Dr. Cathy Eng:
Welcome to The ASCO Post Roundtable Series on Updates in Colorectal Cancer. I'm Dr. Cathy Eng from Vanderbilt Ingram Cancer Center. Joining me today are two of my colleagues. I'll let them introduce themselves.
Dr. Arvind Dasari:
Hello, I'm Arvind Dasari. I'm a medical oncologist in the Department of GI Medical Oncology at MD Anderson Cancer Center.
Dr. Smitha Krishnamurthi:
And I'm Smitha Krishnamurthi. I'm a GI oncologist at Cleveland Clinic.
Dr. Eng:
Thank you so much for joining us. Today, we'll be discussing recent updates in colorectal cancer and integrating these new developments into four patient case studies. Our third installment will focus on HER2-positive colorectal cancer.
So this patient is a 45-year-old gentleman who's never had a prior colonoscopy. He presents to his primary care physician with a change in bowel habits. Alternating with diarrhea and constipation for the past six months, and periodic blood in his stool. He's lost about 10 pounds over the past year. He is an engineer and he works full-time. His ECOG performance status though, has declined to 1. His past medical history is non-contributory. Family history, mother had breast cancer at the age of 72. He's married. He has two young children, both are healthy. And he has one sibling who's younger than himself, but is also healthy. On a review of systems, his only complaint is right shoulder ache, which he attributes to degenerative joint disease for the past three months. On examination, he's slightly overweight, but in no apparent distress, and his conjunctiva was slightly pale.
His hemoglobin was 10.2. His CEA ended up being elevated at 133, and his LFTs were with the normal limits. A colonoscopy was conducted, and rebuilding non-obstructing tumor located 16 cm from the anal verge. And the CT scan demonstrates some nonspecific subcentimeter lung nodules, but CT scan of the abdomen and pelvis reveals bilateral liver metastasis, with a primary rectosigmoid carcinoma with bulky adenopathy. And this is his baseline imaging. On the left, is his primary tumor. And you can see there's some associated significantly bulky perirectal adenopathy, and unfortunately on his diagnostic imaging, he has fairly significant tumor burden to his liver.
He's very anxious. He's young. He wants to initiate treatment as soon as possible. In retrospect, as mentioned earlier, he's had symptoms for the past 6 to 12 months. Next generation sequencing has not yet been completed. He's come to you as a second opinion. The tumor is MSI stable, by IHC at the outside facility. He's been recommended to start FOLFOX plus bevacizumab by his outside physician. And he's here in your office for a second opinion regarding treatment options. So what treatment options would you consider in this patient? Where you're now sending off his NGS testing and it's currently pending, and you've seen the degree of liver involvement.
So, my patient decided to transfer his care to our institution. And because the degree of tumor burden in his liver, I opted to provide treatment with FOLFOXIRI plus bevacizumab. And I'd started it at least for one cycle. And this is based upon the prior phase III TRIBE data. However, his NGS has returned a few weeks later on. His APC is very standard. RAS wild type. BRAF wild type. But he tends to be, it's noted, I'm sorry, is he's HER2-positive. And what are your thoughts with continuing this patient's current therapy? So I would just be curious then Arvind, you've given him one cycle of FOLFOXIRI and bev, because he's so anxious. He's got quite a bit of disease in his tumor burden, but you see he's HER2. What do you do now? Would you continue his current treatment? Or would you pursue considering— Let's say a clinical trial is not available at this time.
Dr. Krishnamurthi:
Yeah, Kathy, I think that in light of the HER2 positivity, that suggests he will not benefit from anti EGFR-antibody, which otherwise could have worked well for him if he didn't have that HER2-positive status. So, I think I would continue the FOLFOXIRI and bevacizumab if he's tolerating that.
Dr. Eng:
Dr. Dasari, thoughts?
Dr. Dasari:
Yeah. Completely agree. Unfortunately, even though he has a left-sided tumor, given that he's HER2/neu amplified, probably no on anti-EGFR therapies. So, continue on current therapy for now.
Dr. Eng:
And that's why you were both my friends and colleagues. So, I opted to continue the patient on FOLFOXIRI plus bevacizumab. He was on treatment give or take about six months with a periodic treatment breaks, and then was placed on maintenance treatment at the, just because it seemed appropriate to switch to maintenance. And he was developing a little bit of grade 3 neuropathy and fatigue towards the 6-month mark. And so he was on 5-FU and bevacizumab. He continued to have non-specific sub sonometer lesions of the lungs, bilaterally. And unfortunately then developed bone mets, the right eighth and ninth rib, his ECOG performance status still remains stable at 1. He's now seeking your advice about treatment options. So you've actually tested his HER2 status, and confirmed it to be 3+ by IHC. What would you recommend for next steps in treatment?
And I bring this up because there was some recent data from one of our recent meeting of the G.I. ESMO meeting. And I wanted to mention to our audience that although the patient is RAS wild type, as mentioned by Dr. Dasari and Dr. Krishnamurthi, these are patients we won't necessarily consider for anti-EFGR therapy. There's been data that's shown that HER2 amplification, and RAS, and BRAF wild type tumors, even though they're RAS wild type may be a predictive biomarker for poor progression-free survival if given anti-EGFR therapy. And basically, this demonstrates that even though the patients may be wild type RAS and BRAF, they should be screened for HER2 amplification before consideration of any anti-EGFR therapy. We also have data from the recent published HERACLES trial, that showed that targeting HER2, was a successful therapeutic strategy in patients with treatment refractory disease, with HER2-positive metastatic colorectal cancer.
And in fact, they had some very nice responses. And even a reported, complete response in this heavily pretreated patient population. So, I just want to touch upon the data from the newer study real quick. Just highlighting some key points. It was presented at the World G.I. Congress meeting, in Barcelona, just hot off the presses a few weeks ago. So this was specifically in patients, and this is called MOUNTAINEER, that had received at least two or more lines of therapy. They had to be HER2-positive based upon local testing by IHC, NGS, or FISH. RAS wild type. They had to have measurable disease. And basically this is looking at Cohort A, which is looking at tucatinib at 300 mg, BID, and trastuzumab. And then patients were then randomized to tucatinib alone (Cohort C) versus tucatinib with trastuzumab (Cohort B). And the consideration of trastuzumab as well. The primary endpoint here is confirmed overall response rate. I'm sorry, this is Cohort A and Cohort B. I apologize. Secondary endpoints, including duration of response, progression free survival, and overall survival.
And basically when you're looking at the two cohorts, which was a total of 84 patients versus the Cohort C arm, which was monotherapy. They're fairly equivalent in regards to age; in regards to sex, there were more males in the combined cohort arm, but equivalent for Cohort C. Really, the main thing was for left sided tumors and rectal tumors. There was slightly more, 90% versus 84.5% for the monotherapy versus a combined arm. And then in regards to patients with liver metastasis, that entry a little bit higher in the Cohort A and B arm. And then lung metastasis only fairly equivalent between the two. What was quite impressive basically for the combination is, there were some CR's, as you can see here. There were three CR's as noted here, and some very near CR's, as you can see by the degree of response. And in addition, I think this was what was most impressive to many of us, was that the progression free survival was 8.2 months.
And then the overall survival in this previously treated patient population. Please keep in mind, HER2 positivity is extremely rare. It's less than 5% of our patient population. And so, that's why it's so critical to test for this patient population. The overall survival for these patients was reported at 24.1 months. So, it's quite impressive based upon these findings. And I guess I would love to hear the thoughts of these results. You know, how would this apply to your practice and what are your take home points from this, from your perspective? Dr. Dasari, and Dr. Krishnamurthi?
Dr. Dasari:
Truly compelling results and very exciting. I must say, as impressive as the response rate is, I think the median PFS, and more so the median overall survival are truly, spectacular. I think it adds to the body of literature supporting the use of anti-HER2 therapy in patients with HER2/neu amplification and colorectal cancer. There are several of these regimens available. I think the unanswered question is, which of these regimens would be best suited? I'm curious to get both of your perspectives. But I think it's hard to figure out what the best doublet would be. Any of these would be reasonable and perhaps saving the antibody-drug conjugate for next line of therapy in these patients that is trastuzumab and deruxtecan.
Dr. Eng:
And you have a very valid point. I didn't mention deruxtecan because I personally would like to reserve it for my back pocket. Because it does show activity in patients that have been previously exposed to trastuzumab. Smitha. I would love to hear your input regarding the MOUNTAINEER Study.
Dr. Krishnamurthi:
Yeah. Thank you so much, Kathy. I also was so impressed by these results. Considering these patients have had disease progression on standard chemotherapy. And then with this treatment, having a median survival of 2 years, was really quite impressive. And just as Arvind has pointed out, what is the best regimen, is really not known unless you have a head-to-head comparison. In other studies, enrolled patients who had already had HER2-directed therapies, some of these studies. So, we shouldn't make cross study comparisons. But certainly this data's very impressive. And the treatment was tolerable. And I thought that was an excellent point you made, about the trastuzumab/deruxtecan having, impressive activity in previously treated patients. And it also has interstitial lung disease toxicity. Which you know, rarely can be fatal. So, I think I would use that as a second line option. And I would be using this tucatinib/trastuzumab as the first HER2-targeted therapy.
Dr. Eng:
Thank you so much. So my key clinical takeaways from this data is, number one, HER2 positivity is, once again, a very rare patient population. Less than 5% of our metastatic colorectal cancer patient population. Prior studies have demonstrated the association of HER2 positivity and anti-EFGR resistance. So we really encouraged testing. HER2 positivity by IHC, or 2+ and FISH amplification, correlates with degree of response. It was noted actually in the original HERACLES trial, that if you are 1+ or 2+ by IHC, those patients did not appear to benefit as much from response with treatment. And the role of HER2 continues to develop and has been validated, I think really based upon several of these small phase II studies, granted, once again, it's a rare patient population with notable response and PFS in heavily pretreated patients.
Really this demonstrates the significance of testing patients by NGS and participation in a clinical trial, which we would encourage. Because here we have some really unique findings. And so I think that this is a great opportunity for further work in this field. And I'd love to see whether or not this gets FDA approved based upon these findings. I'm sure we'll figure this out at some point, a lot of discussion.
So this brings us to the end of this case. Please see the other segments of further discussion about the latest data in colorectal cancer or visit ASCOpost.com.
