PFS and OS Data from TROPiCS-02

EP: 1.Article Introduction and HR+/HER2 mBC Background

EP: 2.The Role of Trop-2 in mBC and the Rationale for Use of Trop-2–directed ADCs

EP: 3.TROPiCS-02 Study Overview and Patient Baseline Characteristics

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EP: 4.PFS and OS Data from TROPiCS-02

EP: 5.TROPiCS-02: PFS Subgroup Analysis, Summary of Response Rates, and AEs

EP: 6.Key Takeaways & Clinical Implications

EP: 7.Recap: Sequencing Therapies for Patients With Relapsed/Refractory Hormone Receptor–Positive Breast Cancer

Dr. Sara Tolaney: We saw these data come out at ASCO where we saw for progression-free survival, there was a statistically significant improvement favoring Sacituzumab with the PFS being about four months in those patients getting physician's choice chemotherapy and 5.5 months in those patients getting Sacituzumab so a delta of about 1.5 months, which was consistent with this hazard ratio 0.66. Maybe, Martin, I'll turn to you first in terms of what did you think about this PFS delta when you first saw it? Was this something you felt was clinically meaningful? How did you think about it?

Dr. Martin Dietrich: Well, I think one of the problems in going back to the trial design is that one of the enrollment criteria that was actually missing was Trop 2 expression. It seemed to be a ubiquitous level of Trop 2 that seemed to more or less confer the same level of benefit. When we originally saw the progression-free survival benefit, I was underwhelmed. I do think that when I look at the drug, I have to really think about who are the long-term benefits. There's certainly an improvement there and that would be interesting, understanding who those patients are that would be benefiting long-term more so than chemotherapy I think would be of great interest. There's a lot of information that would come out of this basically look back and seeing which patients really benefit from Sacituzumab govitecan here. In the all-comers population, there was a statistically measurable but clinically, sort of underwhelming benefit that was seen in this opportunity. I would like to think of this as an additional option with PFS. I think in this serial chemotherapy setting of post-CDK4 progression and not necessarily ultimate measure. I think as we are looking further into overall survival, I believe that's where we really see and the impact of a drug and I think Sacituzumab actually has done much better there so utilizing this early on, probably a very reasonable option with the caveat that we have to acknowledge that we oftentimes will have seen an exposure to a topoisomerase inhibitor 1 prior to use here. I think this is going to be one of the caveats, at least in the HER2-low population. You don't really know how to use it, but when we move into overall survival, I believe we see, and I think there has been some updates also that actually confirmed a meaningful overall survival benefit so I think this a very reasonable option.

Dr. Sara Tolaney: Well, you bring up a lot of very important points here. I think one point being first I'd say this is an area of unmet need because if you look at the PFS and the control arm, it is four months. Again, this is people who have three prior lines of chemotherapy suggesting we do need better therapies here. I think seeing this incremental benefit, well modest at least is a movement forward. You bring up a lot of questions though also about understanding impact in different sequences because obviously, this was at a time where patients were not having had prior T-DXd and so we weren't having patients have prior TOPO-1 payloads that they were receiving and then sequentially going on to receive another TOPO-1 payload, which in the modern era will probably be about two-thirds of our hormone receptor-positive patients that will be HER2-low that potentially will have this sequence. Gregory, what was your takeaway on these initial PFS data? We'll circle to the updates in a minute.

Dr. Gregory Vidal: Just to highlight what you said, the control arm wasn't doing well either but still 1.5 months improvement was a little bit underwhelming when you take that into consideration when we saw DB-04. What? Six months difference in progression-free survival but we have to think about this is a different population. On DB-04, you couldn't have gotten one or two prior chemotherapies and this one was from two to four. It's a completely different population and that may explain some of the differences we see there, but I have to say when I saw it, I was a little bit underwhelmed and wondered whether or not it was clinically significant besides being statistically significant.

Dr. Sara Tolaney: Well, I think again very much important to remember our patient population. As you point out that this median was three prior lines of chemo. The median in DB-04 was one prior line so very different population where resistance mechanisms obviously are going to be very different given the prior exposure. These data were initially presented at ASCO for the interim analysis that was done at the time of the PFS analysis, where you see there was not a statistically significant difference at this time point, but we actually have now seen data from the second interim analysis which turns out to be the final OS analysis of TROPiCS-02 where in fact there was a 3.2-month difference in overall survival between the two arms that was statistically significant favoring Sacituzumab over chemotherapy. Maybe in light of what we all thought was sort of modest PFS benefits, how do you now rethink this seeing true statistically significant OS benefit? Maybe, Martin, I'll pass it back to you in your thoughts there.

Dr. Martin Dietrich: Well, I do think this was quite confirmatory of say an appropriate use in the setting. Greg actually pointed this out I think after four lines of prior chemotherapy. With three lines of prior chemotherapy, obviously, you would have a detrimental expectation between line to line. I like to think of this in a competition setting currently with trastuzumab deruxtecan. If I haven't HER2- patient meaning zero by immunohistochemistry, I believe they should be used after two lines of chemotherapy as a very competitive placement here. Clearly, with an overall survival benefit. I would not reserve it for a late-line setting. It's a very agreeable drug with side effects that we can manage. I do think this is an important addition and it was very reassuring to see the final overall survival update. I believe that gave it a good push forward. Over three months is in my opinion, in this patient population, not only statistically, but also clinically meaningful and really meets my threshold benchmark for clinical usefulness. I think this is going to be a very important part. Placement and sequence is going to be a big discussion. How this is going to shake out overall, only time will tell, but I believe that earlier usage is going to really allow the drug to exert a much broader effect than what we've seen in TROPiCS-02. Based on the design was kind of stacked against the drug in terms of outcome so hopefully, I will be able to place it earlier in our clinical setting and be able to make better use of it more, even more than the three months that we're seeing right now.

Dr. Sara Tolaney: I agree. I think that that very pretreated setting was a challenging setting for it and I think we'd all love to see data for how it performs in an earlier line setting.