Dr. Michael Overman:
Welcome to The ASCO Post Roundtable Series: New Directions in Metastatic Colorectal Cancer. I'm Dr. Michael Overman, a professor of GI and Medical Oncology at the MD Anderson Cancer Center. Joining me today are two of my colleagues.
Dr. Laura Goff:
Hi, I am Dr. Laura Goff. I'm a professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee.
Dr. Katrina Peterson:
I'm Dr. Katrina Peterson. I'm an associate professor of medicine at Washington University School of Medicine in St. Louis and the Siteman Cancer Center.
Dr. Overman:
Today we'll be discussing updates in the treatment of metastatic colorectal cancer and integrating these new developments into three patient case studies. Our last case will focus on second- and third-line therapy for metastatic colorectal cancer.
So, this is a case of a 64-year-old male presenting with metastatic ascending colon adenocarcinoma. CT scan demonstrated extensive metastatic disease with liver, lung, retroperitoneal, lymph node metastases. Molecular testing demonstrated proficient mismatch repair, and HER2 IHC (-), a 100-gene NGS panel demonstrated a KRAS G13D and additional mutations.
The patient is a retired active hunter, and so an active, good, ECOG performance status, initiated on triplet therapy with FOLFOXIRI/bevacizumab with a partial response, and then went on to FU/bevacizumab maintenance therapy, and then developed progression on maintenance therapy.
And so, Laura, I may turn this to you in regards to what are our treatment options now with the triplet in the frontline space going into maintenance progression? I think it gets a little bit complicated, or there's more treatment decision making options that we have. So I'll see what thoughts you have on options here.
Dr. Goff:
Sure. So I think, always, as we take care of these patients, we're thinking in the long term. We take care of these patients over the course of their life, with metastatic disease. Certainly with survival being better hitting upfront with FOLFOXIRI/bevacizumab, for patients who can tolerate it, it is helpful.
But really as we go into now this progression on maintenance space, want to be mindful of maximizing time and quality of life concurrently. So the questions I would have a little bit are how long since the progression? If we've been on FU/bevacizumab for a while, reintroducing one of the other cytotoxics makes sense, either the irinotecan or oxaliplatin.
Here in Tennessee, we have hunters as well, and peripheral neuropathy and guns isn't great. So I lean towards irinotecan as my cytotoxic of choice to reintroduce.
And then I think the question is, you could think about do you keep the FU going and it's a FOLFIRI/bevacizumab, or just a switch to an irinotecan/bevacizumab. And I think both of those would be leading candidates, but certainly irinotecan/bevacizumab is a little bit nicer to patients, in terms of time, unhooked and outside of the infusion room.
Dr. Overman:
Yeah. Kate, what thoughts do you have on... You might say go back to triplet, right? But that's not necessarily my classic practice pattern. So curious your thoughts on what would you'd add in on that decision making here?
Dr. Peterson:
Yeah, I certainly echo what Laura had to say about all those considerations that need to be taking place in one's head at this time.
As a quick aside, always find out at baseline if your patient is a hunter. You ruin one person's season with putting the port on the wrong side and you will find out, you don't do that again. And that's fair because we do a treatment to live, so that's important.
But in this space, typically I will use triplet rechallenge like TRIBE2 as my baseline, and then knock things off with the rechallenge, based on what residual toxicity do they have from the induction, what is their performance status currently at?
And also, I hate to say this, but almost like a gestalt from their sequencing data. So, when I see RAS mutations, and especially with the PIK3 mutations, I do tend to see a little bit more rapid progression. And so, if they have the willingness and the preserved performance status and no significant neuropathy, I will try to reinduce triplet, but cycle by cycle, we'll start taking things away. And even at reinduction, I won't continue the oxaliplatin for more than four to six cycles, but an ATM mutation's always a little bit questionable about platinum benefit compared to the BRCA, the PALB2, but I do feel like there is some platinum benefit there.
Dr. Overman:
Yeah, no, I think we've heard a lot of different options. I think that's the interesting thing after triplet, I think you can go many different ways.
And I think the one thing, the reason I put the hunter in the case is because that was such a meaningful function to this person that really drove the decision to stay away from the oxaliplatin. So really that drove that quality-of-life discussion.
And I think we have all these different options. I think it often comes down to that quality-of-life decision-making on what fits for the patient at that time, and also some of those other factors on pace of progression and disease and things, but a full assessment and discussion decision-making.
So the patient went on and initiated irinotecan/bevacizumab, and then had progression on that. We did go back to FOLFOX/bevacizumab, had progression on that. And so now, the question of treatment decision at this point.
So Kate, I'll ask you, what are the treatment considerations now for this patient?
Dr. Peterson:
So in the third-line space, whenever there's not a clinical trial available and when ctDNA does not show any evolving targets of interest, then really in the third-line setting, we have our traditional TAS-102, with or without bevacizumab, or regorafenib as the options as they currently stand.
I do, ever since the Danish data, which was confirmed by the phase III SUNLIGHT trial that was presented earlier in 2023, it showed a significant benefit with the addition of bevacizumab to TAS-102. So really in the third-line setting, that has become my standard of care go-to at this point.
Dr. Overman:
And then Laura, any other considerations in regards to treatment now or anything that may be coming in the future?
Dr. Goff:
Sure. Yes, I agree with Kate. I think, I lean towards TAS-102 in this setting with bevacizumab. Tolerability is a big issue. Quality of life is a big issue. Regorafenib when it first came out was extremely difficult to tolerate and patients really didn't appreciate that. We've been able to dose it a little bit better, based on their re-dose of the tolerability. And I think really it significantly improved by starting at a lower dose, and some patients have been able to get some meaningful mileage out of that agent. But I think it's a little easier to tolerate, personally still, the TAS-102/bevacizumab, for more patients out of the gate.
And then the other thing is we've seen data promising around the agent fruquintinib, in this refractory colorectal cancer space, and so hopeful that that'll be an agent available for patients, as well.
Dr. Overman:
And I think I would just like to echo the mutational data on how useful it is in regards to treatment decision-making. In this case, KRAS, which helped us in the selection of what not to use. So not using that anti-GFR therapy, but I do think KRAS13D is a target that we're starting to see some development of specific KRAS inhibitors. So there's interest there.
And then I think also the DNA repair pathway, the ATM is an area where there's some investigation of novel targets there.
And so again, you're right, it's an academic setting luxury of the clinical trial space that we have. But I do think I get much more interest in engagement when there's some targets that are having some initial activity in the early phase I space. I think that does cross the threshold of... The quality of life hit of a phase I trial becomes a little more, I think, discussable when there are some targets that help drive that sense of greater selectivity or match, in some regard.
Any other final thoughts in the refractory setting from either of you two?
Dr. Peterson:
Well, actually I had a question for Laura and what her approach is, not to open Pandora's box to your dosing strategy for TAS-102. I believe there's data out of Vanderbilt, and I don't know, maybe some of that, too, was out of MD Anderson about how different dosing schedules might improve the frequency at which we see our most concerning side effect, which are the cytopenias.
So do you tend to take the approach of days 1 through 5 and 8 through 12, or do you space it out and just start it on days where they get bevacizumab?
Dr. Goff:
Yeah, so we have really switched almost completely over to an every-other-week schedule. It's really one of the most confusing for patient's schedules. I think someone developed it. Understand where it comes from and we want to follow the science, but we also have to think of ways that are a little easier for patients to adhere to treatment. But yeah, we have found that the efficacy and the tolerability seems to be significantly better in the every-other-week schedule.
Dr. Overman:
Yeah, I think an example of some of the iteration that, I think that's an early retrospective data suggesting that that looks good tolerability, I think efficacy wise, those small numbers.
But same thing happened as you mentioned with regorafenib. I think the approach of starting low and going high has made it much more tolerable, and that balance of quality of life in the refractory setting is a huge part of what we do. So I think there is a lot of weight that needs to be put into how we give these agents to make sure we're managing that quality of life component. So, iterations on how best to use TAS-102, I think definitely on the table.
So I think as a conclusion here, the key clinical takeaways are really, you heard there's multiple chemotherapy treatment options in the second line following that triplet frontline option. I think a lot of different options, and not really a clear-cut path, but discussion with the patient on what matters.
The recent SUNLIGHT randomized clinical trial for refractory metastatic colorectal cancer, we discussed and have demonstrated an overall survival benefit for the addition of bevacizumab to TAS-102, with median over survival increasing from 7.5 months to 10.8 months with the combination therapy. And I think has really cemented that combination as more the standard with use of TAS-102 in the refractory setting.
And then regorafenib has improved tolerability when prescribing, according to the re-dose clinical trial framework, which was a weekly escalation from 80 to 120 to 160. And I think we'd all agree that that has been a much better, tolerable way to do that agent.
So I'd like to thank my co-hosts with me, and this brings us to the end of this case. Please see the other segments for further discussion about the latest data in colorectal cancer, or visit ascopost.com.
