Round 1—Can an Anti-Drug Conjugate (ADC)-Based Regimen Now Be Considered the New Standard of Care in PD-L1+ mTNBC?

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Tiffany A. Traina, MD: So hopefully that sets a little bit of a quick landscape for us to move into Round 1 of our discussion together, and that's going to be looking at whether an ADC regimen now can be considered a new standard of care.  

Sonya Reid, MD, MPH: Alright, so I'll be taking the slant for advocating for an ADC-based regimen. This is really due to the fact that we know that ADCs, as Tiffany mentioned, have really improved how we are able to treat our patients and to increase a targeted way of giving a high payload to our patients and, therefore, increase cell death. We know that their synergy from combining with immunotherapy agents such as pembrolizumab with anti-PD-L1 activity, therefore increasing, kind of priming the cells with the ADC to have more immune cell death. So, ASCENT-04 essentially looked at our advanced TNBC patients that were PD-L1+; patients were randomized to SG plus pembrolizumab compared to standard of care currently, which is chemo plus pembrolizumab, with the primary endpoint here being PFS. As noted, you'll see the secondary endpoints, including OS and safety, of course. The primary endpoint, PFS, was reported back at ASCO this year. Here, we saw a significant improvement in the median PFS from 7.8 months to 11.2 months with a hazard ratio of 0.65. Then, looking at the overall survival, albeit immature, we saw a positive trend in improvement despite the high crossover rate that was noted between the two arms. And I'll hand it over to Seth.  

Seth Wander, MD, PhD: Thanks. A great pleasure to be with everybody this morning. I think this will be a very friendly chat. The debates will get a little fiercer as the weekend goes on. So I think this is an interesting discussion. It's always hard. You have to look at the new data that we just saw over the last couple of months and try to put it into context, not just in the first-line setting but for the entire spectrum of treatment. First, second, and third line. I'm going to make the backward-looking argument of using chemotherapy first here, as best I can. Here's data from KEYNOTE-355, which I think we would all agree is the current standard of care for a PD-L1+ triple negative patient in the first-line setting, where we're combining pembrolizumab with a couple of different chemotherapy choices. Here we see median progression-free survival of almost 10 months from that original publication.  

What I'm showing you on the right is the primary endpoint from the ASCENT study that we just heard a little bit about from Tiffany, showing in the second-line setting for chemotherapy-refractory triple-negative breast cancer, sacituzumab, lasting about 5 to 6 months. For my friend Sonia, we have to be convinced that the first plus second line, if we were to deploy sacituzumab earlier, could give us a total PFS of somewhere exceeding, I think, 15 to 16 months. To me, we don't know much about the response of triple-negative breast cancer after progression on first-line sacituzumab and pembrolizumab. So I would suspect and be curious to hear what the audience thinks and what my friends up here think. What is the response rate going to be after ASCENT-04? What will the best therapeutic approach be? Can we combine two lines of therapy to exceed 15 to 16 months if we move SG earlier?  

Is it a lead time bias, or are we actually changing the course of disease and seeing clinical benefit? I think the other advantage I have for looking backwards here with this argument is that we have more mature survival data. We actually have a positive survival endpoint for deploying chemotherapy with pembrolizumab. First, here's the overall survival data from KEYNOTE-355 showing an improvement from about 16 to 23 months, which was clinically significant. Now we saw we have an immature trend toward overall survival with ASCENT-04, but at the moment we do not have positive survival data in that setting.  

Then, here is older data from Impassion130; this is atezolizumab with nab-paclitaxel. If you look on the right-hand side, we see overall survival in the PD-L1+ subgroup. Again, showing you that this strategy of chemotherapy plus immune therapy in a treatment-naive metastatic triple-negative setting can provoke overall survival benefit. Now, in the interest of full disclosure, we have to acknowledge that we had a subsequent follow-up from Impassion130 that did not meet its primary endpoint, which is why we're not using this strategy. But again, I'll reflect back on the KEYNOTE-355, and then just to end, which I don't really think is a topic of debate today, this is from the same meta-analysis that I think we were seeing with Tiffany a minute ago, showing that we really don't have that signal for PD-L1− tumors. So, when you're combining immune therapy with chemotherapy in a PD-L1 population, we're really not seeing that same signal of benefit that we are for the two studies that I just showed you that are PD-L1+. This is really an important area of unmet clinical need. We have to develop better therapies to convey the same degrees of benefit for the PD-L1− population in the frontline setting.