Abstract 1531TiP
Background
Claudin 18.2 (CLDN18.2) is expressed in ∼70% of gastric and gastroesophageal adenocarcinomas (GC/GEJ-C), and 50-70% of pancreatic ductal adenocarcinoma (PDAC) patients, correlating negatively with prognosis. CLDN18.2 is only expressed on cancer cells and luminal gastric epithelial cells, making it a promising target for cancer therapy. CD47 is a macrophage “don’t eat me” immune checkpoint widely over-expressed in cancer. PT886 is an IgG1 bispecific antibody targeting CLDN18.2 and CD47. PT886 mediates antibody-dependent cellular cytotoxicity and enhances antibody-dependent cellular phagocytosis (ADCP), stimulating the innate immune system and subsequently increasing tumor neoantigen presentation and T cell-mediated cancer cell killing. The bispecific approach utilizing CD47 binding enables potential activity in low CLDN18.2 expressors and the blockade of CD47 pathway enhances stimulation of the adaptive immune system.
Trial design
Following Phase 1 Dose Escalation, 5 additional cohorts will explore PT886 in combination with additional therapies. Cancer cells use the PD-(L)1 axis as a mechanism of resistance to T cell-mediated killing. This can be overcome by combining PT886 with pembrolizumab treatment (Cohort 3). Furthermore, by combining PT886 with SOC chemotherapy alone (Cohorts 1 and 2), or with pembrolizumab plus chemotherapy (Cohort 4), cancer cells treated by chemotherapy provide an ideal target for ADCP induced by PT886. In addition, patients that have progressed under zolbetuximab may still express CLDN18.2, benefiting from re-introduction of a CLDN18.2 targeted therapy with a differentiated mechanism of action such as the bispecific approach with CD47 (Cohort 5). The TWINPEAK study is a signal generating study of 5 cohorts with approximately 15 patients per cohort, in advanced/metastatic GC/GEJ-C and PDAC patients, in the 1L and 2L+ setting. Patients should have ≥ 10% CLDN18.2 positive tumor cells to be eligible. Endpoints for further development include ORR, safety, OS and biomarkers. The study is adaptive and may further expand with an increase in sample size and additional cohorts.
Clinical trial identification
NCT05482893.
Editorial acknowledgement
Phanes Therapeutics, Inc., San Diego, CA, USA.
Legal entity responsible for the study
Phanes Therapeutics, Inc., San Diego, CA, USA.
Funding
Phanes Therapeutics, Inc., San Diego, CA, USA.
Disclosure
M.J. Overman: Financial Interests, Personal, Advisory Board: Roche, BMS, MedImmune, Merck, Amgen, Takeda, Janssen, Pfizer, Array, Gritstone, Nouscom, Atreca, Bayer; Financial Interests, Institutional, Coordinating PI: Roche, Lilly, Merck, BMS, Phanes, Nouscom. R. Laeufle, G. McGregor, H. Zou: Financial Interests, Personal, Full or part-time Employment: Phanes Therapeutics, Inc., San Diego, CA, USA. H. Singh: Financial Interests, Institutional, Research Funding: AstraZeneca, Dava Oncology; Non-Financial Interests, Institutional, Advisory Role: Merck, Sharpe & Dohme, Dewpoint Therapeutics, Zola Therapeutics. A.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. M. Chisamore: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc. All other authors have declared no conflicts of interest.
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