Andrea Necchi: Thank you, Zach, and thank you today for inviting.
Zachary Klaassen: Absolutely. So when we look at the neoadjuvant space, it's getting quite busy, and what's the rationale to do this study in these residual tumors after patients have been treated?
Andrea Necchi: Yeah, we were interested to do so because we were interested in understanding more on the biology and the shift in biology from pre to post therapy samples in different neoadjuvant therapy situations, taking samples from our own studies, investigative initiative studies starting from PURE-O1, which was neoadjuvant pembrolizumab monotherapy, then SURE-01 and neoadjuvant sacituzumab govitecan immunomonotherapy, and SURE-02, which was a combination of the two.
We look at the gene expression profiling. So actually, we performed a transcriptomic analysis of post and pre-therapy and matched samples for all of these studies. PURE-01 results from pre to post-therapy samples have been already published in European Urology a few years ago. But the point actually was the contribution of ADC component, the anti-Trop-2 component in the tumor tissue samples and the tumor and the biology shifting. So what we saw is particularly important to me because there was clearly a shift in the biology in terms of molecular classification, shift in molecular classification between luminal to non-luminal type, for example.
It was particularly important in SURE-01 and SURE-02 as compared to PURE-01 with immune therapy alone, and all the rest of the transcriptomic signatures or gene expression signatures or gene expressions changed substantially from pre to post-therapy. The major shift was seen in the SURE-01 population, so ADC monotherapy, as compared to immune therapy component with SURE-02 and PURE-01.
Also, another important point that we made is about the shifting expression of potentially druggable targets, meaning Trop-02, which is the target of the sacituzumab govitecan, but also HER2, Nectin-4, and we see globally a decrease in the expression of these targets that are confined to the luminal component of the tumor in the post-therapy samples. So of course, it's a study which is limited by small numbers, limited by the uncontrolled effect, because we are dealing with single arm studies. Each study is a single-arm study without any kind of control, so everything should be validated.
But it's important to make the case of analyzing the post-therapy samples just because we are dealing with the residual infiltrating, maybe it could be defined as a non-responsive tumor, so infiltrating pT2, pT3 or pT4 tumor post-therapy. So when it comes to the definition of a sequential therapy, which is now the goal for any perioperative therapy that entails a neoadjuvant and adjuvant part, shifting treatments, for example, from one therapy to another one based on the shift in biology, it is more than likely that there would be a possibility in the future for the next clinical trials.
Zachary Klaassen: Yeah, that's absolutely exactly where I wanted to go with this, because it's a very elegant trial or a very elegant analysis to inform what happens when these residual tumors have changes. So you had mentioned external validation, continued validation of course, but how do you see this information maybe informing those next trials?
Andrea Necchi: Basically, we analyze the possible target for antibodies, Trop2, HER2, Nectin-4, but if you see that the biomarker results made from the baseline tumor samples reported in SURE-01, which was just published today in NJCO, or SURE-02, biomarker data interestingly are pointing to the payload rather than to the antibody. For example, in SURE-01, we saw that higher gene expression of TOP1, which is the target of the payload, were correlated with or associated with the benefit, event-free survival with saci and radical cystectomy. So the missing part here, and this is certainly something that we are in plan to do in these same samples and in further samples that we collect from other studies, is to look at the biomarkers as potentially associated to the payload.
Zachary Klaassen: I see.
Andrea Necchi: Because the game is played, when it comes to the sequential therapies, the sequencing of the ADCs, it is more than likely that the game will be played on the sequencing of the payloads rather than the targets of the antibodies. This is the emerging data that have been presented also at this year meeting from various studies pointing to, for example, to the activity of the top one ADCs in EV exposed population, and not using the same ADC with the same payload for which the activity drops down. So it's an intriguing part. In general, we are still at the very beginning of the identification of biomarkers in response to ADCs, and in particular biomarkers associated to an optimal sequential strategy in patients with bladder cancer will be the key for the future and for the next five-year biomarker analysis.
Zachary Klaassen: Fantastic answer. I think that's absolutely brilliant. Congratulations on the great work. Anything we haven't covered from your work that we want to highlight before we wrap up?
Andrea Necchi: The story of perioperative therapy is just at the beginning, so the big part that will be targeted in the next studies is that we are dealing basically with studies, with the only exception or SURE-02, studies that take into account a radical cystectomy component and samples taken from radical cystectomy. So the good point here, and this is something that we made for SURE-02, is to analyze tumor samples for patients who receive a re-TURBT or a biopsy or a bladder sparing opportunity. So biomarker associated with pre and post-therapy association in a bladder sparing context will be the next key for the next generation analysis.
Zachary Klaassen: Fantastic. Andrea, congratulations again. Thanks so much for joining us on UroToday.
Andrea Necchi: Thank you for inviting me.