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Dr. John Strickler:
Welcome to The ASCO Post Roundtable Series on targeted therapy for colorectal cancer. I'm Dr. John Strickler, Associate Professor of Medicine at Duke University Medical Center. Joining me today are two of my colleagues, Dr. Stacey Cohen and Dr. Harsh Singh. If you could both introduce yourselves.
Dr. Harsh Singh:
I'm Dr. Harsh Singh. I'm a GI medical oncologist and an instructor of medicine at Dana-Farber Cancer Institute in Boston.
Dr. Stacey Cohen:
Hi, I'm Stacey Cohen. I am Associate Professor in GI Medical Oncology at the Fred Hutchinson Cancer Center and University of Washington in Seattle.
Today we will be discussing the evolving targeted treatment landscape for colorectal cancer and integrating these new developments into three patient case studies. Our first installment will focus on HER2-positive metastatic colorectal cancer, and I'll start with a case from my clinic.
So this is a 49-year-old man who presented to the emergency room with nausea, vomiting, and abdominal pain. A CT scan of the chest, abdomen, and pelvis revealed a bowel obstruction, extensive hepatic metastases, and abdominal lymphadenopathy. Colonoscopy revealed a partially obstructing mass in the sigmoid colon and unfortunately, his performance status was poor. Molecular testing was ordered. And here are the results of the commercial tissue next generation sequencing panel. We see classic APC and TP53 mutations, but also here was an ERBB2 amplification.
So, Dr. Cohen, here's a patient in your clinic who has pretty large disease burden. What would you think about doing next for this patient?
I think it's a great question. In these patients that we don't think would classically tolerate chemotherapy, it really allows us to open up some options that we might have reserved for later lines. So I think it is intriguing this idea with ERBB2 amplification about potentially doing HER2-directed therapy. Of course, as you know, there's way too many options now and we haven't really had good head-to-head comparisons, but especially with some of the data that you've shared, I think this tucatinib/trastuzumab combination would be where I would go next for this patient.
Thanks. Thank you. And, Dr. Singh, the patient made it easy for me because he absolutely refused to take chemotherapy. We were able to address the obstruction. He had a diverting colostomy, so thankfully he was at least not at risk for obstruction, but he was struggling with very high disease burden. And I think that this would be a situation where it would be unclear whether it would be even safe to give chemotherapy in this setting. What would you be thinking about when you think about the landscape of options and what our NCCN Guidelines say? What would you be thinking about and what would factor into your decision for this patient?
Dr. Strickler, these cases are never easy. I think when I look at patients and evaluate patients who have a high disease burden, I try and go for a regimen which would have a highest chance of inducing a response, try and debug the disease as much as possible. Outside of chemotherapy, looking at HER2 therapies, I think we've had now several regimens which have shown activity starting with trastuzumab lapatinib, which was tested in the HERACLES trial, showing a response rate of around 28% in patients who had refractory disease. There's trastuzumab plus pertuzumab, which has been looked at in MyPathway studies, which shows a similar response rate.
And then I think more recent data, which is quite encouraging around improved responses with trastuzumab/tucatinib and trastuzumab deruxtecan. I think the challenge is that they've never really been compared head-to-head, and I think so it makes in some ways the decision of picking a regimen quite challenging. I would think about a non-chemotherapy option and I would lump an antibody drug conjugate with a very potent cytotoxin like trastuzumab deruxtecan a little bit more with having higher toxicity. So I think I may shy away from that in a patient who has a poor performance status.
Oftentimes when we're looking for options, we're trying to get access to therapy. Some of these therapies are not approved. The only FDA-approved therapy at the moment would be the tucatinib/trastuzumab combination. At the time this patient was treated, there were no FDA-approved options and I was able to get off-label access to trastuzumab/pertuzumab, which I think in his case was ideal in that, number one, we could get access to it. Number two, it was a non-chemotherapy-containing regimen and he initially started treatment and his liver disease stabilized. His liver enzymes normalized and he was doing well. The CEA was falling, not rapidly, but it was falling. But then he developed some balance issues. I obtained a brain MRI and unfortunately he was diagnosed with new brain metastases, and they were resected and he received radiation to those brain metastases.
So, Dr. Cohen, now we've got a situation with a patient who has HER2-positive disease. Thankfully he's medically stabilized now, but he has, essentially, failure of trastuzumab/pertuzumab in the brain. Wanted to get your thoughts on how that impacts your decision-making now.
Brain metastases, while very uncommon, are obviously very severe in both their morbidity and mortality as well as the impacts on treatment decision-making. I think we benefit when we have neuro-oncology specialists that we can rely on, including medical oncology surgeons and radiation oncologists that are able to really tailor regimens specifically to the brain. Unfortunately, a lot of our agents don't have the CNS penetration that we might need, especially when we're thinking about targeted therapies. And so typically, depending on what the patient has, if they have more isolated brain metastases, we might try to do resection if it was necessary or maybe SBRT to those brain metastases, or if they have a limited number, try to avoid whole brain radiation therapy unless it's absolutely necessary. But I typically would give something targeted to the brain with the idea that I'm not sure that the systemic therapy is going to stabilize the CNS metastases as much as we would like.
Dr. Singh, are there certain anti-HER2 regimens that may penetrate the central nervous system better?
Yeah, this is a really interesting presentation in sight of failure of disease. If we take a look across HER2-positive disease across different diseases, including gastroesophageal cancer, breast cancer, there seems to be something unique about the HER2-positive subsets that they tend to metastasize to the brain more. At least in the GI oncology space, even though it's starting to be recognized, I think, we have a dearth of literature of what agents to use. I often end up talking to some breast oncologists who see a lot more of these. And I think the couple of regimens which have shown activity with CNS disease would be tyrosine kinase inhibitors. So tucatinib and trastuzumab would have good CNS activity. More recently, at least in breast cancer, which is HER2-positive, trastuzumab deruxtecan has shown reasonable CNS activity. So I think those would be two regimens I would think about.
So that's exactly what happened here. I mean, pertuzumab is a large molecule, so it is not thought to have as much penetrance into the brain. So he was switched from trastuzumab/pertuzumab to trastuzumab/tucatinib. And on that, over 3 months, his CEA fell from over 1,700 down to 25. Tolerated treatment extremely well, had a significant reduction in his liver disease. As shown here, you can see one of these liver lesions was cut in half during that period of time. So overall just did extraordinarily well on that regimen. But we know that treatment failure and treatment resistance is always a possibility. So, Dr. Singh, what would you think next if this patient experiences progression on tucatinib and trastuzumab?
That's a really interesting question. I think, again, I would borrow a little bit about my experience from treating HER2-positive gastroesophageal cancers where one of the observations has been that HER2 tends to be lost. And I think that's something I would definitely check for. Even though we don't quite know whether that happens in colon cancer, I think that's something which would be important to confirm. If the tumor continues to express HER2, I think data from the DESTINY-CRC trial would suggest that patients who've had prior HER2-directed therapy tend to respond at least equally well in small numbers, with the caveat of small numbers. I think they have an equal response rate to trastuzumab deruxtecan. So that would be an agent I would think about, as long as I can confirm persistence of the HER2 positivity.
I think you're bringing up a good point that we're still learning about methods of resistance and these mechanisms and trying to understand what are those pathways, because what works for one HER2-positive patient might dismally fail in another. And while there are many options, I think that they're overlapping in the patient population, largely HER2-naive. And now as we have so many therapies, we're in the more difficult situation of thinking about sequencing of therapies and how we can continue to use targeted treatments.
It's so true. And one of the unique things about trastuzumab deruxtecan, which has been mentioned prior, is that it appears to have a very comparable response rate whether that patient has had prior anti-HER2 therapy or not. So it does suggest that it is a good fallback plan, a plan B for many patients. And so it's important to have that one in our arsenal as well in case the patient does progress but still retains that HER2 expression.
This is an important development in the management of metastatic colorectal cancer. HER2 amplification or overexpression is an actionable target in our patients with HER2-positive metastatic colorectal cancer. There are several anti-HER2 therapies that have demonstrated efficacy and are in our guidelines. We have trastuzumab and tucatinib, which is FDA-approved, has high response rates in PFS with favorable tolerability. Also, trastuzumab deruxtecan, the antibody-drug conjugate also has a high response rate and appears to retain its activity after progression on prior anti-HER2 therapies, at least as long as HER2 expression is still present. And ultimately, we'll need to individualize this to the patient in front of us based on clinical and genomic characteristics, the efficacy of those drugs, and then also the safety profile.
This brings us to the end of this case. Please see the other segments for further discussion about latest data in colorectal cancer or visit ascopost.com.