IO Research Pays Off in MSI-H/dMMR CRC but Misses the Mark in MSS/pMMR Disease

Tanios S. Bekaii-Saab, MD

The use of immunotherapy in patients with colorectal cancer (CRC) is currently largely confined to those with microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) disease, although questions remain regarding the optimal sequencing of immuno-oncology (IO) agents with surgery in colon cancer management, and ongoing studies may find ways to enhance immunotherapy responses in the broader microsatellite-stable (MSS)/MMR-proficient (pMMR) CRC population, according to Tanios S. Bekaii-Saab, MD.

“For CRC specifically, it’s important to look at the 2 subgroups [of patients] where we have [conducted the most research with immunotherapy],” Bekaii-Saab said in an interview with OncLive®. “One is the MSI-H group, and the other is the MSS group.”

In the interview, Bekaii-Saab discussed questions that have arisen regarding the evolving standard-of-care (SOC) use of immunotherapy in patients with MSI-H/dMMR CRC, research aimed at improving the limited efficacy of this class of agents in patients with MSS/pMMR disease, and the potential for trastuzumab (Herceptin) plus tucatinib (Tukysa) to benefit patients with previously untreated HER2-positive metastatic CRC (mCRC).

The phase 3 CheckMate-8HW trial (NCT04008030) showed a progression-free survival benefit with the use of ipilimumab (Yervoy) plus nivolumab (Opdivo; n = 354) vs chemotherapy (n = 132) in patients with previously untreated MSI-H/dMMR mCRC (HR, 0.21; 95% CI, 0.14-0.32; P < .0001), as well as with the use of ipilimumab plus nivolumab vs nivolumab alone (n = 353) in patients with immunotherapy-naive patients with unresectable or metastatic MSI-H/dMMR CRC in the first- and second-line settings combined (HR, 0.62; 95% CI, 0.48-0.81; P = 0003).1 Bekaii-Saab emphasized that further research is needed to confirm the benefit of the combination vs nivolumab alone in the first-line setting.

He also explained that based on positive findings from the final analysis of the phase 2 MOUNTAINEER study (NCT03043313), which showed that tucatinib (Tukysa) plus trastuzumab (Herceptin; n = 84) generated a confirmed overall response rate (ORR) of 39.3% (95% CI, 28.8%-50.5%) among patients with pretreated HER2-positive mCRC, the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) is evaluating the potential efficacy of this combination added to mFOLFOX6 (modified 5-fluorouracil, leucovorin, and oxaliplatin) in in the first-line HER2-positive mCRC setting.2,3

Bekaii-Saab is the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Comprehensive Cancer Center, as well as the medical director of the Cancer Clinical Research Office and the vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic in Phoenix, Arizona.

OncLive: What recent immunotherapy advancements are influencing CRC management for patients with MSI-H/dMMR disease?

Bekaii-Saab: Right now, [the use of immunotherapy is] most relevant for the MSI-H patient subgroup. For MSI-H or dMMR metastatic colon cancer, right now, we have 2 treatment standards: pembrolizumab, and ipilimumab plus nivolumab. The CheckMate 8HW study was interesting in the sense that it showed that adding ipilimumab to nivolumab can improve outcomes vs nivolumab alone, but that was across lines of therapy. We’re still waiting on first-line data with ipilimumab plus nivolumab vs nivolumab [monotherapy], and that may move us from having 2 options to 1 dominant option [of] ipilimumab plus nivolumab. We’ll see where that goes, but today, for most patients, we’re still choosing pembrolizumab. For select patients, we’re increasingly considering adding ipilimumab to nivolumab. That’s an option [for] a younger patient with more symptoms who needs a significant response and in whom we’re less concerned about toxicities.

We also have several datasets with single-agent PD-1 inhibitors [in patients with MSI-H disease]. For rectal cancer, where surgery can be morbid, in MSI-H patients, we can at least consider foregoing surgery and following a ‘watch and wait’ plan with patients who [instead] receive single-agent IO. Dostarlimab-gxly [Jemperli] is one agent that has been investigated expansively, and the results continue to look promising in the management of early-stage rectal cancer.

The question is: Should [single-agent IO] be a standard [for patients with MSI-H rectal cancer]? In my clinic, that’s being offered as an option to patients, and when patients understand the morbidity of the surgery, [they typically prefer to receive] IO first [with] either pembrolizumab [Keytruda], nivolumab, or dostarlimab, whichever is available, pending the final results of [research with dostarlimab in patients with MSI-H/dMMR rectal cancer], which may become the new SOC for [these] patients.

Colon cancer [management is] a bit more complicated because the surgery tends to be less morbid and invasive [than in rectal cancer] and, for MSI-H patients, highly curative. [Approximately] 80% to 90% of patients [with MSI-H colon cancer who undergo surgery] will be cured, even with no chemotherapy or IO beyond [surgery]. At this point in time for colon cancer, although the data [with immunotherapy] look promising, the question we always have in mind is [regarding toxicities]. The toxicities associated with any potential treatment, such as IO agents like PD-1 inhibitors, are not innocuous. [These classes of agents] have their own toxicities—including, for rare patients, the possibility of dying—and the [mortality rates associated with IO agents are] higher than [those associated with] surgery for colon cancer. Therefore, we have to be careful [about choosing IO for patients] who are clearly resectable before we understand a bit more about this treatment class.

The other question is: Do we need to give patients neoadjuvant treatment and then take them to surgery, which [was the design of] most colon cancer studies? The answer is: Why can cure patients with IO-based therapy, do we need to go to surgery? However, if surgery is also highly curative and less morbid, should we] proceed with neoadjuvant therapy and put the patient at risk [of IO-associated toxicities]? That answer today is unclear.

The caveat is that we have a study that will hopefully generate results in 2025. The phase 3 ATOMIC trial [NCT02912559] is investigating FOLFOX with or without atezolizumab followed by atezolizumab (Tecentriq) in patients with dMMR CRC]. That trial may give us a hint about the role of adjuvant therapy—including IO-based therapy—for patients with MSI-H colon cancer [who undergo surgery]. We’ll hear more about this trial hopefully by the end of 2025. This [research will contribute to the knowledge we have about the role of] immunotherapy in MSI-H colon cancer [management].

What have been some of the obstacles to using immunotherapy in patients with MSS/pMMR disease?

[Treatment strategies are different in the] MSS and pMMR patient subgroups [vs the MSI-H/dMMR subgroups]. So far, the data [with immunotherapy in these subgroups] have been mostly disappointing, although some data from several studies have looked somewhat positive for a small percentage of patients. However, these are mostly single-arm studies; there is no randomization, and it’s difficult to understand whether [immunotherapy is] helping these patients.

[The favorable outcomes with immunotherapy in patients with MSS/pMMR disease] also seem to be extremely limited to nonliver metastases. Liver metastases are present in approximately 80% of patients [with MSS/pMMR disease], but it seems like lung metastases draw most of the benefit [with immunotherapy] compared with peritoneal metastases or other [metastatic sites]. That limits [the benefit of this treatment class] to less than 10%—or arguably even 5%—of patients [with MSS/pMMR disease].

Even in that small subgroup of patients, the ORR [with immunotherapy] is a bit higher than average [ORR with SOC agents], but it doesn’t even reach 50%; it’s approximately 20% to 30%. These responses also tend to be short-lived—even in some of the studies that have tried to [improve outcomes] by adding multiple agents together, like regorafenib [Stivarga] plus ipilimumab and nivolumab or more recently, botensilimab plus balstilimab. The data look relatively intriguing, but at this point, they are not powerful enough to suggest a change to our practice.

Other planned or ongoing studies are investigating ways to enhance the immune milieu other than doubling up on checkpoint inhibitors or adding a VEGF inhibitor. They are examining other potential targets that could change the paradigm, like CCR8 inhibitors, EPA[-based agents], and others. These [agents] are also under evaluation in CRC to see whether we can [alter] MSS or pMMR disease into [a state] where immunotherapy may have a role. We’re not there yet. We’re not even close yet, but we’re on our way.

How might ongoing or future research with tucatinib-based regimens improve upon SOCs in patients with CRC?

In CRC, tucatinib plus trastuzumab has become the preferred treatment regimen for patients with HER2-positive [mCRC], based on findings from the MOUNTAINEER study that John Strickler, MD, [of Duke Cancer Center in Durham, North Carolina], and I presented with colleagues. That study showed [notable] outcomes [with the combination]. This was a single-arm study—although [some patients were randomly assigned to receive] tucatinib alone [so we could] understand the separation of the components [of the 2 investigational agents]—and it met its primary end points.

The combination was well tolerated, [and its safety profile looked] better and safer than those of regimens that were previously tested in [patients with HER2-positive mCRC], such as lapatinib [Tykerb] plus trastuzumab or pertuzumab [Perjeta] plus trastuzumab. That [helped] establish [tucatinib plus trastuzumab as] the [SOC for this population]. The combination was approved by the FDA [in 2023 for the treatment of patients with pretreated RAS wild-type, HER2-positive unresectable or metastatic CRC], it’s in the National Comprehensive Cancer Network guidelines, and now it’s being investigated in the first-line setting in MOUNTAINEER-03, which is studying tucatinib plus trastuzumab added to mFOLFOX6 vs mFOLFOX6 alone [or in combination with SOC therapies] in patients with HER2-positive mCRC.

We’re trying to move [this combination] to the first-line setting because we’ve seen that with biologics and immune therapeutics that have activity in later lines of therapy, as you move them to the first-line setting, that activity gets amplified even further. We’re excited about the study, which is accruing and ongoing. If it is positive, tucatinib plus trastuzumab may become our first-line go-to regimen for patients with mCRC.

References

1. Andre T, Elez E, Lenz HJ, et al. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. J Clin Oncol. 2025;43(suppl 4). doi:10.1200/JCO.2025.43.4_suppl.LBA143
2. Strickler JH, Cercek A, Siena S, et al. Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER). J Clin Oncol. 2024;42(suppl 16). doi:10.1200/JCO.2024.42.16_suppl.3509
3. A Study of Tucatinib With Trastuzumab and mFOLFOX6 Versus Standard of Care Treatmentin First-line HER2+ Metastatic Colorectal Cancer (MOUNTAINEER-03). ClinicalTrials.gov. Updated March 18, 2025. Accessed April 4, 2025. https://clinicaltrials.gov/study/NCT05253651