A commentary on key takeaways from TROPiCS-02, remaining questions and unmet needs in the field, and the clinical implications of using SG and other Trop-2–directed ADCs in patients with HR+/HER2- mBC.
Dr. Sara Tolaney: This was a super helpful discussion to think through these data. Maybe, Martin, what would you say your key takeaways are from the TROPiCS-02 study?
Dr. Martin Dietrich: Well, I think now that we have the final overall survival analysis, I believe Sacituzumab has really found its way into the treatment paradigm. I believe that breast cancer has really developed into a molecularly driven and understood disease where the sequence may be dependent on the individual features. This will include PI3 kinase, BRCA, obviously, the HER2 expression now by immunohistochemistry. Now, with the addition of Sacituzumab govitecan in that space, also an all-common drug that really seems to have enough Trop-2 expression for usefulness across the board. I think that's also very helpful. Oftentimes, biomarkers are not available. They may be bone-only disease so that there may be a clinical urgency for repeat biopsies so it's not always a bad thing to have a drug that works in all backgrounds here independent of biomarker assessment. I believe defining the role of Trop-2 is going to be really important but in my opinion, question is where to place it. In my practice and at least for the HER2 negatives right now, I believe this is a second-line chemotherapy choice after CDK4/6 and one line of chemotherapy. Then moving it forward, I'll see the data will become more clarifying as time moves on. Then obviously the optimal pattern of supportive care for our treatments. I think that's another main concern. We talked about growth factors, we talked about prevention of alopecia as a quality of life factor. I believe those are all unanswered questions that we still need some answers for but overall, I'm very excited that we actually have this new opportunity for patients now, fully confirmed with overall survival benefit.
Dr. Sara Tolaney: It is really exciting. I think it has been a challenge for patients who are so pretreated with single-agent chemotherapy where our response rates are fairly low and so to have these other options is tremendous. Hopefully, this agent will also move up earlier as you point out.
There is a trial ongoing actually right out of our group looking at Sacituzumab in patients with zero to one prior lines of chemotherapy with metastatic hormone receptor-positive disease. That data we will hopefully see within the next year or so, so we'll learn more. Technically TROPiCS-02 did allow someone to be second line if you had had early relapse counted it as a line. There were some patients like that in this study. I would agree, I would typically tend to move it earlier in my usage too. If they were HER2-zero, I probably would use it post one line of chemotherapy and use it in a second-line setting. I think you brought up the sequencing issue and one of the analyses also presented at ESMO besides the final OS analysis was this exploratory look at HER2-low status in TROPiCS-02. They went back and looked at those patients who were technically HER2-low in the trial and looked at also how patients who were HER2-zero in this trial did treatment with chemotherapy compared to Sacituzumab in each of those groups. Basically, it suggested that there was benefit in both groups irrespective of HER2-low status. Technically the numerical difference was slightly larger in the HER2-low patients favoring Sacituzumab but even the response rate was actually higher in HER2-low compared to HER2-zero but I thought intriguing. I don't know. Gregory, what did you think when you saw that data? Did that influence you at all in any way?
Dr. Gregory Vidal: What it does is it makes me feel comfortable that if there is a HER2 sort of unknown patient where you don't have the tissue, you do really want to biopsy to recheck HER2. That Sacituzumab still has activity in that population. I have to say I spoke earlier that I felt like the 1.5 was a little underwhelming, but the overall survival took all that away. Another drug that we use, eribulin, a lot of us don't think about it. Really only had overall survival benefit in studies and we use it all the time and it actually has pretty effective. Yes, it really made me feel comfortable that regardless of the HER2 status, we see a response and I suspect we are also going to see that sort of data with T-DXd because if you think about it, theoretically HER2 is expressed on normal cells so there really truly shouldn't be a HER2-zero. It's really more about the threshold of the antibody that we use when we are doing or testing, we may also see that in that. We know that there's some small subsets of data that there is activity with T-DXd also. Again, just to repeat overall survival, that was very convincing to me and I would use that drug in the third-line or greater even after T-DXd and bring it up for the zero or the unknown.
Dr. Sara Tolaney: I fully agree. I think with regards to your comment about the target expression, which is I think very interesting, obviously, it's come up a lot with this HER2-low and that challenges with figuring out who's HER2-low, lack of quantitation of HER2 to really tease this out. I think, what about Trop-2? We saw data from ASCENT where they had retrospectively looked back at Trop-2 expression and found that both the low and medium and high expressors numerically did better with Sacituzumab compared to the control arm. The difference was larger in the intermediate and high expressers between the two arms, but still the difference remained present irrespective of expression level and so at this point in triple-negative disease, we're not testing for Trop-2. We haven't seen data yet from TROPiCS-02 looking at Trop-2 expression, but do you think there's going to be a role for needing to understand Trop-2 expression for selection of Sacituzumab? I don't know. Maybe I'll turn to Gregory.
Dr. Gregory Vidal: I do think understanding the expression would be important. Ultimately, I don't think it's going to guide whether or not we give those patients a drug or not. We do see like you mentioned in ASCENT, even the low, there was some activity there and hopefully, we see the same thing here in TROPiCS-02. Ultimately, I don't know how it would guide our decision clinically but the drug would still be available.
Dr. Sara Tolaney: Well, it shows you we have a lot more to learn about selection for response and resistance to ADCs and also with ADC sequencing, as you both have pointed out.
Dr. Gregory Vidal: I think the future for breast cancer and these drugs and ADC as a whole, is bright because we're recognizing that we can now target these cancers with smaller amount of chemotherapy and hopefully doing less damage to normal cells.
Dr. Sara Tolaney: I totally agree. I think these ADCs are really revolutionizing outcomes in breast cancer and they're more and more in development. We didn't talk about it but Dato-DXd, for example, also targeting Trop-2 with TOPO1 payload. I think it's going to leave us with a lot of questions though because if all these ADCs start moving forward, I think the major issue is going to be sequencing because we have no idea why someone's developing resistance to an ADC. Is it to the target? Is it to the payload? Can you use the same payload if you change the target? There's just so much we have to learn, but it's an exciting place to be in to have these opportunities for our patients that are really improving outcomes. I would say thank you guys so much for this really helpful discussion to think through all that's going on in metastatic hormone receptor-positive disease. Again, very exciting to see new agents like Sacituzumab emerge. Thank you both.
Dr. Gregory Vidal: Thank you.
Dr. Martin Dietrich: Thank you for having us.