[Interview] Novel immunotherapy nelmastobart shows promise in MSS colorectal cancer: early trial data

While PD-L1 expression has revolutionized cancer immunotherapy, it remains an imperfect biomarker with significant limitations.

Notably, many patients with microsatellite stable (MSS) colorectal cancer show minimal response to PD-1/PD-L1 inhibitors despite treatment needs.

Roche’s IMblaze370 phase 3 trial, for instance, revealed that combining atezolizumab with cobimetinib did not improve overall survival in patients with MSS metastatic colorectal cancer.

Similarly, MSD's phase 3 KEYNOTE-975 study found that a combination of pembrolizumab and an anti-LAG-3 antibody failed to enhance outcomes in this patient population.

These setbacks highlight the limitations of current immunotherapies targeting PD-1/PD-L1 pathways in MSS colorectal cancer and emphasize the necessity for identifying new biomarkers and therapeutic targets beyond PD-L1 to improve patient outcomes.

Against this backdrop, Professor Lee Su-hyeon of the Department of Medical Oncology and Hematology at Korea University Anam Hospital recently presented promising phase 1b/2 study interim results for nelmastobart, a novel immunotherapy treatment candidate, at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI 2025), held in San Diego from Jan. 23-25.

Nelmastobart represents a novel approach to cancer immunotherapy, targeting BTN1A1, a newly discovered immune checkpoint protein. Unlike traditional immune checkpoint inhibitors that target PD-1/PD-L1, nelmastobart aims at a protein expressed specifically on dormant cancer cells and chemotherapy-resistant cancer cells.

Korea Biomedical Review met with Lee to discuss the clinical significance of this approach and its potential impact on colorectal cancer treatment paradigms.

"The research presented at ASCO GI is based on data from 12 patients in the phase 1b portion of an ongoing phase 1b/2 clinical trial," Lee said. "While there are limitations due to the preliminary nature of the data, the reason for this presentation was that previously we only had data on nelmastobart as monotherapy, and although Xeloda (ingredient: capecitabine) doesn't typically show significant efficacy in colorectal cancer, we wanted to explore the potential of this combination therapy for certain patient populations."

The primary objective of phase 1b was toxicity assessment. Lee, who led the first-in-human study of nelmastobart, stressed that she was already familiar with the relatively mild toxicity profile of nelmastobart.

“As expected, the toxicity was minimal, but what was unexpected was the response rate,” she said. “Among the 12 patients, two showed partial responses (PR).”

Lee further stressed that the 16.7 percent objective response rate (ORR) is particularly significant given the context.

"When you consider that existing chemotherapies for MSS colorectal cancer after third-line treatment typically show ORRs of 0-1 percent, with a maximum of around 7 percent, this is quite meaningful," Lee said. "Although the patient number is small, making it difficult to draw definitive conclusions, we've seen additional PRs in patients enrolled after the initial analysis from two to four.”

Since this drug's mechanism differs from existing immunotherapies, it could potentially emerge as a new treatment option as the study expands.

The clinical benefit rate has also been impressive.

"In this study, eight patients maintained progression free survival (PFS) for more than four months, with some patients maintaining PFS for more than six months,” she said. “I believe this data suggests an important result indicating the possibility of extended survival compared to existing treatments, especially considering that the average survival period in third-line or later treatment for MSS colorectal cancer is about six months.”

Also, given that this drug shows high response in specific patient groups, it may be possible to select patients using biomarkers in the future, she added.

One intriguing finding relates to BTN1A1 expression, the target of nelmastobart.

"This is still an area under investigation, but we're seeing a trend where nelmastobart's effect is more pronounced in patients with high BTN1A1 expression rates," Lee said. "Based on current observations, approximately 25-30 percent of patients with high BTN1A1 expression show positive results in terms of objective response rate.”

While additional data is needed, BTN1A1 could potentially be used as a predictive biomarker for nelmastobart response, she added.

Lee stressed subgroup analyses targeting patients with high BTN1A1 expression are planned for future studies."

Following these promising results, STCube recently submitted an Investigational New Drug (IND) application to the Ministry of Food and Drug Safety. The company-sponsored trial (SIT) aims to secure data that meets the approval standards of global regulatory agencies, including the FDA, to maximize competitiveness in technology export negotiations with multinational pharmaceutical companies.

For this new trial, nelmastobart will be combined with TAS-102 (Lonsurf) and bevacizumab (Avastin) rather than capecitabine.

Regarding the IND, Lee elaborated on the strategic choice of combination therapy.

"The previous research unveiled during ASCO GI was investigator-initiated, with patients covering the cost of capecitabine themselves,” she said. “However, considering the global market, a combination with the standard treatments TAS-102 (Lonsurf) and bevacizumab (Avastin) might be a more suitable strategy."

Lee stressed that Lonsurf plus Avastin is currently the most recognized combination for third-line treatment, though it's not without significant toxicity.

"Since nelmastobart appears to have minimal toxicity, there's potential to enhance efficacy without adding toxicity in this combination,” she said. “The safety profile of nelmastobart stands out as one of its major advantages.”

For example, immune checkpoint inhibitors can cause long-term immune side effects as they activate immune responses, whereas nelmastobart acts selectively on tumors, reducing such risks, she added.

Lee stressed that no dose-limiting toxicities (DLTs) have been observed so far.

“Some patients reported drowsiness after administration, but it's difficult to attribute this directly to the drug's mechanism,” she said. "In fact, we're conducting long-term follow-up in some patients, and they're showing stable progress without serious aftereffects even after discontinuing the drug.”

Looking ahead, Professor Lee shared that there is a possibility that phase 2 research will be presented at ESMO later this year.

When asked about nelmastobart's potential to change the treatment paradigm for colorectal cancer,

Professor Lee offers a measured assessment: "Currently, there are no drugs that surpass oxaliplatin or irinotecan in MSS colorectal cancer treatment. However, if nelmastobart shows better data compared to Lonsurf plus Avastin, it could establish itself as a third-line treatment.”

While it's not yet revolutionary enough to change first-line treatment, if the nelmastobart combination provides PFS of more than four months compared to the 2 months PFS offered by existing treatments, that would be sufficiently meaningful, she added.