Dostarlimab Delivers Impressive Results in Rectal Cancer, But More Research Needed

Mark A. Lewis, MD

Dostarlimab-gxly (Jemperli), a PD-1 inhibitor and immunotherapy drug, has shown remarkable potential in the treatment of patients with colorectal cancer, specifically in those with locally advanced mismatch repair-deficient (dMMR) rectal cancer. Trials have shown there to be a 100% complete response (CR) rate in this patient population, which could potentially eliminate the need for other treatments like surgery, radiation, and chemotherapy.¹

However, wider adoption requires ensuring all patients are tested for this mutation. While the effectiveness dostarlimab is displaying is exciting, additional research must be done to see if it is unique or if similar drugs can achieve the same results.

In an interview with Targeted Oncology^TM, Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health, discussed the growing excitement of dostarlimab in treating rectal cancer and explored ways to maximize its potential.

Colorectal cancer, medical illustration, 3D illustration : © anatomy insider - stock.adobe.com

Targeted Oncology: Can you discuss the mechanism of action of dostarlimab and some of the updates that we saw at ASCO this year?

Lewis: Dostarlimab is a fascinating drug. Of course, it is 1 of many immunotherapies available now in GI cancer. Specifically, it is a PD-1 inhibitor. And I have to say, although we are talking about [the American Society of Clinical Oncology (ASCO) Annual Meeting] 2024, arguably dostarlimab was kind of the belle of the ball 2 years ago at ASCO 2022 when the Memorial Sloan Kettering group led by Andrea Cercek, MD, first announced really remarkable results. What they announced at that meeting was that in locally advanced mismatch repair-deficient rectal cancer, they were seeing in their first dozen or so patients complete clinical responses to upfront immunotherapy. And by upfront, I mean was originally given with neoadjuvant intent. But neoadjuvant implies that surgery is going to follow. And of course, in rectal cancer for years and decades, our paradigm has been one of trimodal therapy. So typically, radiation and chemotherapy given preoperatively and then surgery.

For a long time, we have been asking the question, well, what if chemo and radiation are enough? Does that actually change the paradigm from TNT, total neoadjuvant therapy, to TDT, total definitive therapy? Because again, adjuvant or neoadjuvant, those are moot points if there is no surgery. But this went one better than that [Memorial Sloan Kettering] study because they showed again, 12 out of 12, 100% complete clinical responses. If memory serves, I think it was on the front page of The New York Times, the same day as plenary in 2022. I know for a fact that my friends and family who are not in medicine knew about it roughly the same time I did. It was a big news story. Dr. Cercek herself has recently been recognized, I think rightly so, as one of the top 100 people in healthcare by Time magazine.

Regardless, the point of this meeting was an update now, 2 years on, not just for those original 12 or so enrollees, but for more enrollees on their trial. Again, the same criteria, mismatch repair-deficient locally advanced rectal cancer getting to dostarlimab for up to 6 months. Still 100%. It is truly remarkable, a 100% clinical complete response rate. What we now have with time is 20 of those patients have what they are calling a sustained clinical response of longer than a year. So, this is amazing. This is the new era of not just neoadjuvant, but definitive management in rectal cancer. It does not require chemotherapy, does not require radiation, does not require surgery, which is absolutely amazing.

I think that the big question is, is this really special to dostarlimab? I think a lot of us wonder about that. And then secondly, I think this just raises the importance of making sure that all the patients who would be eligible for this approach are tested. We are now absolutely in the era where biomarker testing is as important in colorectal cancer as it is in breast cancer. The reason I use breast cancer as an analogy is that no oncologist I know would ever dream or dare of treating breast cancer without at least trying to establish the [estrogen receptor (ER)], [progesterone receptor (PR)], and HER2 receptor status. The entire management of breast cancer is predicated on knowing receptors.

But we are at that point now, and have been in colorectal cancer, and the reason I have reservations about the generalizability of this study is I know from studying real-world practice, only about two-thirds of patients with colorectal cancer are even getting tested for mismatch repair deficiency or microsatellite instability. To me, that means we are missing a full third of patients who could benefit, which is just completely unacceptable. We need to change the paradigm; we need to view breast cancer as sort of the high watermark, and then we need to bring the other tumor types, especially in [gastrointestinal (GI) oncology] up to that level. But do not get me wrong. These are all just my minor critiques. I think this is an incredibly exciting and more mature dataset that the Sloan Kettering investigators have given us.

Moving forward, how can we best counsel patients about the potential for long-term disease control with this approach?

It is super promising. I think in the US, we have been slower to adopt what you might call watchful waiting or nonoperative management than say our colleagues in Brazil who I think could have been extremely forward-thinking in this respect. There are just a variety of reasons for that. If I am being honest, I think part of it has been medical-legal. Now that we have this important and pretty famous precedent, well, I will tell you as my patients now for 2 years, have been asking upfront, Dr. Lewis, am I a candidate for immunotherapy? I saw that almost immediately upon my return from ASCO 2022. It understandably persisted since then, because everybody, if they [could] be eligible for it, would prefer nonoperative management. The hard part is that a fraction of our patients are eligible. Certainly, no more than one-fifth, maybe lower than that. There is a little bit of dangling this prospect of not just notoperative management, but nonchemo[therapy], nonradiation management from the patients and then taking it away. But again, it is important that we ask the question. I love it actually. The patients are so savvy and motivated that they are doing their own research. I mean that praise respectfully, and they are asking that question. But frankly, if the oncologist now is not thinking about that upfront, then we are doing a disservice to the patient.

How likely is this approach to become the new standard of care? What are the key considerations for oncologists implementing it?

I think, arguably, that this should have been the standard now for 2 years. I understand that some of my colleagues wanted to be patient. Every time we see a single-institution study we need to replicate elsewhere, especially in the community. I also think there is a tradeoff here. To say the obvious, nobody wants rectal surgery; however, there is certainly a burden of surveillance that you have to kind of trade off here where if you are doing watchful waiting or nonoperative management, you are signing up for every 3 months, a fairly intrusive reevaluation. Typically, the way we would do that is with endoscopy, so direct visualization, ideally by a surgeon, and also very likely to have repeat MRI rectal protocol. So, there is a lot of imaging and scopes that go along with nonoperative management. But again, when push comes to shove, most patients will tell you to listen. I will sign up for that. One of my patients told me, I will do a colonoscopy every month if it means that I do not require surgery. I am like, well, we do not need to do it that often. But in all seriousness, I think that if we are going to be doing informed consent, part of the informed consent, I think as early as possible in the process, is to prepare patients for this extremely and appropriately vigilant tempo of follow-up if again, they are going to watchful waiting or the nonoperative management route.

The CheckMate-8HW study [NCT04008030] was monotherapy, but are there ongoing trials investigating combinations? What kind of potential benefits do you see with such combinations?

As we think about immunotherapy in colorectal cancer, more often, we have encountered it in the setting of metastatic disease, unfortunately. KEYNOTE-177 [NCT02563002] was a game changer. I know it immediately changed my practice. That was looking at pembrolizumab [Keytruda] as a monotherapy. CheckMate-8HW has been looking for several years now as we have gotten updates from the study's maturation, at the combination of nivolumab [Opdivo] and ipilimumab [Yervoy]. It drives home the point of knowing biomarkers as early as possible, because if you can save a patient from chemotherapy, that is a wonderful thing to do.

I am not personally convinced that most of my patients require the anti-CTLA4 agents that come along with ipilimumab, and I would have to be pretty hard pressed to pick that doublet over pembrolizumab, if I am being perfectly honest. I think you have to ask what you are getting out of that added toxicity or at least risk thereof.

There are [also] ongoing studies. The 1 that comes immediately to mind is called COMMIT [NCT02997228], which is looking at the combination of atezolizumab [Tecentriq], bevacizumab [Avastin], and FOLFOX [leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin], and that should be fascinating to see. It comes out of the AtezoTRIBE [NCT03721653] cohort where patients were actually getting a quintet. They were getting FOLFOXIRI plus bevacizumab plus atezolizumab. It was a couple [of] years ago that we were asking a question, can patients tolerate a triplet? Now, we are talking about quintets, arguably, again with biologics, but here is my point. Not every patient even with [microsatellite instability]-high or mismatch repair-deficient colorectal cancer necessarily benefits from immunotherapy alone. What I mean by that is if you look at KEYNOTE-177, by the time you get out to a year, 45% of the patients on the pembrolizumab arm were experiencing progression. So, the long tail is wonderful, but the question is, is there a subset, potentially a substantial subset of patients, who need something extra upfront?

What always unnerved me about KEYNOTE-177, which again was a seminal trial, still is, the survival curve drops off for pembrolizumab more rapidly than the chemotherapy arm does, and then it crosses over. What that told me was okay, even if you are carefully selecting your patients by biomarkers, there is something here that you kind of lose with this smoothing of the curves. You are losing the granular detail of each curve. What I think that means is, there is a category of patients who are on the verge of visceral crisis, let us say, from liver metastasis, and they need a rapid debulking through chemotherapy. They cannot wait for the immunotherapy to kick in. To me, trials like COMMITT are going to answer that question. I will be fascinated to know if there are patients who would benefit from upfront chemotherapy, immunotherapy, and arguably even anti-VEGF in the mix.

What must a community oncologist know about dostarlimab and the current GI cancer space?

We are in the era, now firmly, of immunotherapy, basically in most of the primary sites in the GI tract. With the possible exception of pancreas, immunotherapy now has a role in almost every GI primary that I treat. Again, a rising tide lifts all boats. The first time I gave immunotherapy was in 2011 to a [patient with] melanoma, and I got to see their melanoma melt away, albeit with some pretty scary toxicities like [panhypopituitarism]. It is amazing to get to offer that to more and more patients [with GI cancers].

REFERENCE:

Cercek A, Sinopoli JC, Shia J, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2024;42(suppl 17):LBA3512. doi:10.1200/JCO.2024.42.17_suppl.LBA3512