 One other point I want to bring out about the KEYNOTE-355 trial was that when you look at the forest plot, and I think, Hope, you alluded to this, the 2 taxane options, the nab-paclitaxel and the paclitaxel, the hazard ratio with the addition of the pembrolizumab was in the 0.5 ballpark. It was quite robust with regard to PFS , very impressive. The point estimate with gemcitabine and carboplatin with the addition of pembrolizumab was not as striking, it was 0.7, 0.74, or something like that.

It is because the patients who recurred quickly were allowed on the trial. As Hope described, as long as they had made 6 months, they were still allowed, and that's a very poor prognosis subgroup. By protocol, they were required to get the gemcitabine, carboplatin. The gemcitabine, carboplatin were the patients who had the poorest prognosis. I think that the choice of gemcitabine, carboplatin and pembrolizumab would be a very reasonable choice. In other words, I'm not deterred at all by those data, and I want to hear from you guys.

Hope, how are you going to decide? Let's say pembrolizumab is fully approved; we don't have OS yet, but where might you think about using gemcitabine, carboplatin, plus pembrolizumab, for example?

 To comment on the approval, I do think it is likely that we'll need an overall survival, but of course we don’t know. I hope that we’ll see that in the not too distant future. But I think that we would use the same criteria that I used when I enrolled patients on KEYNOTE-355. It's patients who did not respond to neoadjuvant taxanes and progressed at 6 months or greater; I would choose gemcitabine, carboplatin. We do have a difficult situation in those patients.

I think we're interested to see if we can capture more of those patients by treating them in the neoadjuvant setting, for example, or post-neoadjuvant setting. I doubt it because if you think about it, if you had residual disease, I don't think post-neoadjuvant treatment will work because you're going to give them capecitabine for 6 months. By then, those people will have started to recur, so you're not going to capture them by giving them a checkpoint inhibitor after that.

That's where our differentials are in clinical practice when we don't use checkpoint inhibitors, and I would use the same. I tend to use nab-paclitaxel if a patient has already seen paclitaxel in that setting at 100 mg per meter squared. Certainly that's the dose we used in IMpassion130. There are some data in the neoadjuvant setting and others that suggest that higher doses are more effective, but it's never been definitive, and you get so much neuropathy, you're limited on duration.

 Thank you. Denise or Tiffany, any other comments about the gemcitabine, carboplatin in KEYNOTE-355?

 I would echo what Hope has said, and I think that our neoadjuvant and adjuvant approaches are rapidly changing with emerging data about the use of checkpoint inhibitors. Interestingly, we have the I-SPY data of pembrolizumab in the preoperative setting. We have neoadjuvant data there suggesting benefit. It'll be interesting to see what happens if that is really moving into the earlier space, how we're treating our patients who recur, whether it's 6 months or later in that first-line setting, who remain PD-L1 positive.

 Exactly. How about you Denise, any final thoughts on KEYNOTE-355?

 I echo the practice comments that both Hope and Tiffany have made. It's a nice ability to welcome and embrace another chemotherapy combination with immunotherapy in triple negative breast cancer. I think a lot of those patients have been taxane-exposed and have toxicities, and there are limitations in being able to deliver that. Being able to have gemcitabine, carboplatin and feeling good about that combination and the results of those combinations, although we're still waiting on the survival, will be a welcome addition. Because there are many patients who either have toxicities with the taxanes or aren't good candidates, from neuropathy, from other medical conditions like diabetes, that now gives us a way to continue to deliver what we think is going to be our standard of care with immunotherapy in that population.

 Right, well said. More options to decrease toxicity and increase efficacy for patients. Real nice data.

Videos

KEYNOTE-355 Regimen’s Role in Treatment Paradigm

 I want to hear from everybody about what you are doing about testing for PD-L1 now in your practice. It almost seems like, the CPS [combined positive score] of 10 or more was seen in 38% of the population, and the SP142 was 40%, 41% in the IMpassion130. The first question is, although they're different antibodies and though the SP142 was just immune cells, the CPS is both tumor cells and immune cells, still it's interesting that they're coming in around 40% of the patients.

First of all, are they the same patients? And secondly, from a practical standpoint, is it going to be where if I get any test that is PD-L1 positive by the definition for that antibody, that I'm going to say I can use whatever checkpoint inhibitor I want?

Hope, is there a real overlap between the 40% in the 2 trials?

 It's interesting, and they'll have to go back on the available tumor samples and use the other testing methods. This is something we did in IMpassion130 and data we presented at ESMO [the European Society for Medical Oncology annual meeting] last year, when we had in-person meetings. What we did was we looked at the biomarker-evaluable population, where about 46% of patients were SP142 positive. This is an antibody where 1% or more of the immune cells need to test positive for PD-L1. We compared it to 22C3 and another antibody, and 22C3 uses the CPS scoring system where you make a ratio that includes both tumor cells and immune cells. In that, 80% of patients were positive.

If you use a score of 1 for CPS, you're measuring most tumors, and that is almost identical to what was seen in the neoadjuvant KEYNOTE-522 trial. Seventy-five percent of patients had a CPS score of 1 or greater. When we looked at the overlap, almost all except for 1% of patients who were positive by SP142, were positive by the CPS score. It does appear that it encompasses the same group of patients. When you do modeling, it's a little bit different, but in this patient group, more patients were positive with CPS.

If you used SP142, you basically got the population that was also CPS positive, so it makes me think by leading in…. And then when they looked at the benefits by progression-free survival and overall survival in IMpassion130, the double positives got the benefit. It was the SP142 that stood out, so you could have a hypothesis that this 39% or so in KEYNOTE-355 are almost a similar group of patients who are positive by SP142, even though we don't know for sure. It does suggest that, it is very unfortunate, but about 40% of our patients can benefit; the rest we need to do more for.

 Thanks, that helps us in practice a little bit. It kind of simplifies things. Tiffany, what are you guys doing at Memorial Sloan Kettering Cancer Center in terms of testing? And how do you think you’ll interpret, now that we have 2 different antibodies, and soon we will have pembrolizumab available to us in practice. What antibody are you guys going to use, do you know yet?

 Great question. We have been using the SP142 antibody, given the atezolizumab indication and the data that we have from IMpassion130 already. I think Hope raises some interesting points about the degree of overlap, and maybe we are looking at the same population when you use the CPS of greater than 10 and the Ventana SP142. It'll be interesting to see what ultimately the indications are and where positivity is set for CPS score.

Honestly, of the hazard ratios and the potential benefit seem so close, even for CPS greater than 1, although that didn't meet statistical significance. I think for now we are still using SP142 as our antibody of choice. Another point that hasn't really been raised is what tissue is used for testing and some of the limitations there. With using SP142 as the antibody of the choice, we know we are unable to do that assay on cytology. We're unable to do that on bone. We tend to prefer using this assay on, say, the breast primary when trying to distinguish what the PD-L1 status is, and I'm curious if perhaps the CPS score may allow for some different testing. I don't know if anyone's experienced that in using the CPS assay.

 Yes, I want to clarify what you just said there, Tiffany. You said for the SP142, it’s not advisable to use it for bone. Was there another tissue that wasn't advisable?

 Yes. You cannot do it on cytology on FNA  you need core tissue for that.

 That's interesting. I think that what has happened, not just in IMpassion130, we don't have the data from KEYNOTE-355 yet, but also from other studies that Sherene Loi, MD, and others have done from the earlier trials with single-agent checkpoint inhibitors, is that the PD-L1 positivity varies by site of disease. People thought that LDH might be a marker of resistance when your LDH is high, and liver metastases were. It's fascinating that that was the lowest percentage of positivity we saw in IMpassion130.

It was a small number of patients, but still, fit into all the other spectrum of data where breast, much more likely to be positive, lung, and soft tissue. In fact, the 1 long-term survivor I have on pembrolizumab from the KEYNOTE trial in the second-line cohort is somebody who had lung metastases. It's fascinating that maybe it's more immune sensitive.

 Interesting. Denise, what about you guys? What are you doing right now with testing around the atezolizumab selection of patients? Do you think that the new KEYNOTE data will make any difference in your testing?

 I think so. Traditionally, based on the FDA approval, we've been using the SP142, but we do a lot of other molecular testing and profiling where we get signals of positivity. That doesn't correspond to the tests that the FDA requires for approval. Now with the exciting data with pembrolizumab, we're having to rethink the strategy of how we're going to incorporate selecting which tests for which patient population. And then moving forward with health care providers, how they are going to look at these 2 immunotherapies as they hit the market for triple negatives.

I think that will be giving us some direction as well, but for the most part we've gotten comfortable with the SP142, and now we're going to have to rethink the algorithms as we have all these diagnostic companion tests that are required by the FDA to be able to utilize those agents based on the exciting data.

 Yes, and it is reassuring to me that if…it happens to be that not all the laboratories carry all of the antibodies, etc, if we get an SP142, 1 or more, it's likely that that's going to be a CPS of 10 or more. It's not 100% overlap perhaps, but it's likely, and vice versa. Personally, I'll feel comfortable, because not all the labs are going to have all of the assays. I take a little bit of comfort as well that the CPS of 1 or more was very close to statistical significance. Even if you were off a hair, give or take, giving the patient the benefit of the doubt of the checkpoint inhibitor doesn't seem to be out of the ballpark.

PD-L1 Testing Standard of Practice

 Let's turn to some new data. I'm going to turn us over to Hope Rugo, who is going to take us through the KEYNOTE-355 study, and also very importantly, how we find these patients who are PD-L1 positive.

 Thanks very much, Joyce. This was a very interesting presentation at ASCO [the American Society of Clinical Oncology annual meeting] this year. We've been waiting for additional data after the striking and practice-changing data from IMpassion130. KEYNOTE-355 differed in a couple of ways. One was that patients were included who had developed metastatic disease, 6 months or greater, so greater than 6 months after they had received their last treatment with curative intent chemotherapy. For example, neoadjuvant or adjuvant taxane or anthracycline. The second difference is that in addition to nab-paclitaxel as a chemotherapy partner, patients were also allowed to receive paclitaxel, and gemcitabine and carboplatin.

Those 2 key differences in design are important for us clinically because we do see quite a number of patients who relapse within that 6- to 12-month period where we believe they have relative taxane resistance. I think we've all been interested to find out whether checkpoint inhibitors can be combined with different agents because essentially all of the data with the exception of a small trial with eribulin has been with nab-paclitaxel, or in some cases paclitaxel. If we think about the single-agent data, I think it's clear to us all that we did need more information about combinations with chemotherapy. The monotherapy data showed response rates in the mid-20%, low-20% range for patients in the first-line setting, but in the second- or greater-line setting, response rates were very low, even when PD-L1 positivity was selected for. Like IMpassion130, the KEYNOTE-355 trial was designed to include all-intent-to treat patients.

Patients were randomized 2:1 to receive pembrolizumab or placebo with a chemotherapy partner of choice, but you basically broke down the study like Impassion, into the intent to treat and then the patients who had PD-L1 positivity. Here's where we get into another major difference, which for the clinician is complex in terms of clinical decision-making. There are a number of different antibodies that are commonly used and different mechanisms of scoring to determine PD-L1 positivity. For pembrolizumab, 22C3 is the antibody, compared to SP142 with IMpassion130, and they used a scoring system called CPS [combined positive score].

A score of 1 or greater has been positive, and in the entire population of KEYNOTE-355, 75% of patients had a score of 1 or greater. When the trial had finished accrual, and before the analysis was done and there was any unblinding, they got the results from KEYNOTE-119 with single-agent pembrolizumab and IMpassion130 and thought, “Well we should really analyze the group of patients who have stronger PD-L1 positivity.” They chose a CPS score of 10 or greater.

That was a little under 40%, almost identical to the number of patients who are PD-L1 positive in the immune cells for IMpassion130. When they looked at the patients who were at a CPS score of 10 or greater, they saw a significant difference in progression-free survival [PFS], with an absolute difference of 4.1 months. It went from 5.6 to 9.7 months, and a significant number of patients met their threshold boundary that they set up.

In CPS of 1 or greater, it was still what we would think significant, 0.0012, but their boundary had been 0.00411. They met that for a CPS 10 or greater, but for a score of 1, the boundary was actually point 0.0011 and the 

 value was .0014. I think for the clinician it's frustrating because we don't totally understand that, but the absolute difference in PFS was clearly shorter at 2 months.

It's interesting, it didn't matter what the chemotherapy partner was either, which is really helpful. When you look at the forest plot, and I'm interested in people's thoughts about this, although we don't have a good mechanism for choosing patients other than PD-L1 positivity, and now we have 2 potential ways of testing that. The interesting thing is if you looked at patients who had not received any prior chemotherapy and those who presented in the de novo setting, it looked in the forest plot like those patients benefited the most, and that's interesting. Presumably you haven't split out the people who already have chemotherapy resistance.

There was no differential toxicity to consider, and I think that what we're really waiting for, and as Joyce explained, we have this 7-month survival difference in IMpassion130, and we don't yet have survival data for KEYNOTE-355. I think these are fascinating data that add to our understanding of how we can use checkpoint inhibitors in the metastatic setting and potentially the early stage setting.

Phase 3 KEYNOTE-355 Overview

® entitled, “Advanced Breast Cancer, Expert Perspectives on Recent Progress.” I'm Joyce O'Shaughnessy from Baylor University Medical Center, Texas Oncology, and US Oncology in Dallas, Texas. Joining me today on this virtual discussion are my colleagues, Dr Hope Rugo from the University of California San Francisco, Dr Tiffany Traina from Memorial Sloan Kettering Cancer Center in New York, and Dr Denise Yardley from Tennessee Oncology in Nashville, Tennessee.

Today we're going to highlight a number of topics pertaining to systemic treatment for advanced triple negative breast cancer and metastatic hormone receptor-positive breast cancers, and we're going to talk about the impact of recent clinical trial data on our clinical decision-making. In this discussion we're going to focus on some of the key data from ASCO 2020 [the American Society of Clinical Oncology annual meeting], the virtual meeting, and we're going to have a robust discussion of all the new data and how to apply it to our practice.

Let's go ahead and get started. We're going to look at triple negative breast cancer first, and I'm going to start us off setting the stage. Where are we today? For patients diagnosed with metastatic triple negative breast cancer, we need to know 2 markers right off the bat. We’ve got to know the PD-L1 status, which we'll talk about in depth with regard to the diagnostics, and we need to know their germline 

We have robust data that we’ll go over with regard to PARP inhibitors for patients with germline 

, and we'll talk about how to incorporate the PARP inhibitors. And of course, we now have FDA-approved treatment for patients with PD-L1–positive, first-line metastatic triple negative breast cancer from the IMpassion130 data. We're going to talk quite a bit about the diagnostics of PD-L1, but suffice it to say that there is a survival advantage of 7 months in favor of adding the checkpoint inhibitor, the anti–PD-L1 agent atezolizumab, to nab-paclitaxel in the first-line setting for metastatic triple negative breast cancer.

I dare say that because survival is the most important end point to our patients and to us, that we're going to prioritize the use of a atezolizumab and nab-paclitaxel in the first-line metastatic setting. We will talk about new data that came out at ASCO, the KEYNOTE-355 trial with pembrolizumab and a slate of chemotherapeutic options, but we do have FDA approved the atezolizumab and the nab-paclitaxel. For patients who are not germline 

 and whose breast cancer is PD-L1 negative, we do have data from the TNT trial published by Andrew Tutt, MB, ChB, PhD, a very nice first-line randomized trial of carboplatin, AUC [area under the curve] of 6, versus docetaxel, 100 mg per meter squared, basically showing equivalence of those 2 strategies.

The only subset that really benefited from one agent more than another were the patients with germline 

 who definitely had a higher response rate and median PFS [progression-free survival] with the carboplatin. But otherwise whether we start with a platinum-based regimen or we start with docetaxel, it seems to be equivalent in terms of overall outcomes. We really do have that choice right now for our PD-L1–negative, germline wild-type patients.

Hope S. Rugo, MD, FASCO, UCSF Helen Diller Family Comprehensive Cancer Center

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