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Alessandro Santin et al. inaugurated the TROP era for antibody drug conjugates (ADCs) in gynecologic cancers with . This of sacituzumab govitecan (SG) in patients with recurrent endometrial cancer that was largely checkpoint inhibitor (CPI) pretreated (85%) and heavily pretreated (61%>3 prior lines of therapy [LOT]) demonstrated a modest overall response rate of 22% (95% CI 11-38) with a median duration of response (DOR) of 8.8 months (2.8-NE).

This should be put in context with , which include either doxorubicin or weekly paclitaxel with an expected overall response rate (ORR) of 15% and median progression-free survival (PFS) of . These data are almost entirely in no prior CPI, so true benchmarks in this space are lacking.

The data also need to be put in context with the new data presented at ESMO 2024 with (ST) and (DD) in a similar but not identical space. ST (n=44) with only 36.5% of patients with prior CPI and 53% > 2 LOT demonstrated an ORR of 27.3%, DOR 5.7 months, and modified progression-free survival (mPFS) of 5.7 months (95% CI 3.7-9.4%).

DD (n=40) with only 22.5% prior CPI and 47.5% > 2 LOT demonstrated an ORR of 27.5% (95% CI 14.6-43.9), DOR of 16.4 months, and mPFS of 6.3 months. Given the differences in prior therapies, these three TROP2-targeting, captothecin payload ADCs look largely the same.

Thus far, exploration of biomarkers has not been definitive. As outlined by Santin and colleagues, assessment of TROP2 via histochemical (H) score has not correlated with response or PFS. DD has not presented biomarker data in endometrial cancer, and ST evaluated an H score > 200 with an ORR of 41.7%.

All these studies have incredibly small numbers, different assays, and thus far, no validation. The question is does the biomarker matter? There are two studies in the second-line, recurrent, post-CPI space that evaluate SG versus investigator-choice (IC) chemotherapy of either paclitaxel or doxorubicin () and ST vs IC (same choices) in the same population. Given the dismal performance of IC in this population, perhaps a biomarker doesn't matter and one of these two ADCs will outperform -- which is good, right? Well, maybe, but maybe not.

Maybe: It would be great to have another active therapy in the post-CPI space for our endometrial cancer population -- I 100% agree with this.

Maybe Not:

• TROP2 is not the only target in town for endometrial cancer conjugated with a camptothecin. There are published data from 40 patients with locally assessed HER2 2+ or 3+ treated with trastuzumab deruxtecan (TDXd) with striking ORR. This has led to an FDA accelerated approval for 3+ (ORR 84.6%) and National Comprehensive Cancer Network listing for 2+ and 3+. While 3+ HER2 seems like a clear decision for TDXd, what do we do with 2+ (ORR 47.1%), or even )? What is the overlap with TROP2 and if comparing two active agents, does the TROP2 biomarker matter in selecting an agent? With captothecin-linked ADCs coming that target B7-H4 and folate and others in the endometrial cancer space, how do we pick the right medicine for the right patient? With data from TDXd and SG in the HER2 low breast space suggesting possible cross-resistance between at least these two captothecin payloads, we have a lot of work to do to figure out selection and sequencing as these new ADCs come into the treatment space.

• Toxicity: Just focusing on TROP2 ADCs, SG and ST are weekly dosing versus DD with q 21 day dosing. Time toxicity for our patients is important. Santin et al. reported 56% diarrhea with 20% > grade 3 with SG and 40% neutropenia with 32% > grade 3. ST and DD are characterized by stomatitis -- 38.6% all grade and 13.6% > grade 3 for ST and 60% all grade and < 5% > grade 3 for DD. Grade 3 diarrhea or stomatitis should not be characterized as "manageable" -- really, is grade 2 diarrhea (4-6 extra bowel movements a day) or grade 2 stomatitis (requiring a modified diet) manageable to patients? What degree of efficacy makes this tradeoff acceptable?

Santin and co-authors are to be congratulated on this first publication of the activity of SG in a population of patients who represent current treatment experience (prior CPI, several LOT) with a modest response.

Now the hard work begins to evaluate the best ADC – TROP2 or not -- for the right tumor at the right time with an acceptable (to patients) risk-benefit ratio. I am excited for us to get to work.

Kathleen N. Moore, MD, MS, is deputy director and the Virginia Kerley Cade Chair in Developmental Therapeutics, and co-director of the Cancer Therapeutics Program of Stephenson Cancer Center at the University of Oklahoma Health Sciences Center. She is also a member of the Board of Directors of both ASCO and the GOG Foundation.

Read the study here and an interview about it here.