Memorial Sloan Kettering Cancer Center (MSK) researchers presented exciting advances in medical oncology for a range of cancer types at the European Society for Medical Oncology Congress 2025 held October 17 to 21 in Berlin, Germany.
Highlights included the latest updates on three phase 1 trials testing innovative treatment approaches for select patients with advanced solid tumors, non-small cell lung cancer (NSCLC), and pancreatic cancer. Additionally, MSK researchers presented new insights about mismatch repair deficient solid tumors that may inform tailoring personalized treatments, and an educational session on managing “unfit” patients with stage 3 NSCLC.
MSI-High/MMRd Solid Tumors: Werner Helicase Inhibitor Demonstrates Acceptable Safety and Durable Responses
Microsatellite instability-high (MSI-H)/mismatch repair deficient (MMRd) solid tumors require DNA repair by the werner helicase (WRN) protein for survival. HRO761 is an oral selective WRN inhibitor that deactivates WRN by locking it in place.
Gastrointestinal medical oncologist Michael Foote, MD, presented interim results from the first-in-human phase 1/1b study of HRO761 (NCT05838768) in patients with advanced MSI-H/MMRd tumors that had progressed on all standard-of-care therapies, including immunotherapy, chemotherapy, and targeted therapies. The interim included 57 patients, of whom 58% had colorectal cancers, 11% had endometrial cancers, 11% had gastric/gastroesophageal junction cancers, and 21% had other solid tumor types.
HRO761 was very well tolerated with minimal grade 3 side effects and no patient discontinued the medication from side-effects.
Preliminary results showed that nearly 80% of patients with colorectal cancer exhibited disease control. Notably, progression-free survival (PFS) was 8.1 months for patients with colorectal cancer at all doses and was not reached for therapeutic doses over 200 mg. Furthermore, about 70% of colorectal cancers with detectable circulating tumor DNA (ctDNA) at baseline were clear after about one month of HRO761.
The study continues with dose optimization for HR0761, as well as separate combination arms of HR0761 with either pembrolizumab or irinotecan.
Read ESMO Congress 2025 Abstract 925MO. The study was sponsored by Novartis Pharmaceuticals. Access disclosures for Dr. Foote. Learn more about MSK clinical trials for patients with solid tumors, including colorectal cancers.
NSCLC and Other Solid Tumors: First Safety and Efficacy Report from the Phase 1 Trial of Iza-bren
Izalontamab brengitecan (iza-bren/BL-B01D1) is a potential first-in-class antibody-drug conjugate (ADC) comprised of an EGFR x HER3 bispecific antibody conjugated to a novel topoisomerase 1 inhibitor payload.
Thoracic medical oncologist and early drug development specialist Helena Yu, MD, presented the first report of safety and efficacy results of the dose finding/escalation phase of the global phase 1 BL-B0161-LUNG-101 study (NCT05983432) of iza-bren for heavily-pretreated patients with metastatic or unresectable NSCLC and other solid tumors. The trial is taking place at 22 locations in the United States. Dr. Yu is principal investigator at MSK.
Among 107 patients, hematologic treatment-related adverse events, such as neutropenia and anemia, were common yet effectively managed by standard measures. Granulocyte colony-stimulating factor prophylaxis was not mandatory in this cohort but has been implemented in the ongoing dose-expansion phase of the US-Lung 101 study and global registration studies.
As of July 23, 2025, iza-bren was demonstrating promising efficacy. Among 20 patients who received 2.5 mg/kg, the confirmed objective response rate (cORR) was 55% and the median PFS was 5.4 months. Efficacy was higher for 10 patients with NSCLC who received the 2.5 mg/kg dosage, with a cORR of 75% and median PFS not reached.
Global registrational studies in first line metastatic triple negative breast cancer (NCT06926868), second line metastatic EGFR-mutant NSCLC post tyrosine kinase inhibitor (NCT05983432), and second line metastatic urothelial cancer post checkpoint inhibition (NCT07106762) are ongoing, with studies in other indications planned.
Read ESMO Congress 2025 Abstract 921MO. The study sponsor Systimmune entered a joint global collaboration with Bristol Myers Squibb in December 2023 to co-develop iza-bren. Access disclosures for Dr. Yu. Learn more about MSK clinical trials for patients with solid tumors, including NSCLC.
BRCA/PALB-Mutated Pancreatic Cancer: Chemotherapy plus Autologous Stem Cell Transplantation Shows Promise in SHARON Trial
Patients with advanced pancreatic cancer with germline BRCA 1/2 or PALB2 mutations often develop resistance to multiple lines of chemotherapy, leaving them with few options.
Gastrointestinal medical oncologist Kenneth Yu, MD, presented a poster summarizing interim results from the phase 1 SHARON trial (NCT04150042). This novel study is evaluating the safety and efficacy of targeted chemotherapy plus autologous stem cell transplantation for adults with stage 4 pancreatic ductal adenocarcinoma who have a deleterious germline BRCA 1/2 or PALB2 mutation.
The trial is a collaboration between gastrointestinal medical oncologists and transplant specialists at MSK and Massachusetts General Hospital, with MSK enrolling a majority of patients. After stem cell mobilization and apheresis, patients receive a chemotherapy regimen that includes melphalan and BCNU (carmustine), followed by stem cell transplantation. The chemotherapy regimen and stem cell infusion are repeated six weeks later.
Among the 12 patients included in the interim analysis, the treatment was generally well tolerated, with manageable and expected adverse effects consistent with the known safety profiles of melphalan, BCNU, and autologous stem cell infusions. Since the researchers added prophylactic dexamethasone to the protocol, there have been no instances of cytokine release syndrome and elevated plasma cytokines.
The researchers observed a strong efficacy signal in patients without disease progression at enrollment. Among those with stable or responding disease at trial entry, the median PFS was 14.2 months, and two patients were disease-free at 23 and 48 months post-therapy.
MSK aims to recruit an additional 15 patients in the continuing trial. Learn more about the SHARON trial at MSK.
Read ESMO Congress 2025 Abstract 2228P. The study was sponsored by General Oncology. Access disclosures for Dr. Yu. Learn more about pancreatic cancer clinical trials at MSK.
MMRd Solid Tumors: The MMRd Mechanism Informs Survival Outcomes with Immune Checkpoint Blockade
Current guidelines state that solid tumors should be assessed for MMR status by immunohistochemistry or MSI status by sequencing. However, a new study led by researchers at MSK has found that the specific MMR protein loss and the mechanism of loss (genetic or epigenetic) drive distinct patterns that alter sensitivity to immune checkpoint blockade.
The study was led by Benoit Rousseau, MD, PhD, Assistant Member of the Gastrointestinal Oncology Service and presented by Violaine Randrian, MD, PhD, a visiting scientist from France. The MSK research team assessed the impact of MMR protein loss on survival in two large pan-cancer cohorts treated with immune checkpoint blockade: an MSK cohort of 1,958 patients and a validation cohort of 13,421 patients provided by Caris Life Sciences. In addition to assessing outcomes after immunotherapy based on the mechanism of MMR loss, the researchers evaluated the genomic architecture and immune profile for each mechanism of inactivation overall and in select cancer types.
Importantly, they found that the mechanism of loss informed the outcome. PMS2-deficient tumors and MLH1-hypermethylated tumors compared to MLH1-mutated tumors, had shorter overall survival (OS) after immune checkpoint blockade. Having an MSI-high or Lynch status were the strongest prognostic factors for longer OS. MSS, especially in genitourinary and rare cancer types, was the strongest predictive factor for shorter OS. Part of the worse prognosis was explained by discordances between MMRd and MSS status, with MMRd/MSS tumors more frequent in tumors that were deficient in only PMS2 or MSH6.
Overall, these findings suggest that it is essential to assess both MMR and MSI status for patient stratification and to tailor future personalized immunotherapy treatment.
Read ESMO Congress 2025 Abstract 111O. The study was supported by funding by Swim Across America, Fondation Nuovo Soldati, Institut Servier, Mobilite chercheurs Ligne Contre le Cancer, Bourse Tournut SNFGE, Université de Poitiers, and CHU de Poitiers. Access disclosures for Dr. Rousseau. Learn more about MSK clinical trials for patients with solid tumors.
Other Notable MSK News from ESMO Congress 2025:
NSCLC: How to Manage “Unfit” Patients with Stage 3, Unresectable Disease. Thoracic medical oncologist Jamie Chaft, MD, presented an educational session on on an increasingly relevant topic in our clinics, the management of unfit patients with locoregionally advanced, stage 3 NSCLC. This is a patient population often too sick for randomized trials. Her talk covered the utilization of immunotherapy as monotherapy for patients with stage 3 not fit for chemoradiotherapy, as in the EMPOWER-Lung trials. She also highlighted recent data updates for immunotherapy with radiotherapy, including the DART study, completed at MSK, where patients not fit for chemoradiotherapy were treated with immunotherapy and definitive radiation, greatly outperforming the historical control arm. This has been replicated in the DOLPHIN study from Japan and DUART in Europe. Access disclosures for Dr. Chaft. Learn more about MSK clinical trials for patients with NSCLC.