tend to order both, just in case I can get the tissue. It’s critical for creating a treatment plan. I agree with Joleen, I also do it as well when I have a patient where the disease biology appears to have changed especially, and I want to see what new molecular markers are available so I can put them on a clinical trial.

 This is one of the questions that came up during my discussions with one of the community oncologists. I agree, ctDNA is a great tool; liquid biopsy should be frequently done. But there are cases where these can add to financial toxicity for patients, and community oncologists are more sensitive to that. In those cases, the anti-EGFR rechallenge specifically, it’s reasonable if somebody has had a good duration of response, a good response on a prior EGFR, to reintroduce EGFR, 6 to 8 months after the initial exposure, because we know that most of those clones go away by that time. Although I would never do it on anyone who has primary resistance to an anti-EGFR drug in the first place.

Videos

The role of molecular assays, including liquid biopsies, in providing information on resistance mechanisms in metastatic colorectal cancer and the impact of testing results on decisions for rechallenging with a previous therapy.

Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center

Articles

Second-Line Treatment of mCRC: Rechallenging Therapy