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Dr. Michael Overman:
Hello, welcome to The ASCO Post Roundtable Series: New Directions in Metastatic Colorectal Cancer. I'm Dr. Michael Overman. I'm Professor of GI Medical Oncology at the MD Anderson Cancer Center. Joining me today are two of my colleagues.
Dr. Laura Goff:
Hi, I'm Dr. Laura Goff. I'm a Professor of Medicine at Vanderbilt-Ingram Cancer Center and Vanderbilt University Medical Center.
Dr. Katrina Pedersen:
And I'm Dr. Katrina Pedersen. I'm an Associate Professor of Medicine at Washington University in St. Louis and the Siteman Cancer Center.
Today we'll be discussing updates in the treatment of metastatic colorectal cancer and integrating these new developments into three patient case studies. Our first installment will focus on front-line therapy for metastatic colorectal cancer. So case 1 is a 77-year-old male with a history of resected prostate cancer, and now presented with rectal bleeding. Colonoscopy demonstrated transverse adenocarcinoma to resected at T3, N1, M0, localized tumor. The patient initiated four cycles of adjuvant FOLFOX, but then during adjuvant therapy, developed chest pain, which led to a CT scan to rule out pulmonary embolus. And that actually demonstrated left supraclavicular adenopathy as shown there on the image. So I'll turn it over to the panel and I'll ask, what would be the next steps in regards to the management of this patient? So Laura, do you want to start off?
Sure. So I think this is pretty unusual, getting progression in the middle of adjuvant therapy. Thankfully most patients will do well. But wanting to confirm that this is metastatic colorectal cancer, first. Assessing that with pathology and other testing. But assuming this is metastatic colorectal cancer, we're going to need to know some of the molecular findings for that.
Great. Kate, any other thoughts?
Yeah, no, I really agree with everything that Laura said and especially considering he has had other primary cancers in his past. Even though supraclavicular lymph node is much more likely to be of GI origin than prostatic, I think it's really wise to get that tissue.
Yeah, agree. I think I always debate this issue, but I think if you debate it long enough, you just do it. Right? It's kind of the question I often tell some of our trainees. So biopsy was done, which was adenocarcinoma, CDX2+, CK7-, CK20-, a little bit unusual pattern. And then the molecular did reveal loss of MLH1/PMS2, with MLH1 methylated. So kind of a sporadic deficiency and mismatch-repair. There was an NGS panel that did demonstrate BRAF V600E and then some other mutations and full staging actually demonstrated liver and adrenal metastasis. So Kate, any thoughts on the testing results there and how that fits into the case?
I mean, when a patient does progress on early cycles of adjuvant therapy, it’s usually either that metastatic disease was not identified in the beginning or this exact case, where they’re microsatellite unstable or have deficient mismatch repair as we see here, and they tend to be more chemo-refractory. So this certainly fits the picture overall, for me. One thing that I always think about with these, in selecting the next line of therapy, is certainly, what is the MMR status, what is the RAS, what is the RAF, as primary considerations in treatment selection? And here whenever you see a BRAF V600E, I think in this day and age, with targeted therapy that's been approved for that, we tend to think of as a knee jerk, of going toward that. But with MSI-high disease, really all other mutations to me are passengers and it is that loss of MLH1, PMS2 and the microsatellite instability that results, that's the driver. And so that's typically the target I'll go for, will be immunotherapy for that.
Yeah. Laura, what do you think about next treatment options here for this case?
Sure. So yeah, I think we're always very excited for our options, when we find a patient who has microsatellite instability because the targeting treatment, as Kate said, with immunotherapy is really important. Of course, immunotherapy is not without toxicity. So I believe this is a 77-year-old who has been through some stuff, it sounds like. And so I think the decision we're faced with, is single vs doublet immunotherapy. You always want to have a shared discussion with patients. We don't have really clear guidance, whether or not two vs one is going to be ultimately better, even from other diseases, I think it's still debatable. So I am generally a fan of maximizing quality of life for patients, but having a discussion with them. So I think for this patient, I probably would encourage single agent immunotherapy in a 77-year-old, but certainly thinking about that. So pembrolizumab I think is what is FDA approved. Probably all of the agents have some degree of activity, but that's often the direction we would go.
No, it sounds great. I think in this case, the patient did initiate on single agent nivolumab. Actually it's a little interesting from this case, it's one of my cases. The patient had a lot of pain actually, from the lymph node and very quickly the pain actually got better after initiating therapy. I think there can be sometimes quick responses to immune therapy that I am always kind of impressed by, it turns out. But very quickly, within a few weeks that kind of pain resolved. There was a decision-making in radiation vs immune therapy and we did immune therapy and actually solved the symptomatic issue really quickly with just the systemic therapy.
So the interesting part in this case, is after a year of therapy, the patient had a very nice partial response and then developed actually progression at the two adrenal lesions. So all the supraclavicular area, the liver got better, the one initial adrenal got smaller and then started to grow again and the other adrenal started to grow again. And so had a very kind of interesting, isolated, bilateral, adrenal progression, which was kind of unique in character. And so open it up to either of you, in regards to thoughts on how we should approach it this time now. So progression, I think adaptive resistance, progression on single-agent nivolumab. So maybe Kate, I'll turn it back to you.
So in theory, we should consider switching to a second-line agent, but in reality, when I've been in these situations in the past, when it has been an isolated met with otherwise good control, there have been some instances, especially with Krukenberg metastases down at the ovary, which just tend to be more refractory, I tend to send them for a laparoscopic resection. And in those cases, actually, there've been multiple times, where it's been completely necrotic.
So even though it was an enlarging mass and appeared to be progressing, we found actually, it was an ongoing great response and all that necrosis was driving that change. So this might be one of those times, where I wouldn't go to an adrenalectomy per se, but it might be worth considering a biopsy if it's safe to do, just to see if there does appear to be any viable residual tissue, before I make a move. And if there is, again, with isolated progression, this isn't really a standard of care approach, but I might think about minimally invasive localized therapies including SVRT or something to them. But also, switching to second-line systemic, is fine.
Yeah. Laura, any other comments?
I think the only other thing is, I think now I recognize that this is just a few years ago, but things have changed rapidly. Now, I think a sampling for if there's been any change in a peripheral blood, molecular profile, identifying additional targets, I think is interesting. But yeah, I totally agree with Kate, that we are targeting isolated sites of metastasis in directed ways, in ways we wouldn't have thought of doing 10 years ago.
I'm not going to lie, in these situations since CheckMate 142, there are literal times, where I think, "What would Mike do?"
Well, it is my case, so there is a little bit of, "Let me tell you what we did." To some degree here. But I think all good points, right? I mean I think it is interesting and on the molecular side, the fusions tend to be higher in MSI-high and tend to be higher in the sporadic patients. So could there be a fusion that'd be targetable? Would be an interesting question in this case. Right? And then, could you second-line therapy or add in the CTLA4 question, do you double down on immune therapy? I think there's a lot of different interesting questions. I will say in this case, it was very interesting in that, other sites were better. We did biopsy and it was actually proven to have viable cancer. And so we actually decided to do radiation to both adrenal glands. So we radiated both adrenal glands and then just continued the nivolumab for another 2 years, from that point.
And then the patient has stopped therapy and since that time has been NED and fine since we stopped therapy many years ago. And so a case, that clear kind of isolated progression that you can kind of treat and then get away with just the same therapy in a way. And I do think in the immune progression that's adaptive, I think there is some interesting patterns there, where you do see, for some reason, a few sites that seem to progress, but the other sites are already kind of taken care of. I mean, we see some of that experience in the metastatic setting, where you go in, there's something still there and it's past DR, right? And so I think there is some interesting progression patterns that we see in the response to immune therapy, that's different than our classic chemotherapy. Chemotherapy progression, tip of the iceberg, kind of phenomenon.
So I think to conclude this case, I would just finalize with the key clinical takeaways. And so I think pretty fundamental, that all patients with colorectal cancer should have MMR testing. I think our initial treatment decision making for metastatic colorectal cancer, really requires that MMR testing. I think luckily, we can get that quickly with immunochemical testing and so you don't have necessarily wait for your NGS panel though I think all of us would say, an NGS panel is needed for treatment decision making.
And then for metastatic deficient mismatch repair colorectal cancer, there's both monotherapy and combination therapy, which have high activity. And I think that, as was alluded to by Laura, that's really I think, a decision making, based on the patients, in regards to which choice do you want to do. And then I think this adaptive progression can also prevent as oligo sites of disease and local therapy, I think a little bit anecdotal at this point, but I think is something that can be considered in the immune therapy progression space, which is a little different than classic chemotherapy progression space.
I think with that, I think we'll end this case. And so I think this brings us to the end of the case. Please see the other segments for further discussions about the latest data in colorectal cancer or visit, ascopost.com.