Role of Immune Checkpoint Inhibitor-Based Therapy in ES TNBC

Joyce A. O’Shaughnessy, MD: Kevin, take it away. Why are these studies different—NeoTRIP and IMpassion031—yet KEYNOTE-522 and IMpassion031 are very similar? Importantly, what do we do with these data now, Kevin?

Kevin M. Kalinsky, MD: Many thoughts here. One, I would say in NeoTRIPaPDL1, the study was powered to look at event-free survival, so the study was not powered. One of the secondary objectives was to look at pCR [pathologic complete response]. I do think that with that study, a smaller study, and then KEYNOTE-522, which Sara had mentioned, we still need to follow the patients out. To me, just to summarize some of these things, in the KEYNOTE-522 and the IMpassion031, the things that were consistent between those 2 studies were that Adam and Sara had mentioned that PD-L1 expression can associate as being a predictor for response to chemotherapy but not necessarily predict who benefits from adding in checkpoint inhibitor. The other thing, I would say, is that when I was watching the presentation that was consistent between the 2 studies, those patients who had node-positive disease seemed to benefit the most with the addition of checkpoint inhibition.

We may not be seeing this benefit in NeoTRIPaPDL1 could be a few reasons. One of the things I proposed is there could there be a difference between PD-1 vs PD-L1 inhibitors, and maybe this had to do with blocking PD-L2. But clearly, we see a randomized study where there is a benefit with a PD-L1 inhibitor. So I don’t think that’s it. I also think that maybe this has to do with giving an anthracycline. I think 1 of the other studies that Sara Hurvitz had mentioned is the ubiquitous I-SPY2 study. They also had presented some data at San Antonio [Breast Cancer Symposium] in which patients received pembrolizumab plus a taxane followed by pembrolizumab alone without an anthracycline, and that was a negative arm. There may be some additional immune sensitivity with giving an anthracycline.

There is another thing I want to throw out. When I was watching the data being presented, in the arm in IMpassion031, which was a noncarboplatin-containing arm, we were seeing—not to compare studies—pCR rates that were relatively similar to what we saw in KEYNOTE-522, in which patients received a platinum. To me, it still asks this question: Do we give immunotherapy, whether patients really need to escalate with giving a platinum or not?

Joyce A. O’Shaughnessy, MD: That’s another very, very important question coming out from these data. Go ahead, Adam.

Adam M. Brufsky, MD, PhD: I’m fascinated because, from a scientific point, why the node-positive ones are the ones that have benefited from the I/O [immuno-oncology] in comparison, and it’s telling us something. Maybe it’s telling us that those are the people whose immune systems aren’t dealing with the cancer, and that’s the 1 that needs the extra boost.

Joyce A. O’Shaughnessy, MD: Of course, the cancer is sitting in the lymph nodes, so you’re starting to kill the cancer. It’s in the lymph nodes the TILs [tumor-infiltrating lymphocytes] are there.

Adam M. Brufsky, MD, PhD: This goes back to Bernie Fisher, right? The lymph nodes are just a marker that your whole body can or cannot deal with the cancer. It’s a radical idea, right? I don’t know if this is right or not, but we’re on this thing, so we can speculate and say whatever we want. The bottom line is that it maybe that’s what it is. Maybe it’s the fact that those are the people who need a checkpoint inhibitor because the fact that it got to the lymph nodes is telling you that your body may not be able to deal with it as well. I don’t know. I’m just raising that as a possibility.

Joyce A. O’Shaughnessy, MD: Let me turn to the Saras and see what you think in terms of our practice. Of course, we wait for regulatory approval. We want the FDA to see all the data and look at everything that’s critically important. Nonetheless, we do have very, very high-risk patients in our practice. Even tomorrow, we have very high risk patients. Do we use them now? Do you think we’ll be using them? Also, what about this carboplatin question? It’s difficult to do cross-trial comparisons because the percentage of patients with nodes positive was not exactly the same. The KEYNOTE-522 trial, which had a higher-risk population, had more node-positive patients and, as I recall, also more stage III patients. It was a higher-risk population.

With the carboplatin, the pCR rate was 64.5% or something—not quite 65% but over 64%—vs just over 57%, so it was a little higher with the carboplatin in a more high-risk population. But close, as Kevin said, close. You’re not that far apart. Let’s get your perspective. We need to see and have more time to chew on it. Let me just ask Sara Hurvitz, what are your impressions?

Sara A. Hurvitz, MD: The data—it seems like every day something else comes out, and that challenges the notions and the preconceived understanding of what’s happening. We make sense of it and then a study comes along and we have to rethink our paradigm thinking. We are thinking that perhaps paclitaxel isn’t the right thing to use with immune checkpoint inhibitors because you have to use steroids. We have several studies now that show increased pCR rates with paclitaxel. This anthracycline notion—there is something to it, Kevin. I hate to say it coming from the West Coast. I’m reluctant, I have to say, to use these routinely in all triple negative in the neoadjuvant setting.

However, in the neoadjuvant setting, if we’re seeing a patient not respond or frankly progress, this is where I’ve used it. I have to say, I’ve seen some very impressive responses to patients who I started on the taxane platinum, and the tumor did not budge. It’s clearly in the nodes, and we’re going in the wrong direction. I’ve switched to dose-dense AC [doxorubicin, cyclophosphamide]. I’ve been able to use the pembrolizumab in spite of it not being approved here, and I’ve had RCB-I [residual breast cancer stage 1] in 2 patients. I’m becoming a believer. I do think we really need to wait for the EFS [event-free survival] data before we use this routinely and need to have a better understanding of the biology and predictors of who really benefits.

Joyce A. O’Shaughnessy, MD: Thank you. When you end up using it, just because you have tended to start with the taxane-carboplatin anyway, that’s probably going to be the paradigm you use hopefully, once we get full approval for these patients. How about you, Sara Tolaney?

Sara Tolaney, MD, MPH: I’ve also been struggling. As Sara said, all these data keep coming out. I was en route with KEYNOTE-522 thinking, “OK, I know that there is an improved pCR, that this pCR difference is actually very large in the stage III patients.” The delta pCR is a little over 20%. It’s really a very big improvement. This is a population that has a very high risk of recurrence, and we do need to do something to improve outcomes. But where I’m a little weary is that there are—I’m sure we’ll get into more discussions about this—toxicities to weigh here.

Without a good biomarker to select which patients are the ones benefiting, we have to be very cautious in our patient selection. At this point we’re going to have to end up using anatomic risk because we don’t have a good biomarker. PD-L1 is not predicting who is benefiting. We see that the benefit is larger in these high-risk patients. Once we get an approval, that’s probably the direction I’d go: taking my node-positive patients as the patients that I probably would consider for adding immunotherapy. As everyone has alluded to, we really do want to see the long-term outcome data.

KEYNOTE-522 is powered for EFS. It was a very smart design to have a coprimary EFS end point, because that’s what we also really care about. Lack of pCR is associated with poor long-term outcomes. But on a trial-level basis, this is where we have not had good concordance definitively with PCR and EFS. We just want to see it. The trend is quite clear that it is heading there, but we do want it. IMpassion031 unfortunately was not powered for EFS. We’re never going to get from that trial a sufficiently powered EFS without the platinum backbone, which is a shame. They’ll get their data from their adjuvant trial.

That’s where it’s hard to make that decision, because we won’t be able to cross-trial compare EFS to know if we should be giving the platinum. It’s going to be based on risk, and I probably will avoid the platinum if I can because I feel like I’m already escalating therapy by adding immunotherapy. The delta was quite impressive in IMpassion031 without the platinum, with about a 16% delta. I probably would omit it. But in truth, it’s obviously not a data-driven decision because we don’t have that EFS to make that call.

Adam M. Brufsky, MD, PhD: Can I ask a question about a propensity match? This whole propensity matching was iffy 1 way or the other. But propensity matching across the 2 trials tried to find the patients who are most similar in the control arms of each to see whether the platinum is of benefit. I’m just thinking about an offhand way to figure this out.

Joyce A. O’Shaughnessy, MD: Yeah, the numbers in IMpassion031 are going to be the things that are limiting. There will be data from the GeparDouze trial, which is preoperative. That does have carboplatin, paclitaxel, and AC in it, and that’s with atezolizumab.

Adam M. Brufsky, MD, PhD: We can talk about it later, but doesn’t B-59 require carboplatin also?

Joyce A. O’Shaughnessy, MD: Yes, that’s what I was saying. There’s the B-59. There will be another big 1 that maybe will help. We’ll have enough numbers because we may have an apples-to-apples comparison there.

Transcript Edited for Clarity