DYP688 / Novartis - LARVOL DELTA

A first-in-human study of DYP688, an antibody drug conjugate delivering a direct Gq/11 inhibitor, in patients with metastatic uveal melanoma (MUM) and other GNAQ/11 mutant melanomas. (ASCO 2025) - P1/2 | "SDZ475 (FR900359) is a potent GNAQ/11 inhibitor, however in vivo toxicity has precluded clinical development...Of the 66 treated pts, 60 (90.9%) had prior antineoplastic therapy; 38 (57.6%) received ≥2 lines, and 22 (33.3%) received prior tebentafusp... DYP688 shows favorable safety and tolerability at all doses tested and promising preliminary clinical efficacy at doses ≥ 12mg/kg Q2W; the RDs for dose optimization are yet to be declared and dose exploration is ongoing."

Clinical • Metastases • P1 data • Anemia • Endocrine Disorders • Eye Cancer • Fatigue • Hematological Disorders • Hypotension • Melanoma • Metabolic Disorders • Oncology • Solid Tumor • Uveal Melanoma • Xerostomia • GNAQ • PMEL

An anti-PMEL antibody-drug conjugate with a Gq/11 inhibitor payload in GNAQ/GNA11-mutant melanomas: a phase 1 trial. (PubMed, Nat Med) - P1/2 | "In summary, DYP688 was well tolerated and showed preliminary efficacy, supporting this novel therapeutic approach. ClinicalTrials.gov identifier: NCT05415072 ."

First-in-human • Journal • P1 data • Eye Cancer • Hypotension • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNA11 • GNAQ • PMEL

Uveal Melanoma: Changing Paradigms of Treatment. (PubMed, Ocul Oncol Pathol) - "In 2022, tebentafusp became the first approved systemic therapy to improve overall survival in metastatic UM...As half of the patients are HLA A02:01 negative, alternative strategies are under investigation, including the protein kinase C inhibitor darovasertib in the NADOM neoadjuvant/adjuvant trial and in combination with crizotinib in metastatic UM. DYP688, a first-in-class PMEL17-targeting antibody-drug conjugate that inhibits GNAQ/11 signaling, has shown promise in metastatic UM and other GNAQ/11-mutant melanomas. The landscape of UM treatment is rapidly evolving following the identification of new targets and pathways such as PKC or PRAME. Combination of liver-directed therapies with personalized systemic immunotherapies or targeted agents in the metastatic disease, as well as the early use of systemic therapies in the primary tumor setting will refine treatment strategies in UM and suggest improved outcomes in the near future."

IO biomarker • Journal • Review • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ • PMEL • PRAME

A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas (clinicaltrials.gov) - P1/2 | N=66 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=124 ➔ 66 | Trial completion date: Sep 2025 ➔ Oct 2027 | Trial primary completion date: Sep 2025 ➔ Oct 2027

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ

QSP modeling of a transiently inactivating antibody-drug conjugate highlights benefit of short antibody half life. (PubMed, J Pharmacokinet Pharmacodyn) - "DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. Finally, we performed the successful preclinical to clinical translation of DYP688 PK, including the payload inactivation kinetics, evidenced by good agreement of the predicted PK to the observed interim clinical PK. Overall, this work highlights early quantitative pharmacokinetics as a missing link in the ADC design-developability chasm."

Journal • Oncology

Real world experience of molecular landscape of uveal melanomas: Implications for personalized medicine strategies. (ASCO 2024) - "GNAQ/GNA11 mutations are known to activate the MAPK/ERK signaling pathway, contributing to uncontrolled cell proliferation; its presence qualifies for entry into clinical trial testing DYP688 in metastatic UM... These findings underscore the need for a comprehensive genomic approach in guiding therapeutic decisions, understanding prognostic implications and advancing personalized medicine strategies for UM patients. Our study provides an overview of the molecular landscape of UMs with delineation of key molecular features, thereby enhancing our understanding of UM biology and setting the stage for the development of targeted therapies tailored to the unique genomic profile of each patient."

Clinical • IO biomarker • Real-world • Real-world evidence • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BAP1 • BRCA • EIF1AX • GNA11 • GNAQ • HRD • PD-L1 • PRAME • SF3B1 • TMB

A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas (clinicaltrials.gov) - P1/2 | N=124 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2026 ➔ Sep 2025 | Trial primary completion date: Mar 2026 ➔ Sep 2025

Metastases • Trial completion date • Trial primary completion date • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ

A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas (clinicaltrials.gov) - P1/2 | N=124 | Recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Nov 2025 ➔ Mar 2026 | Trial primary completion date: Nov 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ

A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas (clinicaltrials.gov) - P1/2 | N=124 | Recruiting | Sponsor: Novartis Pharmaceuticals | Not yet recruiting ➔ Recruiting

Enrollment open • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ

A Phase I/II study of DYP688 treatment alone in patients with eye cancer and other types of cancers of the skin and mucosal membranes in the body (clinicaltrialsregister.eu) - P1/2 | N=124 | Sponsor: Novartis Pharma AG

New P1/2 trial • Eye Cancer • Melanoma • Mucosal Melanoma • Ocular Melanoma • Oncology • Skin Cancer • Solid Tumor • Uveal Melanoma • GNAQ

A Phase I/II Study of DYP688 in Patients With Metastatic Uveal Melanoma and Other GNAQ/11 Mutant Melanomas (clinicaltrials.gov) - P1/2 | N=124 | Not yet recruiting | Sponsor: Novartis Pharmaceuticals

New P1/2 trial • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • GNAQ