Dr. Michael Overman:
Welcome to The ASCO Post Roundtable Series: New Directions in Metastatic Colorectal Cancer. I'm Dr. Michael Overman, I'm a professor of GI 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 at Vanderbilt University Medical Center in Nashville, Tennessee.
Dr. Katrina Pedersen:
And I'm Dr. Katrina Pedersen. I'm at Washington University School of Medicine and the Siteman Cancer Center, and I'm an Associate Professor of Medicine.
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 second case, we'll focus on second-line therapy for metastatic colorectal cancer. So this is a 46-year-old female with a locally advanced, poorly differentiated rectal adenocarcinoma. Neoadjuvant chemoradiation was given, followed by a resection that revealed a ypT4N1 tumor. Adjuvant FOLFOX was given for eight cycles, 4 months, and that ended in early 2019. Approximately 5 months later, the patient was then noted to have a number of growing pulmonary nodules. These were all sub centimeter, but in greater than 10 in number in kind of both lobes of the lung. At this point, I'll turn this over to Kate in regards to, what additional studies or kind of thoughts or approaches should we take in a patient like this?
Dr. Pedersen:
Right. In an ideal world, I'd be confirming at least the first metastasis with a tissue biopsy. Maybe some of that, the more peripheral one could... I don't know. It's pretty iffy. They look pretty small in general. I do utilize a lot of circulating tumor DNA assays in my studies, so chances are around this time with lung mets, usually when we're identifying mets, the ctDNA assays for minimal residual disease will be turning positive. They don't tend to have quite as much lead time as what I see in other sites of metastasis, but it's pretty rare that I see one that's fully negative. So that might give me a little bit more confidence. Though in this lady, it's unlikely to be too much else considering her clinical history. And then certainly, based on whatever tissue I do have on hand, I will want to send that for next generation sequencing and assess for any mutations that are relevant. I don't see microsatellite status either, so I'd want all that information to help set up the next steps.
Dr. Overman:
Yeah. Laura, I might ask you, I think it's kind of an interesting case in that we have multiple lesions, but they're all smaller. So I mean, what's your sense on that conversation with the patient on, yes, high concern, but do we watch it? Do we kind of try to engage? How do you kind of frame that?
Dr. Goff:
Sure. So this is a young patient, 46-year-old, so decreases the likelihood that something else is going on, a little bit, not completely. Also, back to the primary tumor, that T4, those T4 tumors are high risk for recurrence, even higher risk than T3 by a significant amount. So I think very concerned. I always follow the CEA as that some more circumstantial evidence. But they're tough. It's certainly a scenario where I think with 10, with the background clinical picture, especially as Kate said, if we have circulating tumor DNA and ongoing evidence of growth, you could follow. And I have some patients who opt to follow for a short interval follow-up, and I'll do 6 to 8 weeks and watch and see if it's changing. But yeah, those are tough conversations.
Dr. Overman:
Yeah, no, I think... So the patient, so we did watch for a period of time, and then actually did do a lung biopsy. I think the discussion on how success rate of biopsying small lung nodules, there's a plus, minus there. There's some risks with maybe chance of nondiagnostic. And I think also the number kind of suggested that the idea of oligo treatment modality, I'm not sure that's in the cards, because there's just so many small things. So I think we did decide to wait a little bit, and then we did go on and biopsied it, so it was adenocarcinoma. The molecular profiling exactly, we want that, and that was proficient mismatch repair. HER2 IHC was 2+, the HER2 FISH demonstrated an amplification with a copy number of 8.6. The NGS panel just had a TP53 mutation, was the only other kind of mutation on her gene panel.
And then on that follow-up restaging, the lesions got a little bit bigger and one did cross that 1 centimeter kind of threshold. So that's kind of what triggered us to say a little bit easier for biopsy. That kind of is often how close it is, but that's a threshold sometimes we utilize for biopsy or not.
But I think at this point, Laura, maybe I'll turn this back to you in regards to, what are some of the treatment options in this patient now that has multiple kind of metastatic lung spots, progressed pretty recently from the FOLFOX? So I think we would say we're kind of in that second-line setting. So what would you think about based on the profile and everything?
Dr. Goff:
Sure. So I think it's been a rapidly evolving space for the treatment of colorectal cancer. And HER2 is one of those targets that's rare but finally considered actionable. So I think our earlier studies looking at single agents were kind of disappointing, but in the past 2 to 3 years, it feels like the field has exploded. So I think it would be looking at targeting HER2. Alternatively, chemotherapy is certainly, I think, still a fair option for her with irinotecan-based therapy.
Dr. Overman:
Yeah. Kate, I think exactly, there's been a rapidly advances here where we have now a plethora of options in HER2 space, which is kind of wild. So I don't know, Kate, how do you think through some of those different combination treatment options in HER2?
Dr. Pedersen:
Yeah. And especially in a patient like this, where the timeline is a little bit tricky, because being at an academic institution, I always want to check and see if I can support any of the trials in this space, especially with such a rare mutation, or amplification. I think about 2% of metastatic colorectals might have HER2 amplification. So this lady, I'd probably say, because the lung nodules, even if they weren't biopsy proven in June because they were first seen and ultimately proven to be, I would use that argument to say that the adjuvant was frontline.
To make my life easier because the labeled indication, as of January 2023, I think, for tucatinib and trastuzumab is as second-line therapy. So I would probably angle toward that as my first HER2 treatment option, because unlike trastuzumab and pertuzumab, I don't believe pertuzumab or lapatinib technically have that labeled indication. So there's definitely that practical aspect of, "What will make me have to fight less to get this regimen for the patient?" And of course, ensuring that their RAS wild-type, as this patient is, is an important consideration. If they were RAS-mutated, I would go with more of a second-line standard chemotherapy option as these HER2-targeting TKIs don't appear to have efficacy in the RAS-mutated population.
Dr. Overman:
Yeah, no, I think you're right. I mean, I think guidelines give us now that the trastuzumab/pertuzumab, pertuzumab/lapatinib, pertuzumab/tucatinib, so we have these options. And I think your rationale makes a ton of sense. I think we have a lot of cross-trial comparisons, and that's kind of all we have. So which one to pick, I'm not sure there's a clear-cut efficacy-based answer to that, though there's ongoing data that's being collected.
So it did turn out this patient did actually go on a clinical trial. There was the SWOG 1613, which was a randomized trial of irinotecan/cetuximab vs trastuzumab/pertuzumab. So the patient went on that and got randomized to the irinotecan arm. Interestingly, actually, was on the irinotecan arm for over a year, which was kind of an interesting event. So kind of a statement of the need to do randomized studies, I think, is kind of what this case alluded to. And then got crossed over to trastuzumab/pertuzumab and was on that for almost a year as well, so had a very good kind of response to that, HER2 targeting after more of the classic second line.
But I would kind of agree, I think HER2 is kind of become more of that second-line space in this kind of molecularly selected HER2 kind of category. I think now though that we have a progression now on the initial trastuzumab/pertuzumab, I might turn it back to you, Kate, and see what thoughts you'd have for next kind of treatment options here.
Dr. Pedersen:
So since the DESTINY-CRC001 trial of the ADC (antibody-drug conjugate) trastuzumab deruxtecan was performed showing that in a HER2-positive population, you can use the HER2 not really to shut down growth signaling, but more as kind of the target to deliver a payload to these malignant cells since it's more prevalent on their surface. And in that study, I think that what was unique about that compared to pertuzumab and lapatinib and tucatinib is that they did allow people who had previously been on one of those agents to be on that trial and they still showed a response to that therapy. So in this day and age, in these rare cases where I see a HER2-amplified metastatic colorectal, that is kind of the second-line agent I tend to go towards, just because the ILD toxicity concerns me and there isn't really any proof of second HER2 line of therapy efficacy for the TKIs.
Dr. Overman:
I think ILD, interstitial lung disease, which is, I think, a unique toxicity from trastuzumab deruxtecan. Laura, I mean, what would be the other kind of, I think, treatment options just to round out the discussion for this patient? I think the continued HER2 targeting of trastuzumab deruxtecan, I think I would agree, that makes sense. I think a high response rate in that setting. But I'm just curious, what would be some of the alternatives, just to compare to why we maybe chose that?
Dr. Goff:
Sure. Yeah. I think that getting at your point about cross-trial comparison is difficult, but the response rates being significantly higher. Because, of course, otherwise, as this patient has already received both FOLFOX and irinotecan/cetuximab hasn't yet had an exposure to bevacizumab, so that I think you could think about a capecitabine/bevacizumab as an option, or certainly TAS-102 with bevacizumab, or even regorafenib. But the response rates for all of those regimens are going to be significantly lower than what looks to be coming out of continued HER2 targeting.
Dr. Overman:
Yeah, no, I agree, and I think alluded to a little bit, I think trastuzumab deruxtecan also is unique in that it can work after TKI targeting and antibody targeting of pathway suppression, but also in RAS-mutated. That's kind of another setting where I think there's some unique activity where we don't see that with some of these other combinations.
So I think to conclude this case, some of the key clinical takeaways, our second line really there are a lot of decision-making, I think, options in regards to patient preferences, extent of disease. The genomic profile really is starting to factor in heavily into that space, as you heard today. And then the efficacy safety kind of profile those treatments, which we talked about a bit. HER2 amplification expression is an actual target for second-line metastatic colorectal cancer. And that's really, I think, important for us. Trastuzumab deruxtecan, again, has activity in patients that have prior progressed on anti-HER2 therapy, as demonstrated in this case. And that is what this patient went on to following that progression on trastuzumab/pertuzumab.
