Immunotherapy Success Signals Paradigm Shift Toward Nonoperative Management in Select GI Cancers

Michael J. Overman, MD

The use of immunotherapy regimens in select patients with gastrointestinal (GI) cancer has become increasingly viable and effective, particularly in localized mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) cancers like rectal cancer, challenging traditional surgery-first paradigms and allowing for the potential integration of more nonoperative management approaches, according to Michael J. Overman, MD.

In his presentation at the City of Hope Annual Advances and Innovations in Endoscopic Oncology and Multidisciplinary Gastrointestinal Cancer Care meeting, Overman discussed the feasibility of nonoperative management in GI cancers and the role of predictive markers for identifying patients who may benefit from this approach.

“Neoadjuvant immunotherapy has arrived for localized dMMR cancers, and its success in the rectal cancer space should make us consider [using nonoperative management strategies for] other localized dMMR cancers,” said Overman, who is the associate vice president of research in the MD Anderson Cancer Network. Overman is also a professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, and chair of the Division of Executive Committee of the Medical Staff at The University of Texas MD Anderson Cancer Center, in Houston, Texas. “It’s an exciting space to be exploring and is changing the paradigm of how we approach patients.”

During an interview with OncLive^®, Overman discussed the rationale behind utilizing nonoperative approaches in GI cancers; emphasized data detailing the efficacy of immunotherapy in dMMR cancers and its potential to spare patients from surgery; and discussed the need for further research to establish the safety and feasibility of nonoperative immunotherapy approaches vs traditional surgery and chemotherapy in various tumor types.

OncLive: What is the rationale for utilizing a nonoperative management approach over traditional surgery in GI cancers, and what data have supported this strategy thus far?

Overman: Immunotherapy is the main driver for nonoperative therapy. This space has probably generated the most excitement and interest related to the subset of GI cancers that are dMMR or MSI-H. Historically, we’ve used nonoperative management in a few rare scenarios in GI cancer. However, to [successfully] use nonoperative management, we have to have therapy that works at a high rate and can cure the cancer without classic surgery. That tends to be a rare phenomenon. However, with PD-1 therapy for dMMR cancers in the localized setting, we’re seeing response rates over 80%, with pathologic complete response [pCR] rates in that same range. The rate is high enough that there is now this discussion on nonoperative management. This area is pushing us [forward].

For example, there was a study with dostarlimab-gxly [Jemperli] in a limited number of patients with rectal cancer that demonstrated tremendous activity. Some other publications have also demonstrated high activity levels [with this approach].

As of last year, National Comprehensive Cancer Network practice guidelines have allowed for patients with dMMR rectal cancer to have PD-1 therapy as neoadjuvant therapy with the option of nonoperative management. This has become an approach that’s being used in clinical practice. Rectal cancer was the easiest [disease to use this approach in]. This is partly because surgery for rectal cancer can be very dramatic in how it changes one’s functionality, [such as determining the need for] ostomy bags. This is an area where we would like to keep organ function intact, so we’ve historically [used nonoperative approaches].

Please expand on which patient subsets have experienced the most benefit with nonoperative approaches to date. What questions still need to be answered to successfully incorporate nonoperative strategies in other tumor types or patient populations?

Recognizing that we can use [nonoperative management] in that setting does beget the question: Why don’t we do this in other tumor types that are dMMR or in other locations? If we can do it there and spare [patients from] getting adjuvant chemotherapy or surgery, that seems like a reasonable approach [so long as] outcomes are the same. We don’t have any data on adjuvant immunotherapy for dMMR cancers, so at present, surgery and chemotherapy [are the main approaches.]The idea is that you could just [administer an] immunotherapy, which is active, and you don’t need those other 2 [modalities]. In a way, you’d actually [be administering] less therapy.

When you look at metastatic disease, a lot of us would say that immunotherapy for dMMR cancers is the best systemic therapy. That’s predicated on some recent data and some older data in MSI colorectal cancer [CRC]. CRC is a common cancer, and hence, has a large fraction of this rare genomic subset. [Accordingly, CRC is a disease in which] we can run some randomized trials [with patients who have dMMR tumors]. There have been 2 main randomized trials [of nonoperative immunotherapy] in metastatic [MSI-H/dMMR] CRC. One was the [phase 3] KEYNOTE-177 study [NCT02563002] of pembrolizumab [Keytruda] vs chemotherapy. The other one was the [phase 3] CheckMate-8HW trial [NCT04008030] of nivolumab [Opdivo] alone and [in combination with] ipilimumab [Yervoy] vs chemotherapy [in this subset of patients]. Both of those trials demonstrated the superiority of immunotherapy vs chemotherapy in the frontline [treatment] of patients with metastatic disease, [indicating] that the best systemic therapy for dMMR cancers is immunotherapy. If we’re going into a localized setting, our best systemic therapy is probably immunotherapy now. However, historically, all our datasets in the adjuvant setting are chemotherapy based, so even now, the classic adjuvant therapy for a dMMR cancer is chemotherapy even though it’s different in the metastatic setting.

There’s a real question of whether we need surgery and adjuvant chemotherapy [or whether] we can use our best systemic therapy [instead], and that’s where the space is moving. Rectal cancer was the first [to see this shift], and now we have a lot of efforts to do this in MSI gastric cancer, biliary cancer, or colon cancer, where this would be something that would make sense. The topic is so relevant because this makes logical sense, and it appears that there are some early data in small, phase 2 studies suggesting that this could work. Still, how do we use [this approach] in practice? What are the criteria used to determine whether it’s working, what are the criteria used to [determine when not to do] surgery, and what are the criteria you use to determine how much therapy to administer? These are areas that we’re still trying to figure out. The lecture that [I presented during the meeting looked] at this idea of what factors we can use to predict how we’re doing and help guide nonoperative management of patients.

What research is currently being conducted to determine the safety and feasibility of nonoperative immunotherapy approaches vs surgery and chemotherapy in this space, and what still needs to be done?

There is a real question of how to use [nonoperative immunotherapy approaches] safely and appropriately for patients. There are several studies looking at its role in this space, [including the previously referenced] randomized study with dostarlimab, but that study is still predicated on the classic approach of immunotherapy [followed by] resection vs resection and adjuvant chemotherapy. It doesn’t quite ask the question that I think is the most interesting and relevant, which is the nonoperative question. We already know that PD-1 therapy works extremely well for dMMR cancers and could cure [approximately] 30% to 50% of metastatic patients. In the majority of patients, surgery is not necessary. That study does [assess whether] using immunotherapy before surgery is better than our standard approach, and that’s relevant, but it still has surgery as the crux of the approach. We need studies that look at the nonoperative question, because that’s going to be the question patients are going to want [answered].

We’ve done studies in this space for a while. The initial [phase 2] study [NCT04082572] we had was looking at pembrolizumab for localized dMMR cancers. We initially let patients go to surgery or they could decide in a discussion with their doctor to not have surgery and [opt for] watchful waiting. The directionality of what patients decided changed over time, in part because [they saw] such amazing responses [with immunotherapy. We were doing surgeries, and the surgeons would see these pCRs] and say, “I didn’t see anything on endoscopy and there’s not much on the CT scan, so why are we doing surgery?” That has been our experience in a small dataset. We’re going to see the same thing as [this approach] rolls out across more of a global population. If the majority of [surgical] cases are [patients who achieved] pCRs, why are we de facto doing surgery when it’s likely that we don’t need to?

What is your main message for your colleagues regarding the role of nonoperative management in GI cancer?

Instead of [approaching disease management with] classic surgery [first followed by other treatments], we’re thinking about [utilizing] immunotherapy [first], and [then perhaps] we don’t need surgery. That’s a pretty dramatic [change] because the classic paradigm has been surgery-first for forever. Now, we have a therapy that works so well that we might not need [surgery].

We should be working together to find out how to best and most appropriately [use immunotherapy] for patients; that requires a team effort. These are localized patients, so we need to be evaluating what’s happening. We need the medical oncologist to be providing immunotherapy. The surgeons often see these patients first because that’s the classic intake process, so surgeons need to be aware of this and talk to their medical oncologists. Medical oncologists then need to talk with endoscopists. This new team integration is needed. It’s important to ensure everyone’s aware of the capabilities [of nonoperative approaches [and the success of immunotherapy in this subset of cancers.