Urothelial carcinoma (UC) is characterized by expression of a plethora of cell surface antigens, thus offering opportunities for specific therapeutic targeting with use of antibody-drug conjugates (ADCs). ADCs are structured from two major constituents, a monoclonal antibody (mAb) against a specific target and a cytotoxic drug connected via a linker molecule. Several ADCs are developed against different UC surface markers, but the ones at most advanced stages of development include sacituzumab govitecan (IMMU-132), enfortumab vedotin (ASG-22CE/ASG-22ME), ASG-15ME for advanced UC, and oportuzumab monatox (VB4-845) for early UC. Several new targets are identified and utilized for novel or existing ADC testing. The most promising ones include human epidermal growth factor receptor 2 (HER2) and members of the fibroblast growth factor receptor axis (FGF/FGFR). Positive preclinical and early clinical results are reported in many cases, thus the next step involves further improving efficacy and reducing toxicity as well as testing combination strategies with approved agents.
TPS399 Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies (excluding beta-emitting bone-targeted radioisotopes) provided adequate organ function will undergo imaging with 68Ga-PSMA-11 PET/CT followed by a single dose of 225Ac-J591. Single-subject cohorts will be enrolled until grade > 1 attributable toxicity, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to 93.3 KBq/kg of 225Ac with fixed 20 mg J591. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS, and patient reported outcomes (FACT-P and BPI-SF). Correlatives include baseline/follow up PSMA imaging, CTC count (CellSearch) changes, tissue and circulating genomic assessment, and immune studies. Enrollment began in October, 2017. Clinical trial information: NCT03276572.
TPS5093 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of radiolabeled anti-PSMA antibody J591 revealed 1) targeting and safety [Bander 2003]; 2) safety and prelim efficacy [Milowsky 2004, Bander 2005]; 3) efficacy and initial dose-response [Tagawa 2013]; 4) dose-fractionation allows higher doses, ability to combine with docetaxel, confirmation of dose-response (PSA and overall survival) [ASCO 2010, 2014, 2016]; 5) predictable, reversible myelosuppression is dose-limiting [Tagawa 2013]. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and are widely used for imaging and treatment in Europe. 177Lu-PSMA-617 is the most commonly used, but experience is mostly anecdotal/retrospective and no formal dose-escalation studies have been performed. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function will undergo imaging with 68Ga-PSMA-HBED-CC PET/CT followed by escalating fractionated doses of 177Lu-PSMA-617. Cohort 1 = 3.7 GBq x2 two weeks apart up to 11.1 GBq x2 in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu-PSMA-617, CTC count (CellSearch) changes, tissue and circulating genomic assessment of DNA repair pathways, patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03042468.
272 Background: PSMA targeted therapy has recently emerged as a promising approach for patients with advanced prostate cancer. However, there is still a need for reliable biomarkers that provide information about clinically meaningful outcomes and treatment responses. Methods: Baseline, treatment and outcomes data along with tumor whole-exome sequencing (WES) data were retrospectively evaluated in anti-PSMA-treated patients (pts). Statistical comparisons utilized Cox regression analysis and Kaplan-Meier method for association with overall/progression-free/survival (OS/PFS) and PSA response. Results: We analyzed 25 pts treated with PSMA targeted radionuclide therapies refractory to standard therapy. 15 received 177Lu-J591, 8 received 177Lu-PSMA-617, 1 received both, and 1 225Ac-J591. WES data (n=28) showed an incidence of AR, BRCA1, BRCA2, ATM alterations (copy number variations and point somatic mutations) in 71.4% (n=20), 11.1% (n=3), 29.6% (n=8), and 14.3% (n=4), respectively. Variables found with backward selection with AIC criterion for PFS and OS suggest significant clinical and molecular predictors of PFS/OS (Table). Conclusions: Knowledge of prognostic factors such as baseline narcotic use and ALP, and BRCA1/BRCA2 and TP53 alterations may have potential clinical utility in patients being considered for anti-PSMA targeted radionuclide therapies. Validation of these findings in larger prospective trials is warranted.[Table: see text]
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