At the recent European Society for Medical Oncology (ESMO) Congress 2025 held in Berlin, researchers from Memorial Sloan Kettering Cancer Center (MSK) unveiled groundbreaking advancements in the treatment and understanding of various cancer types. These studies encompass innovative therapeutic approaches for advanced solid tumors such as lung and pancreatic cancers, as well as new insights into tumors characterized by mismatch repair deficiency (MMRd), potentially revolutionizing personalized medicine in oncology.
One of the most promising developments presented was the initial data from the phase 1 clinical trial of izalontamab brengitecan (iza-bren/BL-B01D1), an experimental bispecific antibody-drug conjugate (ADC). This innovative molecule uniquely targets tumor cells harboring mutations in both the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) genes. Unlike conventional ADCs, which typically latch onto a single mutation, iza-bren’s dual targeting mechanism allows it to deliver chemotherapy directly to cancerous cells expressing either mutation, enhancing selectivity and potentially improving efficacy.
The trial, conducted at 22 locations across the United States with Dr. Helena Yu as principal investigator at MSK, has so far enrolled 107 patients with advanced solid tumors, prominently non-small cell lung cancer (NSCLC). Among the subgroup of 10 NSCLC patients who received the optimal dose, an impressive 75% showed tumor shrinkage, indicating a robust response to the therapy. While the most prevalent adverse effects were manageable cytopenias, their treatability renders the drug’s safety profile encouraging as trial enrollment continues with plans for extended investigations.
In the realm of pancreatic cancer, MSK’s phase 1 trial SHARON addressed a particularly refractory subset of patients: those with advanced disease driven by inherited mutations in BRCA1/2 or PALB2 genes. These genetic aberrations confer increased therapeutic resistance, exhausting standard chemotherapy options. The SHARON trial combines targeted chemotherapy regimens with autologous stem cell transplantation, a sophisticated approach wherein patients’ own hematopoietic stem cells are harvested prior to chemotherapy and then reinfused post-treatment to aid marrow recovery.
This innovative protocol was presented by Dr. Kenneth Yu and is jointly conducted with Massachusetts General Hospital, reflecting an interdisciplinary collaboration. Interim findings in 11 patients with stage 3 pancreatic cancer displaying hereditary mutations revealed a median progression-free interval of 14.2 months among those with disease control. Remarkably, two patients remained disease-free at 23 and 48 months post-therapy, with no unexpected toxicities reported. These encouraging outcomes have prompted plans to expand enrollment, aiming to refine safety and efficacy parameters further.
Delving deeper into tumor biology, MSK researchers shed light on the complexities of mismatch repair deficiency (MMRd) and microsatellite instability-high (MSI-H) conditions. Both genetic phenomena are pivotal in predicting responsiveness to immune checkpoint inhibitors—therapies that have transformed the landscape of cancer immunotherapy. However, the new research, spearheaded by Dr. Benoît Rousseau and presented by Dr. Violaine Randrian, reveals that the specific mechanisms inciting MMRd or MSI-H have a significant impact on therapeutic success and patient survival rates.
By analyzing an extensive dataset comprising nearly 2,000 MSK patients alongside an external commercial laboratory database surpassing 13,000 individuals, the team correlated immunotherapy outcomes with tumor types and underlying genetic mechanisms for mismatch repair defects. Their findings emphasize that inherited conditions such as Lynch syndrome and tumors exhibiting true MSI-H are associated with more durable responses and favorable survival, suggesting the necessity for nuanced molecular diagnostics to tailor immunotherapeutic regimens accurately.
Adding to the arsenal against MSI-H/MMRd tumors, MSK investigators introduced preliminary findings from a first-in-human phase 1 study of HRO761, a novel targeted agent designed to inhibit Werner helicase, a DNA repair enzyme critical for maintaining genomic stability in cancer cells. Dr. Michael Foote presented data involving 57 patients with advanced solid tumors refractory to prior immunotherapies, chemotherapies, or targeted drugs. HRO761 demonstrated a notable disease control rate of nearly 80% in colorectal cancer patients, with around 70% exhibiting clearance of circulating tumor DNA within one month, marking a formidable early proof-of-concept.
Importantly, the safety profile of HRO761 was favorable, with no treatment discontinuations due to adverse events, underscoring its potential in overcoming resistance mechanisms in MSI-H/MMRd malignancies. Ongoing dose-escalation and combination studies aim to elucidate optimal therapeutic use, paving the way for potential integration into standard care frameworks pending confirmatory efficacy data.
Collectively, these multifaceted investigations highlighted at ESMO 2025 underscore MSK’s commitment to pioneering personalized and precision oncology, leveraging genetic insights and novel therapeutic platforms to tackle historically intractable cancers. From bispecific ADCs revolutionizing lung cancer treatment paradigms to leveraging hematopoietic stem cell transplantation in genotypically defined pancreatic cancer, and refining immunotherapy based on mechanistic subtleties of mismatch repair deficiencies, these studies represent a watershed moment in cancer research.
These advances also exemplify the critical importance of collaborative clinical trials and integrative research approaches, which are essential for translating molecular discoveries into tangible patient benefits. The emerging data not only inspire optimism for improved survival and quality of life but also set the stage for further inquiries into combinatorial and mechanistically tailored interventions.
As MSK and their partners continue to enroll patients and refine these therapies, the oncology field watches closely, recognizing that such innovations could redefine treatment algorithms and offer hope to patients with few remaining options. Precision targeting of cancer vulnerabilities at the molecular and genetic levels, as demonstrated in these forefront studies, is poised to transform standard-of-care paradigms and manifestations of personalized medicine.
The presentations and ongoing studies highlight an era of cancer treatment characterized by both technological ingenuity and deep biological understanding. By exploiting dual mutation targeting, integrating stem cell support with chemotherapy, and unearthing how genetic mechanisms influence therapy response, MSK’s research at ESMO 2025 exemplifies the future of oncology—where treatments are no longer one-size-fits-all but strategically designed to outsmart tumors at their unique molecular weaknesses.
Subject of Research: Innovative therapies for advanced solid tumors and insights into mismatch repair deficiency-related cancers.
Article Title: Memorial Sloan Kettering’s Breakthrough Studies Redefine Treatment and Understanding of Advanced Solid Tumors at ESMO 2025
News Publication Date: October 2025
Web References:
- MSK Lung Cancer
- MSK Pancreatic Cancer
- MSK Iza-bren Phase 1 Study
- MSK SHARON Trial
- MSK MMRd and MSI-H Research
- MSK HRO761 Phase 1 Study
References: Information derived from MSK presentations and clinical trial data at ESMO Congress 2025.
Keywords: Advanced solid tumors, non-small cell lung cancer, pancreatic cancer, bispecific antibody-drug conjugate, immunotherapy, mismatch repair deficiency, microsatellite instability, targeted therapy, stem cell transplant, clinical trials.
