RE:RE:Trodelvy dose escalation trial resultsIt seems the phase Ib was a basket trial that ended up as a phase I/II in TNBC that led to accelerated approval. In this phase I/II in TNBC on 108 patients that had a response rate of 33.3% with 36 patientients with partial or complete response, including three patients with complete response, and the clinical benefit rate was 45.4%. Clinical benefit includes patient with tumor response or stable disease for at least 6 months. The median time to see a response was two months. This is good to know about Th1902. You likely need many cucles to see a response. Trodelvy is by no mean a cure since that by the time of the data cutoff of this study, 77 of the 108 patients had died.
https://www.nejm.org/doi/full/10.1056/NEJMoa1814213
Wino115 wrote: Wonder what 1b showed? I haven't looked that up. So 2/25 (8%) partial (meaning 30% reduction or greater in tumor) and mostly just showing stable disease. It's enlightening to see that this is how the billion dollar cancer treatment started out. I think that's more or less the percentages we would optimistically see given the smaller size. I think 1b should be far more interesting and I suspect we'll hear about some changes to it based on 1a too. I guess the point to take is that 1a really is just dosage and safety and even hot-shot drugs don't show a whole lot of response in a properly conceived, all-comer 1a.
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/