Dr. Cathy Eng:
Welcome to The ASCO Post Roundtable Series on Updates in Colorectal Cancer. I'm Dr. Cathy Eng at Vanderbilt Ingram Cancer Center. Joining me today are two of my colleagues.
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, medical oncologist in the Department of Hematology and Oncology at Cleveland Clinic.
Dr. Eng:
Today, we'll be discussing recent updates in colorectal cancer and integrating these new developments into four patient case studies. Our final installment will focus on MSI-high rectal adenocarcinoma first, and then MSI-stable rectal carcinoma. This case is a 62-year-old gentleman with a history of altered bowel movements leading to a colonoscopy revealing a large fungating non-obstructive tumor 6 cm from the anal verge, biopsy consistent with adenocarcinoma. MRI of the pelvis demonstrates a tumor 6 cm from the anal verge and 4 cm in craniocaudal length. The tumor invades the mesorectum, and there are enlarged mesorectal and superior hemorrhoidal lymph nodes. No EMVI is noted. The mesorectal and CRM margin is greater than 2 mm, so it appears to be a T3a node positive tumor. CT chest and abdomen did not reveal any evidence of metastatic disease. And the CEA was unremarkable.
Immunohistochemistry reveals deficient mismatch repair tumor with loss of MLH1 and PMS2. Further evaluation reveals MLH1 promoter hypermethylation, and BRAF V600E mutation demonstrating that this is basically a sporadic colorectal cancer that is developed, and this is not consistent with Lynch syndrome because it is a BRAF V600E mutation, the positivity in an MSI-stable, I'm sorry, MSI-high tumor. He inquires about treatment options that may omit radiation and/or surgery, because he's read a lot of information on the internet and he's very curious as to what his options are. Dr. Dasari, would you like to elaborate upon the current landscape in deficient mismatch repair rectal carcinoma at this time and your thoughts?
Dr. Dasari:
What we know from small retrospective studies is that patients with MSI-high or deficient mismatch repair rectal cancer may not respond adequately to neoadjuvant chemotherapy, although they may respond fairly well to chemoradiation. And given the activity that we've seen for immunotherapy, PD-1 and CTLA for antibodies and MSI-high cancers, then the question is, what is the activity of these agents in MSI-high rectal cancer? There's a study presented by Dr. Cercek and colleagues at ASCO this year that generated a lot of excitement. This was a phase II study of dostarlimab, which is an anti-PD1 monoclonal antibody in patients with deficient mismatch repair or MSI-high stage II, III rectal cancer. And this was supposed to be a two stage design, but the results were presented after the first 16 patients were enrolled. Given how compelling the data were, what they noted was that, the patients who were valuable at the time of presentation of the data, so that was 12 patients, all these patients had a clinical complete response, and none of these patients actually required subsequent chemoradiation or surgery that was part of the original study design. So, they're truly compelling data.
Going back to the patient's case that was presented. This is a patient who was actually enrolled on a clinical trial done here at our institution. And this was a trial of neoadjuvant pembrolizumab in patients with localized or locally advanced MSI-high or deficient mismatch repair solid tumors. This trial was led by doctors, Ludford and Overman. Patients received a neoadjuvant pembrolizumab and were evaluated after a couple of doses for clinical benefit. And those who got benefit were allowed to receive adjuvant pembrolizumab, and they could go on to get surgery if they had continued response or could continue on therapy for a total of 1 year on pembro.
The primary endpoint was pathological complete response. There were several secondary endpoints, including overall response rate and organ-sparing at 1 year for patients who declined surgery. Of the 35 patients who were enrolled, about 14 patients underwent adjuvant surgical resection and 19 patients did not, with about 9 of these 19 patients receiving only pembrolizumab and having good response. And another 9 patients or so was still on therapy at the time of presenting data.
The overwhelming majority of patients had GI cancers with about 75% of these having colon or rectal cancers. Looking at the results, in patients who underwent surgeries, out of the 13 patients who were valuable for pathological response, about 70% had pathological complete response, so the vast majority did have complete response.
Looking at the overall radiographic response, again, this was very, very high with several patients actually having complete radiographic response as well.
Overall, these data suggests that the response to immunotherapy in these patients with localized or locally advanced MSI-high tumors is very high, both radiographically as well as in terms of pathological response in those who undergo surgery, both these data trials are single institution trials. So, we would need larger multi-institutional data trying to replicate these results. And also as we've seen, perhaps not everybody may have a complete clinical or pathological responses we've seen in the trial that was conducted at our institution. So, what is the role of more intensive immunotherapy with dual checkpoint inhibition would be the question. And this trial question is being addressed by the ongoing EA2201 trial, which is a phase II study of neoadjuvant nivolumab plus ipilimumab in patients with MSI-high rectal tumors. Patients would be treated with this combination and evaluated and, pending a proposed amendment, they would receive radiation and or surgery as needed. This trial is being led by Dr. Ciombor and Dr. Eng. So, maybe I'll turn it over to her to comment on additional details of this trial.
Dr. Eng:
Thanks so much. I think it's really important to keep in mind, and Smitha, please chime in as well. It's really important to keep in mind that the MSI-high rectal patient population is also extremely rare, it's less than 5% of all patients. And I think the data from the Memorial Sloan Kettering group is very provocative. Obviously it's 100% response rate with a medium follow-up thus far of 6 months.
I think one of the challenges for many of us moving forward, and I hope we'll learn more through the ECOG 2201 study is, how do you evaluate clinical complete response? So, I think that's extremely challenging in the community because not everybody is going to be able to undergo a dedicated MRI of the pelvis adequately versus a high-volume institution versus what is available in the community in which endoscopic ultrasounds are still commonly done.
Smitha, I'd love to get your opinion regarding what you think about the role of IO therapy. I really do think that the MD Anderson data and all MSI-high tumors is also very interesting, but it clearly shows that it wasn't 100% CR2, so I do find it very provocative.
Dr. Krishnamurthi:
Yeah. Thanks, Cathy. I agree. I think the MD Anderson data and the Memorial data are so impressive, but we need more data because it's probably not going to be 100% as we've seen in MD Anderson. We're not going to get 100% pathologic response. So, kudos to you and to Kristen Ciombor for conducting this study, which will allow radiation if need be.
As you point out, we don't have long term follow up, so we really don't know will the immunotherapy be sufficient to prevent a recurrence? Will there be some added benefit to adding radiation? We have a single institution study here at Cleveland Clinic, which is the traditional capecitabine and radiation with three doses of pembrolizumab for patients with deficient mismatch repair disease. It would be wonderful if patients don't need radiation to avoid all that morbidity, but we really don't know at this point what is the optimal treatment.
And as you pointed out, the incidence of this cancer is rare. We've just looked at our own institutional data. And for the last several years, we've only had 3% of our patients with rectal cancer having deficient mismatch repair. So, it's been hard to find patients to enroll to the trial. I know your study's enrolling and that's wonderful.
Dr. Eng:
Thank you so much. And also I'd be really curious to see what's going to happen between those patients. And Arvind, and I'd love to hear your input. Those patients that are BRAF wild-type that are not hypermethylators, that are truly Lynch syndrome patients, versus those patients that are hypermethylators, BRAF mutant, and just have somatic development of MSI status. I don't know if we have enough information in this early stage setting.
Dr. Dasari:
Yeah, absolutely. And I think it's hard to answer those questions definitively in a small patient population like this. Within those limitations, the data from MD Anderson suggests that perhaps the outcomes would not be different, which is what we're seeing in the metastatic setting as well.
Dr. Eng:
Yeah. I just mentioned it. I was just curious because the MSK data, it was 100% BRAF wild-type, so I just thought that was very intriguing. But I hope to learn more. Arvind, can you please enlighten us a little bit regarding the current landscape that's available in MSI-stable rectal cancer, the more common presentation?
Dr. Dasari:
Yeah, absolutely. And like both of you pointed out, unfortunately MSI-high rectal cancer accounts for less than 5%, perhaps 3 to 4% at the most of all locally advanced rectal cancer patients. The vast majority of patients still would get the conventional trimodality approach, which over the last couple of years or so, a year or so, has increasingly moved towards the TNT approach, total neoadjuvant therapy approach, where say for instance, taking the patient that we just discussed, keeping everything same. If the patient were microsatellite stable, likely the patient would've been offered a trimodality approach and perhaps with TNT in some centers. Whether we do short course radiation or chemoradiation, whether we do induction chemotherapy or consolidation chemotherapy, those are questions that are often discussed with our clear black and white guidelines. But nevertheless, no matter how we sequence these therapies, they do bring along the risks of toxicities, especially as the demographics change. And we're seeing more and more younger patients with rectal cancer.
The question is, how do we really optimize the risk-benefit ratio? Can we move from the trimodality approach to deescalating therapy and trying to omit one of the three modalities of therapy.
The data that's been accumulating over time suggests that perhaps about a third or so of patients may have clinical complete response, and these patients may be eligible for watch and wait approach. So, the question is, how do we improve the proportion of patients who may have complete clinical response? That's one of the things I'll go over. And second thing is, does everybody need radiation? I mean, can we skip radiation given the implications of toxicities in the short term and also potential issues in fertility.
With regards to the radiation question, the PROSPECT trial that has finished enrollment, enrolled patients with rectal cancer who were candidates for sphincter-sparing surgery, and they would be randomized standard of care arm, where they would get chemoradiation, surgery, and chemo versus initial chemotherapy, then evaluated for a response. So, the chemo would be FOLFOX for six cycles. And those who have adequate response would skip radiation, proceed to surgery and adjuvant chemotherapy. And those who do not have adequate response defined as at least 20% tumor regression would then get chemoradiation, surgery, and adjuvant chemotherapy as needed. The trial has finished enrollment and we are eagerly awaiting the results.
With regards to the earlier question that are raised about watch and wait, and can we increase the proportion of patients who may have clinical complete response, there is a trial that is being developed and has been approved by the GI Steering Committee. This is a joint effort between NRG, SWOG, and Alliance, where we're asking the question of intensifying neoadjuvant chemotherapy. The sequence of our treatment would be long course chemoradiation followed by consolidation chemotherapy based on data from OPRA, suggesting that the sequence is probably optimal. The question is, can we intensify the consolidation chemotherapy from fluoropyrimidine plus oxaliplatin to triplet chemotherapy, to folfirinox with a primary end point of increasing a complete clinical response from approximately 50% to 67%.
The protocol is under development and we're hoping that the trial will open in the next quarter.
Dr. Eng:
Great. And thank you, Arvind, for leading these efforts from a medical oncology standpoint, so we're very grateful for this contribution, which may be completely groundbreaking in regards to outcomes and conservative management and sphincter preservation. So, we'll be very curious to see what happens here. I'm very curious, Smitha, just really quickly, what are your thoughts regarding the landscape right now in rectal cancer, especially for our MSI-stable patient population?
Dr. Krishnamurthi:
Oh, thanks, Cathy. I think that the organ preservation goal is so exciting to see if we can avoid colostomy for a subset of our patients. And I'm really excited to open the study when we're able to. We've been using long course chemoradiation here followed by chemo. I think that's important to, when organ preservation is the goal, to give the radiation first so you have time for subsequent tumor shrinkage. And very much looking forward to the PROSPECT results as well.
Dr. Eng:
I agree with you on that as well. And I really just want to highlight really quickly, this consideration of sphincter preservation and watch and wait really originated from Angelita Habr-Gama in the 1980s, if I'm correct, and she's a surgeon. She was ahead of her time, so it's quite impressive. And now we're actually moving it forward to phase II/III clinical trials, so it's fantastic.
Our key clinical takeaways right now is the current approach to locally advanced rectal adenocarcinoma is trimodality therapy. MSI-high locally advanced rectal adenocarcinoma is a rare subset, sorry, that responds well to immunotherapy with durable responses. And obviously we would encourage you to enroll to clinical trials for further data. Ongoing trials are evaluating deescalation of trimodality therapy in MSI-stable tumors by the consideration of omitting radiation and/or surgery.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in colorectal cancer or visit ascopost.com. Thank you so much for your attention and thank you for our wonderful colleagues today, Dr. Krishnamurthi and Dr. Dasari, for their insight and input.
