jfm1330 wrote: To better set the expectations about efficacy in the current phase Ia of TH1902. It is good to look at what was achieved in a similar first in human study wit Sacituzumab Govitecan (Trodelvy) an ADC with SN38 (Govetican) as the cytotoxic agent linked to an antibody. This study was also open to all comers, so no selection of patients based on target receptor expression (Trop-2). SN38 is much more potent than docetaxel, but the ratio antibody/SN38 was only 7.6 SN38 molecules (mean) per antibody molecule. This is low when compared with TH1902 on a molecular weight basis. As a comparison, on a molecular weight basis TH1902 can carry around 18 molecules of docetaxel. Also, Trodelvy is not internalized by the cancer cells. 18/7.6 = 2.36
Also, 12 mg/kg dose is equivalent of 360 mg/kg. So a 360 mg/m2 of TH1902 delivers is equivalent to 850 mg/m2 of Trodelvy based on SN38 content. All that to say that SN38 is more potent, but TH1902 should allow to deliver much higher doses.
Results
Twenty-five patients (52-60 years old, 3 median prior chemotherapy regimens) were treated at dose levels of 8 (N=7), 10 (N=6), 12 (N=9), and 18 (N=3) mg/kg. Neutropenia was dose-limiting, with 12 mg/kg the maximum tolerated dose for cycle 1, but too toxic with repeated cycles. Lower doses were acceptable for extended treatment with no treatment-related grade 4 toxicities and grade 3 toxicities limited to fatigue (N=3), neutropenia (N=2), diarrhea (N=1), and leukopenia (N=1). Using CT-based RECIST 1.1, two patients achieved partial responses (triple-negative breast cancer, colon cancer) and 16 others had stable disease as best response. Twelve patients maintained disease control with continued treatment for 16-36 weeks; 6 survived 15-20+ months. No pre-selection of patients based on tumor Trop-2 expression was done.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558321/