Grothey (00:05):

Hello, I'm Axel Grothey from the West Cancer Center and Research Institute in Germantown, Tennessee. Today we'll be discussing one of my favorite topics, how we personalize care in metastatic colorectal cancer. Joining me is Crystal Denlinger, chief of GI medical oncology at Fox Chase Cancer Center in Philadelphia. Welcome, Crystal.

Denlinger (00:26):

Hi Axel, thank you. It's great to be here tonight.

Grothey (00:29):

Yeah, I know this is our favorite topic to talk about, optimizing treatment approaches for patients with GI malignancies, in particular colorectal cancer. We have seen a lot of improvement in long-term survival, but at least until recently never seen this one breakthrough event for the majority of patients. Patients really benefit from incremental additions of these steps we've seen that improve outcomes over time. I think patients benefit from being offered all available treatment options that we have if the treatment option has a chance to work. And I think our idea is really to expose patients to as many lines as possible to improve outcome.

Grothey (1:07):

And we've seen that patients actually remain good candidates for treatment approaches, even clinical trials. They maintain their performance status in a lot of patients after multiple lines of therapy. Now, more and more we see special treatments, targeted approaches for molecularly defined. And Crystal, what I think we should start talking about is really, what are the molecular characteristics you'd like to see tested up front or over time in a patient with metastatic colorectal cancer?

Denlinger (1:40):

Axel, I think that's a really good question, because as you pointed out, our patients are now surviving years. So when I'm thinking about someone who has a newly diagnosed metastatic colorectal cancer, the markers that I want to know about at the time of diagnosis or at the beginning of treatment planning include their microsatellite status, their RAS status, including their KRAS and NRAS status, their BRAF status. I would also like to know, are they HER2 positive or HER2 negative, if they are pan-RAS and BRAF wild type. For a certain group of patients, we would also like to know their NTRK fusion status. So I think all of these are important, because depending on those types of molecular profiles, the treatment strategy may be different in the first line, as we've learned over the course of this past year with immunotherapy and the EGFR inhibitors, as well as in later lines of therapy, as we're learning with, say, HER2 positive disease.

Grothey (3:29):

Yeah, that's exactly what I do too. Let's talk really quickly about some of these subgroups that you just mentioned. You already talked about MSI high, mismatch repair deficient cancers that have high tumor mutation burden, we consider them immunogenic. These are the sporadic tumors and the Lynch tumors hereditary syndrome. And I think we have seen data from the KEYNOTE-177 study, which pretty much settles the case in favor of using pembrolizumab, at least for now, as a PD1 antibody in first line because we saw pretty convincing progression-free survival benefit compared to chemotherapy in front line. And what I thought was interesting, that the durability of response was quite remarkable, even though there was, and I would like you to comment on that, a subgroup of patients that actually seemed to do better with chemotherapy up front because there were more patients that had progression of disease as best response on pembrolizumab compared with good old chemotherapy, doublet chemotherapy plus an antibody. So what do you make out of that and what do you think is happening here?

Denlinger (4:36):

Yeah, so I think that is a good question. There are some patients in the KEYNOTE-177 study, about 29% of patients had progression of disease as their best response. And I think that we still need to understand that patient population better, that there may be other drivers in that patient population for whom immunotherapy may not be the most effective treatment up front, whether that's something around the patient and disease burden characteristics, or is it more something related to the innate biology of these tumors?

Grothey (5:10):

Yeah, I would like to see an analysis based on tumor mutation burden, RAS data. We really need to understand better who these patients are who might actually potentially benefit from a combination with chemotherapy. And I know these trials are ongoing. Or combination of PD1 antibody plus CTLA4 antibody like the data we've seen with nivolumab and ipilimumab. So I agree there's a lot that needs to be really looked at in this setting. But I think we're all happy that we now have a good standard of care that we can build upon. We always improve upon our standard of care.

Grothey (5:43)

Now let's move to BRAF mutations. Because also with the idea of BRAF V600E-mutant tumors, there is some overlap with MSI high tumors and particularly in the right-sided tumors, older patients, et cetera, sporadic tumors. So we have active treatments now against BRAF V600E-mutant cancers, which we otherwise know have poor prognosis based on the data of the BEACON study and also the SWOG study that was recently published. So I think we understand that we need to inhibit BRAF by itself and counteract compensatory rebound pathway activation by using EGF receptor antibody. Is that what you see currently as standard of care in a second or third line setting?

Denlinger (6:26):

Absolutely. In the BEACON trial, this was a study that randomized BRAF V600E mutated patients. So either a triplet using encorafenib, a MEK inhibitor with binimetinib, and cetuximab, or the doublet of just encorafenib and cetuximab, versus the control arm of folfiri and cetuximab. And the results were really striking in terms of response rate. The response rate was 20% or so with the doublet, almost 28% with the triplet, versus 2% with fofliri and cetuximab, which is a dismal response rate. Progression-free survival was also better with the combination and overall survival was better. And after this updated analysis, it turns out that the doublet therapy with encorafenib and cetuximab has the same overall survival of about 9.3 months compared to the triplet where the MEK inhibitor was included.

Denlinger (7:19):

And I think what we have learned from this updated analysis is that perhaps that doublet of encorafenib and cituximab is enough for most BRAF mutated patients, that the extra toxicities of a MEK inhibitor in terms of the ocular toxicities and the potential cardiac toxicities are not really necessary, but there may be a small group of patients with a high volume disease where that triplet drug might be necessary. But in general, for second line patients with a BRAF V600E mutation, encorafenib and cituximab in my mind is the standard second line treatment.

Grothey (7:56):

Yeah, I would agree with that. The data are pretty convincing for that. Now, let me ask you, Crystal, about the question that I see discussed quite a bit. You have a BRAF V600E-mutant tumor and you have an MSI positive tumor at the same time. What's your preference? Do you go for PD1 antibody or BEACON?

Grothey (8:57):

Perfect. So in the end, we, for these patients, would have two non-chemotherapy lines of therapy with some level of evidence that we have generated so far. That's actually pretty cool. Now let's move on, the last targeted group that I'd like to talk about is HER2 positive tumors. And we know that HER2 in colorectal cancer is not common. It is only about 2% to 3% of unselected patients, but if you have a left-sided, RAS, BRAF, PIK3CA wild type cancer, cancer that might not have responded to EGF receptor antibody therapy, you can enrich the patient population and you might see a yield of about 20% to 25% of patients being positive for HER2 overexpression. So it refines the patient population further that should not receive cetuximab/panitumumab. So tell me a little bit about what you see is emerging right now as HER2 targeted agents. And perhaps you might want to comment on the NCCN guideline changes that we've recently seen.

Denlinger (9:55):

So going back a few years now, the HERACLES trial was the first study that looked at HER2 directed therapy in this patient population. This was trastuzumab and lapatinib. And in this patient population there was about a 30% response rate and a 59% disease control rate. And these were heavily pretreated patients. Median number of therapies was four or five. This was definitely a patient population where we did not have a lot of good options. And this really demonstrated not only good disease control, but that translated into prolonged survival for this group. And then we have the MyPathway study, which looked at pertuzumab and trastuzumab. Again, median survival approached a year, and this was again a very heavily pretreated patient population who had received multiple cytotoxic combinations as well as the standard antibodies with bevacizumab.

Denlinger (10:45):

But I think the drug that I'm most excited about is actually trastuzumab deruxtecan, which has actually been presented at ASCO this year. And this was the DESTINY-CRC01 study. And this had a multi-cohort study looking at the HER2 truly positive with an IHC3+ or IHC2+ and ISH positive. And this group of patients would receive trastuzumab deruxtecan every three weeks. And there was a median progression-free survival of 6.9 months and the median overall survival, as of the report of this trial, had not been reached. And so this was a really exciting study because the response rate was also pretty high. If I recall correctly, it was around 45%, and this is a group of patients, again, heavily pretreated. And some of them were even allowed to have had prior HER2 therapy, HER2 directed therapy.

Denlinger (11:43):

The one thing that I'm cautious about that I think we need to pay attention to is the interstitial lung disease risk that's associated with this particular drug. In the DESTINY-CRC01 study there were two interstitial lung disease related deaths, and this is something that we've seen, interstitial lung disease has been something we've seen in the other studies that have looked at this agent in either gastroesophageal and breast cancer. So I think we have to be mindful of this risk, but I do think it's a really promising drug. It has made it to the NCCN guidelines for HER2 directed patients. And so I think this is a very exciting thing.

Grothey (12:24):

Now, on the other hand we've talked a lot about molecularly defined patient population, where we have all the exciting treatment options, but the vast majority, unfortunately, of patients with metastatic colorectal cancer, when they hit us after two lines of therapy, they don't have targeted treatment options. We've all tried to look at, let's say, liquid biopsies, have some targets emerged? Have we missed something? And hopefully we will be expanding our targeted portfolio of targeted agents over time, but then there are drugs like regorafenib and TAS-102, which are part of our standard of care. And these drugs actually were developed, both of them were developed I think very soundly, scientifically soundly in randomized trials, phase three studies, worldwide, sets of two studies each, comparing against placebo, and have survival benefit. So Crystal, what do you think, what's the value of these agents, and where would you place them in the sequence of your algorithm for metastatic colorectal cancer?

Denlinger (13:13):

I think for both regorafenib and TAS-102, trifluridine/tipiracil, the survival benefit and the benefit of these drugs is really in the ability to stabilize disease. Both of these drugs in general are not significant tumor shrinkers. The objective response rate is 1% and 2%, and the progression-free survival may not necessarily be long. Median progression-free survival for both of these agents is around two months. However, there is an overall survival benefit with both regorafenib and trifluridine/tipiracil of somewhere between six weeks and two months. I think that the difference between these two drugs really is in some of the toxicity profiles that we see. So regorafenib typically has the side effects of VEGF inhibitors with hand-foot syndrome, diarrhea. There have been some studies suggesting that regorafenib's benefit may be greater in younger patients under the age of 65. Whereas trifluridine tipiracil, the greatest toxicities are around neutropenia and potentially some GI toxicities with diarrhea. And again, in some retrospective analyses, that drug may be more beneficial in older adults over the age of 65. That being said, I do think that for each of these drugs, in someone who has a good performance status, who is a good candidate for systemic therapy after treatment with folfox, folfiri, with antibody therapy, that trying to get both of these drugs in if possible is a good idea.

Grothey (15:08):

Yeah, I would agree with that. One comment that I always like to make when we look at the efficacy of these agents and we see, for instance, there's a 1.4 months difference in median overall survival, I think a lot of people have in their mind that this is, every patient has a benefit or improvement of 1.4 months. That's not true. Some patients have no benefit at all from regorafenib or TAS-102, tumors are refractory. But some patients have longer benefit. And unfortunately we don't know exactly who these patients are right now. We try to narrow it down by saying younger patients, older patients, more heavily pretreated versus less heavily pretreated patients. But I think I've been surprised by some of the patients that I've seen that have longer benefit, for instance, on regorafenib. We should not miss the opportunity to see that these patients potentially benefit from these agents beyond the standard assumption of 1.4 months, median gain of overall survival.

Grothey (16:11):

I would also like to highlight that we've fortunately now found ways in particular with regorafenib to make it more tolerable by starting with a lower dose, half the standard package insert dose, in the first week per day, then ramping up in the first cycle. In the so-called ReDOS data, which Tony Bekaii-Saab led, I think it has given regorafenib this second chance and people have looked at it again. And hopefully we'll be able to preserve quality of life for patients longer when we use this escalating dosing approach, which I assume you also use in your clinical practice, Crystal.

Denlinger (16:46):

So the ReDOS strategy in my mind is the only way, actually, to dose regorafenib, the 80mg for a week, 120mg for a week, 160mg for a week for that first cycle. And I have seen it's much easier to get the drug into patients and to be able to allow those patients to continue into cycles two and beyond so that they are able to get the benefit of the drug, as opposed to starting at the full dose and then having a lot of toxicity during cycle one that limits their ability to go on to further cycles to derive benefit.

Grothey (17:18):

Yeah, from my end, two points to go beyond TAS-102 or regorafenib as single agents, there are data now emerging from randomized comparison, looking at the addition of bevacizumab to TAS-102, and this seems to work, seems to be a benefit with later line data, with first-line data.

So I think, Crystal, we've covered a lot of ground in metastatic colorectal cancer. Any takeaways that you might have, anything that you're excited about right now?

Denlinger (18:21):

Yeah, so I think probably the most important things and the things that I tell my fellows, is that the best outcome is when patients get all the drugs for which they're eligible. And so we should know from day one what our pathway is going to be for our patients. And in 2021 that means doing biomarkers, doing a panel of biomarkers, not individually one here and there, and knowing which bucket or which treatment pathway you should be going down over the course of a patient's cancer journey. So doing all the biomarkers up front and then understanding what your treatment pathway through multiple lines of therapy should look like or could look like, and trying to do everything possible to get your patient through all of those treatment options is probably going to be associated with the best long-term outcome, understanding that sidedness matters as well.

Grothey (19:21):

Yeah. I tell my patient it's a marathon, not a sprint, so we need to pace ourselves. And I think that you summarized it very well. And what I try to get my fellows, I try to get them excited about GI oncology and colorectal cancer in particular, which is really an amazing field.

Denlinger (19:40):

Yeah, absolutely. It's a really exciting time to be a GI oncologist right now.

Grothey (19:44):

Perfect. Thank you, Crystal. Thanks to the audience for joining. I hope you learned a lot about management of progressive metastatic colorectal cancer. Thank you again.

Denlinger (19:55):

Thank you.