Colorectal Cancer Podcast

Breakthroughs in HER2-Amplified Colorectal Cancer

Benjamin L. Schlechter, MD; John Strickler, MD


August 01, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Benjamin L. Schlechter, MD: Hello. I'm Dr Benjamin Schlechter, and welcome to Medscape's InDiscussion series on colorectal cancer. Today, we're discussing HER2-amplified colorectal cancer with Dr John Strickler. Dr. Strickler, you've led the conversation in colorectal cancer in the treatment of HER2-amplified disease, and your work has resulted in the recent approval of tucatinib with trastuzumab for HER2-amplified colorectal cancer in the metastatic setting. Before we get to this topic, I'd love to hear a bit more about your path to becoming a gastrointestinal (GI) oncologist.

John Strickler, MD: I did my medical oncology training between 2008 and 2011, and at that time, there was an explosive growth in this idea of precision cancer medicine. And I knew I wanted to be part of that growth of that field. It was not that long ago when there were no actionable targets in colorectal cancer. The only thing we had when I was a trainee was KRAS exon 2, which was an unactionable target. We knew what not to give. I was attracted to this idea of bringing precision cancer medicine to a difficult-to-treat disease where outcomes were poor and we were heavily reliant on conventional chemotherapy. I was hoping that during my career, we could move away from cytotoxic chemotherapy into more targeted approaches. Of course, we didn't even know about immune therapy at the time. I remember being a fellow and seeing this presentation at the American Society of Clinical Oncology (ASCO) meeting about an immune therapy for melanoma, and I thought to myself that it will never come to us either. And now we can see how it's even applied to GI cancers. For me, it was an opportunity to make an impact on a field that was still highly dependent on traditional chemotherapy.

Schlechter: Yes, the immune therapy is an important one. We do have a podcast with Dr Marwan Fakih with the City of Hope on that very topic. First, let's dive into HER2-amplified colorectal cancer. I think the first thing we should do is define it. How should we define HER2-positive colorectal cancer, and what testing should we be using? Is this an immunohistochemistry (IHC) test? Is it a next-generation sequencing test? Where should we go? What should be introduced into practice at this point?

Strickler: In truth, there is no national standard for how to define HER2-positive disease. The traditional way to test in both gastric cancer and breast cancer is with immunohistochemistry and fluorescence in situ hybridization (FISH). There are specific criteria that have been developed to define that HER2 positivity for those two diseases. We don't have the same adopted standard in colorectal cancer. There was an attempt in Europe to create a standard for colon cancer using IHC and FISH, but it never really caught on in the United States. Interestingly, when you use the gastric criteria or the breast criteria for colon cancer, the same applies, and we see pretty high concordance between those two different scoring methodologies in colorectal cancer. The truth of the matter and the pragmatic fact is that we're generally testing for HER2 out of our next-generation sequencing tests. That's how we're usually finding it these days. It appears that there's fairly high agreement between the classic IHC and FISH assays that we're accustomed to using gastric and breast criteria and the next-generation sequencing profile. It is ambiguous how it's defined. The good news here is that it really doesn't matter at the end of the day. If you use a standardized, Clinical Laboratory Improvement Amendments–(CLIA)-certified assay, and it says it's HER2 amplified or overexpressed, odds are pretty good that the patient will benefit from anti-HER2 therapies.

Schlechter: Do we know if there's a distinction between tissue-based assays vs circulating tumor DNA (ctDNA), for example?

Strickler: There is an important distinction. With ctDNA, the commercial tests we use are also next-generation sequencing tests, but they are based on fragments of DNA detected in blood. It is somewhat trickier to detect an amplification in blood than in tissue. The interesting thing is you need more shedding or a higher tumor fraction to detect amplification in blood than you would with a typical KRAS mutation. That can make it tricky. You can trust a positive result. If it says HER2-amplified by ctDNA test, it's probably HER2 amplified. But if it's not amplified in blood, I would still revert back to tissue testing to confirm that it's not amplified in tissue. You can trust a positive result, but you really can't trust a negative.

Schlechter: Excellent. That's really helpful. That seems to be the story with ctDNA. It looks like tissue testing still has legs. Do we know of any differences in left-sided vs right sided? Clearly this is a big story in BRAF and KRAS. Are there differences in HER2?

Strickler: It's a really interesting question. There are some features to HER2-positive disease in colon cancer. Number one, it has a much more homogeneous staining pattern by the traditional IHC criteria. It stains a little bit like a breast cancer, which will be more homogeneous. Gastric cancer will be more heterogeneous. It tends to be on the left side of the colon, not the right side. Maybe around 80% of these HER2-positive colon cancers will be left sided, and those are some of the unique features of it. It also will tend to be on the IHC 3+ side of things. It's not very common to see an IHC 2+ FISH-positive result that tends to be at that higher level of expression. There are some unique features of this, and I think that explains why these anti-HER2 therapies are so active for HER2-positive colon cancer.

Schlechter: Let's talk about the MOUNTAINEER study — your study. This made a big splash, and people were excited to see the results. Can you tell us the background of that trial, what you did, and what you found?

Strickler: I'll go all the way back to when I joined the faculty. When you're joint faculty at an academic medical center, you feel like you're clinging to the cliff side. I wondered if I was going to make it in academia. My mentor at the time, Herb Hurwitz, gave me a little trial of a first-in-human phase 1 study of an anti–c-Met antibody called ABT-700. We struggled to find these patients who had MET amplification. One of the things we found out was that this tended to be easier to detect in blood as a resistance alteration than tissue. We made a partnership with a little company at the time that turned out to be Guardant Health, and we started to look for MET amplification in blood. I was looking at these patients with RAS wild-type metastatic colon cancer and finding that a number of these patients actually had HER2 amplification in blood — not MET amplification. Because we were not testing for HER2 at the time, I would go back and look at the tissue by breast cancer criteria and sure enough, they were HER2 positive all along. There were these grumblings that maybe there were these HER2 therapies that would be active. At the time, I was seeing some very intriguing data about tucatinib and trastuzumab in combination with capecitabine, and I wrote up a little one-page proposal for a tiny company in Seattle called Cascadian, saying, "Hey, your drug is new in the clinic — very active, very selective, and very well tolerated. Let's see if it's active for HER2-positive colon cancer." They got back to me in about an hour and said, "Let's talk about this. Let's see if we can put this together as a pilot." It took off from there and was a ton of fun to run. I'll give a special thank you to my colleagues. This was an investigator-initiated national study. I called up all my friends, including those at your institution, Ben, and we all pitched in as investigators. I also want to give a special thank you to the patient advocacy groups. There's a group on Facebook called COLONTOWN, and they took this trial under their wing, as well. They really got the word out there for this pretty rare alteration, saying that if you know anybody in the United States who has it, here's an amazing trial. It was an example of investigators working together as a team, patients and patient advocacy groups working together as a team, and industry giving us the tools we needed to make it happen. It was a lot of fun to get that off the ground.

Schlechter: It's such a great story. And it's funny you call it rare. I was thinking about the incidence of HER2-amplified colorectal cancer compared to, say, mismatch repair–deficient advanced colorectal cancer. How do they compare? Because when there's a big splash in mismatch repair–deficient disease, it is front page news.

Strickler: Absolutely. They're pretty similar in terms of their prevalence. We see HER2-amplified or HER2-positive disease in about 3% of patients. It depends what dataset you look at when you look at mismatch repair–deficient colon cancer. That tends to be in the 3%-5% range, as well. They're pretty comparable in terms of how often you'll see it. The good news is we test for both out of our classic next-generation sequencing panels. This really hammers home that the moment you see a patient with newly diagnosed metastatic colon cancer, order that next-generation sequencing panel. It will test for microsatellite instability, and it will test for HER2 amplification. And then, of course, all the more common variants like KRAS, NRAS mutations, and even BRAF mutations are almost similar in frequency to HER2 amplification.

Schlechter: So now back to MOUNTAINEER. What exactly did you find with this tucatinib combination?

Strickler: We initially presented the first results of what we call cohort A — that's tucatinib and trastuzumab — at the European Society for Medical Oncology Congress in 2019 and posted a very impressive response rate: 46%. Based on that result, we knew that this had the potential to become a US Food and Drug Administration (FDA)–approved standard of care one day. We transferred the investigational new drug ownership over to the company. Cascadian was acquired by Seattle Genetics, and they took it forward and turned it into a global study. In those combined cohorts, A plus B, the confirmed objective response rate was 38%, progression free survival was over 8 months, and overall survival was over 2 years. What was particularly impressive was the duration of responses. When patients responded, they responded for a long time. In fact, the very first patient we enrolled is still thankfully doing great today. This is somebody who enrolled many years ago, and we have durable complete responses even today. We see that in these very high durability of response numbers. It's an exciting breakthrough for our patients. I really appreciate the fact that it's a chemotherapy-free regimen. That was the goal at the very beginning.

Schlechter: How is it tolerated compared to chemotherapy? How are people doing on tucatinib/trastuzumab?

Strickler: Thankfully, most patients do fantastic with it. The strength of this regimen is that it's highly selective for HER2. You do see some diarrhea in about half of patients. Most patients describe it more as a nuisance and not really intolerable. It'll pop up every couple of days, and it's usually well controlled with loperamide (Imodium). Occasionally you'll see a rash with it. Very rare cases of liver enzyme elevations will lead to discontinuation. That's probably the one thing that will lead to a treatment discontinuation. We only saw that in single-digit rates, so in a very low number of patients in MOUNTAINEER. That's the main toxicity to look out for. And for a patient who's had a lot of exposure to chemotherapy, this will come as a very welcome respite.

Schlechter: I have to say, I have a patient who is still on it, and she's 2 years in. In the beginning she kept saying, "Are you sure I'm not getting the placebo?" And I said, "There is no placebo." So I know exactly what you mean. I have seen some diarrhea as well, but overall, I agree — it is very well tolerated.

Strickler: In fact, we found that one of the more common side effects was weight gain. People felt so great that they were eating and living life, and all that weight they lost with their cancer diagnosis came right back.

Schlechter: We need to add that to the quality assessments — weight gain as a sign of quality of life.

Strickler: Absolutely.

Schlechter: The other big innovation in HER2-directed therapy are antibody-drug conjugates, and in particular, trastuzumab deruxtecan in colorectal cancer, as well as in gastric cancer and breast cancer. Trastuzumab deruxtecan even got a standing ovation last year for HER2-low breast cancer at ASCO. Where does that fit into the paradigm for colorectal cancer? How do we give it? How do we dose it? Where does it stand?

Strickler: You're referring to trastuzumab deruxtecan, which is also a breakthrough for our patients with the HER2-positive colon cancer and something I've used in the clinic, as well. As a reminder, DESTINY-CRC01 results were presented 2 years ago now. And there was a recent paper that updated results from DESTINY-CRC01. There was an impressive response rate out of that initial cohort: 45%. But there were some interesting signals from that cohort. First, almost all the responses occurred in patients with IHC 3+ or the highest level of expression. I believe there was only one response in patients with IHC 2+. It seemed unlike the story we heard from last year at ASCO with HER2-intermediate and HER2-low breast cancer — it seemed like all the benefit was concentrated in patients with very high expression. Additionally, there was a very concerning signal of grade five, or fatal, interstitial lung disease or pneumonitis. Now that those data have been updated, three patients in that initial series have died, and that unfortunately reflects an unacceptably high death rate from that 6.4 mg/kg dose. It was those two issues that inspired the next trial, DESTINY-CRC02, which we just saw presented at ASCO a little more than a week ago, to randomize patients to either the higher dose, 6.4 mg/kg, or the lower dose of 5.4 mg/kg. This was done to really answer the question of what's the safest dose and what's the most active dose. And the results came as a surprise. Number one, the activity was not reduced with that lower dose of 5.4 mg/kg. We actually saw a slightly higher response rate at that lower dose: 38%. Secondly, once again, all of the responses except one occurred in patients with IHC 3+ disease. Another important finding and unmet need is that patients with RAS mutations appeared to experience significant benefit from trastuzumab deruxtecan. Now we have an option for patients who have both HER2-positive disease along with a RAS mutation. And then finally, once again, we saw this signal from DESTINY-CRC01, but it was confirmed in this latest DESTINY-CRC02 trial. Response rate appears to be identical whether or not you've had prior anti-HER2 therapies. This lays out a story for us of how to manage these patients in our clinic. The lesson, is number one, test for HER2 right out of the gate. Treat those patients with upfront chemotherapy and bevacizumab. Then, when they are in the refractory setting if they have RAS wild-type HER2-positive disease, start with tucatinib and trastuzumab, and when they progress, then you have trastuzumab deruxtecan as a backup option. If they have HER2-positive disease but a RAS mutation, go straight to trastuzumab deruxtecan. That will be our emerging paradigm for how to manage these patients.

Schlechter: Excellent. That is a super helpful summary and great story for how we landed here. When you see this pulmonary toxicity from trastuzumab deruxtecan, how are you treating it? I know we are lacking in prospective data. I'm curious to hear your particular approach here.

Strickler: When this drug came into the clinic, we turned to our breast oncology colleagues and asked them how they were managing this. Number one, they were using the lower dose of 5.4 mg/kg to start with. At the time, I was uncomfortable with the high death rates they saw in DESTINY-CRC01. So, I always adopted that lower breast cancer dose of 5.4 mg/kg. They also have a protocol that we developed at our institution where we do a baseline pulmonary function test, and then we check pulmonary function test results every 6 weeks for the first few months to look for a drop in the diffusing capacity for carbon monoxide. We're looking for signs of pneumonitis or interstitial lung disease, and we have consults built up with our pulmonary service who will support us if we see that drop in diffusion capacity. That's how we manage it at Duke. Knock on wood, I've not had problems with trastuzumab deruxtecan yet, but unfortunately, it is a known toxicity of this drug, and it's something we have to be very careful about.

Schlechter: What about the cardiac signal? I remember from my fellowship with trastuzumab and all the cardiac monitoring, are we seeing cardiac issues in the GI population? Are these patients living long enough for that?

Strickler: Historically for us, the main cardiac issues we have are cardiovascular disease and coronary artery disease, which limit our ability to give bevacizumab. Our patient population tends to be a little bit higher risk for coronary cardiovascular disease. Sometimes I've stumbled into cardiovascular disease just by virtue of the standard echocardiograms every 3 months. We did see a couple of a symptomatic left ventricular ejection fraction drops in the MOUNTAINEER study. Fortunately, they were asymptomatic and reversible. It does not appear that we see higher rates of these left ventricular ejection fraction drops in our population of HER2-positive colon cancer patients than in the breast cancer population. Fortunately, the cardiac signal has not been an issue, at least in my experience so far. I don't know if in your experience if you've had any difficulties with it.

Schlechter: No. I really haven't. I've had the same experience as you. I've been diligent about pulmonary toxicity, but I have not seen any cardiac toxicity in my personal patient population. It's a tour de force, a very impressive effort in HER2, and a fantastic summary. You seem to pick your targets well. What are the other targets should we be looking at? What's coming forward?

Strickler: Fortunately there are more targets, and I think the first — that we are in the process of cracking right now — is KRAS G12C , which interestingly has almost identical rates in colon cancer as say HER2 — about 3% of colon cancer patients have this KRAS G12C alteration. It is highly targetable with the dual KRASG12C anti-EGFR combinations. We've seen publications in The New England Journal of Medicine and presented at multiple conferences, so I suspect that combination will enter the clinic sooner than we might expect and potentially in the next year. We'll see when those data come out and we see an FDA approval. I'm also a targeted therapy proponent and very interested in KRASG12D. I do think we're on the cusp of some important therapies coming into the clinic to target KRASG12D. There is really fascinating chemistry behind this. It's not an easy target. There's a reason why it's taken so long to get to this one. Another really interesting class of drugs that I'm curious about are the pan-KRAS inhibitors. KRAS G12D is one of the more common alterations we see in the clinic, but we see G12R and G12V, so we see other KRAS variants. I would love to get my hands on those as well one day and bring them to the clinic. Almost certainly they'll be combined with an anti-EGFR therapy to deepen and lengthen the responses.

Schlechter: I'm also looking forward to the change from a neutral amino acid to a polar one we can target. But these other changes are going to be hard. I'm looking forward to hearing you come join us to talk about it.

Strickler: Yes. I can't wait.

Schlechter: Today we've been discussing HER2-amplified colorectal cancer with Dr John Strickler. We've discussed that HER2 testing should be considered in all patients with advanced colorectal cancer, and particularly next-generation sequencing options, which should be applied for all patients with advanced disease. Tissue-based assays are critical because ctDNA testing may miss the disease. IHC testing is also important, but the 3+ disease seems to be the population deriving the most benefit from this type of testing. We reviewed the data from the MOUNTAINEER study, which Dr Strickler led, and this showed that the combination of tucatinib plus trastuzumab has a high response rate and durable responses in RAS wild-type HER2-amplified cancers with a manageable safety profile. This combination has some minor GI toxicity and some transaminase elevations, which patients can tolerate with a nonchemotherapy approach. We also discussed the antibody-drug conjugate of trastuzumab deruxtecan from the DESTINY-CRC studies, and we showed that 5.4 mg/kg is both safer and as effective as the higher-dose regimen to mitigate the risk for dangerous pulmonary toxicity and concerns over cytopenias we see with other chemotherapies. And then finally, we talked about some promising targets, particularly KRAS, which I think is in many ways the holy grail of colorectal cancer as it stands now. Thank you for joining us. This is Dr Ben Schlechter for InDiscussion.


KRAS Exon 2 Mutations as Prognostic Indicators in Advanced Colorectal Cancer in Clinical Practice: A Mono-Institutional Study

Tucatinib Plus Trastuzumab for Chemotherapy-Refractory, HER2-Positive, RAS Wild-Type Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER): A Multicentre, Open-Label, Phase 2 Study

Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients With Advanced Solid Tumors

Comprehensive Genomic Profiling of Circulating Cell-Free DNA Distinguishes Focal MET Amplification From Aneuploidy in Diverse Advanced Cancers

109P – Cell-Free DNA to Detect Focal Versus Non-Focal MET Amplification in Metastatic Colorectal Cancer Patients: Combined Analysis From Japan and the United States


HER2 in Colorectal Cancer: The Long and Winding Road From Negative Predictive Factor to Positive Actionable Target

4795 – Trastuzumab and Tucatinib for the Treatment of HER2 Amplified Metastatic Colorectal Cancer (mCRC): Initial Results From the MOUNTAINEER Trial

Seattle Genetics to Acquire Cascadian Therapeutics, Adding Late-Stage Breast Cancer Program to Its Oncology Pipeline

Trastuzumab Deruxtecan (T-DXd) Versus Treatment of Physician's Choice (TPC) in Patients (Pts) With HER2-Low Unresectable and/or Metastatic Breast Cancer (mBC): Results of DESTINY-Breast04, a Randomized, Phase 3 Study

DESTINY-Breast04 Establishes Trastuzumab Deruxtecan as a New Standard of Care for HER2-Low Metastatic Breast Cancer

Final Results of DESTINY-CRC01 Investigating Trastuzumab Deruxtecan in Patients With HER2-Expressing Metastatic Colorectal Cancer

Trastuzumab Deruxtecan (T-DXd) in Patients (Pts) With HER2-Overexpressing/Amplified (HER2+) Metastatic Colorectal Cancer (mCRC): Primary Results From the Multicenter, Randomized, Phase 2 DESTINY-CRC02 Study

Targeting KRAS G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

KRAS G12C Inhibition With Sotorasib in Advanced Solid Tumors

315O – Sotorasib in Combination With Panitumumab in Refractory KRAS G12C-Mutated Colorectal Cancer: Safety and Efficacy for Phase Ib Full Expansion Cohort

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