Testing for PD-L1 Expression in mTNBC

Joyce A. O'Shaughnessy, MD: How about you, Sara? What do you do with all the data at hand right now in your practice? What’s your approach to testing for PD-L1?

Sara Tolaney, MD, MPH: Right now, we are testing with SP142 on that Ventana platform. Really, because as Sara Hurvitz very nicely reviewed that analysis that Hope Rugo, MD, had done, suggesting that the SP142 antibody was really the best predictor of benefit to atezolizumab. Given that, we did feel like we even had to validate the platform at Dana-Farber Cancer Institute in order to do that, because for the other diseases, our pathologists have been using a different antibody. We had to just do this for breast cancer, but they made it happen because of the strong data there are to support using it as a predictor for atezolizumab benefit. As Kevin alluded to, we are waiting to see if pembrolizumab is going to be approved based on KEYNOTE-355.

Obviously, as we discussed, that does utilize a different antibody with 22C3. We have had some discussions with our pathologists about what the impact of that would be at our institution. Are we going to start testing with one antibody vs the other, or both? They told us they will not test for both, and that we really have to make up our minds and pick one. I do think we are going to have to make a decision here because it’s hard to do all of these tests, and there is some discordance, even in Hope’s very good presentation. If you looked at the CPS [combined positive score] 10 subgroup and SP142-1, there was still some discordance, even though the CPS 10 did seem to have the most overlap compared to CPS 1 or 22C3 with 1. There was still some discordance. You could have one assay be positive and the other one negative.

This is why this field is so confusing. We’ll probably end up continuing with the SP142 since that’s what our institution has now figured out how to do. Then the question is going to be what do you pick? Are you going to pick using taxane with pembrolizumab vs nab-paclitaxel with atezolizumab? Are you going to use carboplatin-gemcitabine? It’s probably going to depend on the patient. The nice thing about KEYNOTE-355 is it did include patients who had early relapse. We don’t have that yet, we’ll eventually get that from IMpassion132, but we don’t have those data yet.

We’re stuck with a taxane backbone with atezolizumab, and I think that’s not what we want to give to someone who relapsed soon after adjuvant taxane, and we don’t yet have data for that. I probably would use carboplatin-gemcitabine-pembrolizumab in an early relapsed patient. That being said, if you look at the subgroup analyses in KEYNOTE-355, they didn’t quite do as well as the taxane group. We all have to be cautious because obviously the carboplatin-gemcitabine arm is more weighted with early relapsed patients who are bad performers compared to the taxane arm. That study is not powered to compare the chemotherapy. We cannot use it to say one is a better backbone than the other. It does make us wonder, obviously, how good is carboplatin-gemcitabine-pembrolizumab in an early relapsed patient? How much benefit are we really seeing in that specific subgroup?

Because we do see them, unfortunately, not infrequently. In that group I probably will use pembrolizumab. I will also throw my hands up in the air about IMpassion131. One thing I will point out, and I was totally surprised, I really thought it was definitely going to be true that paclitaxel-atezolizumab would be the same as nab-paclitaxel-atezolizumab. It is interesting if you look at the study design, the number of patients in the control arm who are PD-L1 positive is very small. That control arm is performing much better in terms of survival than the IMpassion130 control arm. It does make you wonder why is that? Is there some difference in the patient populations?

I think Kevin was alluding to that. Technically it’s the same number of patients who had had prior taxane exposure, but we don’t know the nuances of that. How long ago was that prior taxane? Was it different in the 2 studies? The number of de novo patients is also smaller in IMpassion131. There are some very subtle differences. We don’t know the differences in PD-L1 testing on primary vs metastatic, and there are some very small differences that potentially could pan out here. I agree I didn’t really think steroids were going to make a difference because we saw in the early disease setting it probably doesn’t matter. This is a different setting, it’s a metastatic population where the immune microenvironment isn’t as good.

It sounds like most people do continue their steroids through the whole time they’re on chemotherapy for most patients in IMpassion131. They were getting it for quite a long time, not just for a couple of doses, so maybe it had a little impact. I honestly don’t know what the right answer is.

Joyce A. O'Shaughnessy, MD: Thank you so much, lovely.

Kevin M. Kalinsky, MD: Can I make one comment before you go on?

Joyce A. O'Shaughnessy, MD: Yes, go ahead, sure.

Kevin M. Kalinsky, MD: The steroid issue was an interesting one because if you look at the adverse events of special interest, there were less in IMpassion130.

Joyce A. O'Shaughnessy, MD: Interesting, good point. Yes.

Kevin M. Kalinsky, MD: I agree. Maybe it’s just mismatching. I think it’s still the most likely explanation.It’s likely that PD-1 low positivity, it’s a patient selection issue, maybe a random patient selection. But I’m still looking at that steroids and looking at the fewer adverse events of special interest.

Joyce A. O'Shaughnessy, MD: Yes, that’s an interesting point there. It sounds like’s in summary, we’ve got 2 trials now with now with nab-paclitaxel and atezolizumab—the IMpassion130 with a survival advantage, that’s firm, and then the IMpassion031 in the preoperative setting that has a very nice delta on pathologic complete response. Atezolizumab is really doing well with nab-paclitaxel, that ought to be the standard of care for our patients who we’re going to give a taxane to, correct me if I’m wrong. There are some patients where the taxane may not make sense for a variety of reasons. Then we do have the gemcitabine, carboplatin, and pembrolizumab. It’s not FDA approved yet, but it’s not an unreasonable choice for patients where taxane is not the best choice for them.

Then we do have the pembrolizumab approval as well for tumor mutational burden high. I don’t know if that’s actually approved, but the MSI [microsatellite instability] high is approved. We have data in metastatic breast cancer that’s tumor mutational burden high, where pembrolizumab can have a positive impact as a single agent. There are some durable responses in those patients, and then MSI high. We don’t find those very often when we do next-generation sequencing, but we will find them occasionally. We do have the opportunity to use pembrolizumab for those patients.

We will stay tuned as some of the data mature, like KEYNOTE-355 on survival, and as we see other trials that we’ll talk about a little bit later to try to improve upon the impact with the immune therapy in the metastatic setting. Thank you guys so much for that summary. I think that brings us right up to date about where we are.

Transcript Edited for Clarity