NEO-MEL-T Study: Mooradian Explores TIM-3/PD-1 in Resectable Melanoma
Melanoma: © David A Litman - stock.adobe.com
Findings from the investigator-initiated, noncomparative randomized phase 2 NEO-MEL-T study (NCT04139902) indicate a significant benefit in major pathologic response (MPR) with the addition of a T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) inhibitor, cobolimab, to PD-1 monotherapy in high-risk resectable melanoma.1
The study, presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting by Meghan Mooradian, MD, medical oncologist at Massachusetts General Hospital, highlights an effective strategy to address unmet needs in patients who may not achieve optimal response with current standard-of-care immunotherapy.
Rationale for Novel Strategies in Melanoma
The landscape of treatment for macroscopic stage III and resectable stage IV melanoma has seen a significant paradigm shift, with perioperative PD-1–based therapies becoming routine. Despite these advancements, a notable proportion of patients do not achieve complete or lasting responses, underscoring the ongoing need for novel therapeutic strategies.
"We recognize that, despite the clear advancements we have seen, a portion of patients won't respond to existing treatments," said Mooradian in an interview with Targeted OncologyTM. "Additional strategies are warranted for us to be investigating as an academic community."
The TIM-3 receptor emerged as a rational target for investigation. Preclinically, TIM-3 is known as a key co-inhibitory receptor expressed on various immune cells within the tumor microenvironment, including antigen-presenting cells and T cells. Upregulation of TIM-3 on T cells, often induced by cancer-associated antigen activation, contributes to T-cell terminal differentiation, exhaustion, and dysfunction.
TIM-3–positive T cells are recognized as among the most dysfunctional T cells within the tumor microenvironment. Blockade of TIM-3, particularly in combination with PD-1 inhibition, has been shown to restore T-cell proliferative capacity and function, thereby augmenting antitumor immune responses.
NEO-MEL-T Study Design and Methodology
The NEO-MEL-T study investigated the combination of dostarlimab (Jemperli), a PD-1 inhibitor, and cobolimab, a TIM-3 inhibitor, compared with dostarlimab monotherapy in patients with high-risk resected melanoma. Eligible patients were treatment naive and had either macroscopic stage III or resectable stage IV cutaneous melanoma.
The study design enrolled approximately 30 patients in the monotherapy arm and 27 in the combination arm. All patients underwent 2 cycles of neoadjuvant therapy. Following this, patients underwent radiographic restaging, and if their tumors remained resectable, they proceeded to therapeutic lymph node dissection. Postoperatively, all patients were eligible for an additional 48 weeks of adjuvant dostarlimab monotherapy.
The primary end point of the study was MPR in either arm, compared with a historical PD-1 monotherapy control, which had an MPR rate of 30% and a 1-year disease-free survival of 63%. Key secondary end points included safety and other antitumor efficacy markers such as relapse-free survival (RFS), overall survival (OS), and overall response rate (ORR).
Mooradian clarified that the study was not powered to directly compare MPR rates between the 2 arms unless the combination arm exceeded the monotherapy arm by 28%, but rather to assess each arm against the established historical control.
Efficacy and Safety Findings
The study demonstrated favorable safety and significant efficacy signals. The treatment regimen was found to be tolerable, with no unusual safety signals observed in either arm. Most toxicities were grade 1 or 2, with approximately 12% of patients experiencing grade 3 toxicities. Notably, there were no grade 4 or 5 events, and no adverse events that prevented or delayed planned surgery. Furthermore, 100% of patients in both the monotherapy and combination arms completed their 2 planned cycles of neoadjuvant therapy and subsequent therapeutic lymph node dissection.
Regarding the primary end point, patients who received the combination (n = 27) achieved an MPR rate of 55.6% and those who received dostarlimab alone (n = 30) experienced an MPR rate of 33.3%. The pathological complete response rates were 37% and 33.3%, respectively. A total of 18.5% and 3.7% of patients in the combination arm experienced a pathological major response or a pathological partial response, respectively. Crucially, the MPR rate in the combination arm significantly exceeded the historical control of 30% (P =.0029, 1-sided z-test).
Radiographic responses showed a consistent discordance with pathologic findings; a phenomenon observed across various tumor types. The ORR by radiographic assessment was 16.7% in the monotherapy arm and 33.2% in the combination arm, highlighting the importance of pathologic evaluation for treatment efficacy.
RFS also supported the combination strategy. While there was a nonsignificant improvement in the combination arm (1-year RFS of 87%) compared with the monotherapy arm (82%), the 87% 1-year RFS in the combination arm significantly surpassed the historical control of 63%. Consistent with other trial data, a strong correlation between MPR and RFS was observed: 100% of patients who achieved an MPR (defined as less than 10% viable tumor in their pathologic sample) were relapse-free at 1 year, irrespective of their treatment arm.
Biggest Takeaway and Future Directions
Mooradian emphasized that the study clearly demonstrates the additive benefit of TIM-3 inhibition in this setting.
"I think the value of doing a randomized study is that you are able to see the contribution of parts and the contribution of components," she noted. "Though we saw very similar rates of MPR with dostarlimab monotherapy as we had seen in our historical study, we saw that when we added TIM-3, we clearly demonstrated a delta with respect to those pathologic responses that patients were able to experience."
This finding validates further exploration of TIM-3 in a PD-1–naive setting, both in perioperative and metastatic disease. The tolerability of the regimen also opens the door for considering TIM-3 not only in combination strategies but potentially in triplet regimens.
Future research plans include extensive correlative analyses using serially collected tumor, blood, and stool samples. Through advanced techniques such as single-cell RNA sequencing and multiplex immunofluorescence, researchers aim to delve deeper into the cellular states and types critical for response. This will help validate preclinical hypotheses, such as TIM-3's role in improving T-cell functionality and augmenting antigen presentation.
