番茄社区

In this exclusive virtual roundtable video from 番茄社区, three expert leaders in the field of breast cancer discuss the latest emerging and potentially practice-changing data from the just completed San Antonio Breast Cancer Symposium.

Moderator , is joined by , and in this first of four episodes, where they discuss immunotherapy in triple-negative breast cancer.

Following is a transcript of their remarks:

Hope Rugo, MD: Hello and welcome to this virtual roundtable where we will be discussing some of the key data that emerged from this year's San Antonio Breast Cancer meeting. I'm Hope Rugo, professor of medicine at the University of California San Francisco's Comprehensive Cancer Center, and I'm joined today by two expert leaders in the field of breast cancer and great colleagues, Dr. Jennifer Litton from the MD Anderson Cancer Center and Dr. Jo Chien from the University of California San Francisco's Comprehensive Cancer Center. Thanks for joining me today.

So today, in our first discussion, we're going to talk about immunotherapy. This generated great interest at San Antonio and, of course, at all of the major meetings today that discussed breast cancer this year in 2020. I think we saw updates on immunotherapy that are potentially practice-changing at ASCO and ESMO Breast Cancer and ESMO, and now at San Antonio. Jo, do you want to start and talk a little bit about the update on KEYNOTE-355 and some of the other controversies that have arisen with the presentation of updated overall survival with IMpassion130, and then the very interesting and intriguing data from IMpassion131?

A. Jo Chien, MD: Sure. Just briefly, KEYNOTE-355, this is the first-line trial in metastatic triple-negative breast cancer that randomized patients to chemo + pembrolizumab versus chemotherapy alone. It was previously reported that the PFS was significantly improved in patients who had PDL1-positive tumors, specifically with a CPS score greater than or equal to 10. At San Antonio this year, the biomarker correlative data was presented by Dr. Rugo, actually, and specifically looking at a few things.

One is was there any difference in the chemo backbone. In this trial, patients could have received either paclitaxel, nab-paclitaxel or gemcitabine carboplatin. The patient population included patients who had de novo metastatic disease, which I think made up about 20% or 30% of patients, and then most patients were more than 12 months from their adjuvant treatment and I think a minority within 12 months.

What was reported is that there was no difference between chemotherapy arms in terms of the benefit, so all patients, no matter which chemotherapy backbone they received, benefited from pembrolizumab if they had PDL1-positive tumors.

There were some trend towards more benefit with taxanes, but that's probably because those patients were less heavily pretreated. I suspect that patients who were getting gem/carbo in the first-line setting either were within the first 12 months of adjuvant therapy, so a short disease-free interval and received prior taxanes. That's not surprising.

This question is really important given the results from Impassion130 and 131. 131 was with atezolizumab and nab-paclitaxel versus nab-paclitaxel alone, in a similar first-line metastatic triple-negative population that was positive, showing an overall survival benefit. However, IMpassion131 with paclitaxel-atezo versus paclitaxel alone did not show any benefit, so why is that? To be honest, I think it's not clear. We don't know, but it is good to know that in 355 there seemed to be no difference between those groups.

Personally, I think given the overall survival data with IMpassion130, if I were to choose a taxane backbone, I am still leaning towards giving nab-paclitaxel because of the IMpassion130 data, but it's also good to know that gem/carbo would be very reasonable based on KEYNOTE-355.

The other endpoints that were reported at San Antonio this year were the secondary endpoints of response and duration of response, which also were similarly superior in the pembrolizumab arm compared to the control arm, so that was very reassuring and consistent, what we've seen in the PFS data.

Rugo: Yeah. I thought one of the interesting parts of the data from KEYNOTE-355 to me was the duration of response and in responders. Clearly there's some way to select out a group of patients who are more likely to benefit and a CPS of 10 or more is the best we have right now from that trial. But the duration of response in the CPS 10 or more was 19 months compared to about 7 or so months in the pembro versus placebo arms, which I thought really fits with our clinical experience where you get these people who just do very, very well. I think there's probably... I don't know if we'll ever figure it out, but there's clearly some other determinant and maybe it's other mechanisms of resistance to chemotherapy that play a role there. It's hard to know.

I agree, the differences between 130 and 131 are very hard to understand. I think that for IMpassion131 one of the striking findings that's been discussed some is that it was a 2:1 randomization. If you looked at the patients who had PDL1-positive disease by SP142 of 1% or greater, it's only about 100 patients, a little under 100 patients. Their overall survival was 28 months. If all of these phase III trials, nobody's lived 28 months as a median, so my thinking is there is something we don't know about that we're not stratifying for that probably makes a difference.

Maybe those are the hormone receptor-positive in early stage and triple negative in metastatic patients, but I don't know if they'll really ever figure it out. I agree completely with you about the chemo partner. It's a really interesting time and obviously we're looking forward to the overall survival from KEYNOTE-355. But there's going to be tremendous crossover that's going to impact that with all the patients who were treated in the US, and maybe in Europe, on the KEYNOTE-355. Because if you have PDL1-positive disease and you were not on pembro, you would get atezo second-line.

There has been a lot of interesting data, Jennifer, in the early-stage setting as well as neoadjuvant therapy. We saw an update by Beth Mittendorf on IMpassion031 in terms of patient-reported outcomes, which I thought was quite interesting. Maybe you could tell us a little bit about your sort of overall take on the neoadjuvant scene and then the PROs.

Jennifer Litton, MD: Sure. We now have two randomized phase III trials that have reported looking at neoadjuvant chemotherapy with both an anthracycline and taxane-based plus or minus carbo, plus an immune checkpoint inhibitor, both showing improvements in pathologic complete response.

Interestingly, we're not seeing the same signal yet for the PDL1 staining as we are in the metastatic setting, but both improved pathologic complete response. Neither are FDA approved for that indication yet and neither have matured enough to show us the event-free survival that I suspect will be one of the things absolutely needed as they are moving on.

But one of the things that always comes back to immunotherapy is that the toxicities are manageable for the most part, but for some patients, if you get an endocrinopathy per se, it's for life. For those small portion of patients who do get it, you will have hypothyroidism for life or you will have type 1 diabetes for life, and when you're in the curative setting, that is certainly something to be thoughtful about.

The PROs were really interesting because thinking that you would have a lot more side effects and that's actually not what Dr. Mittendorf showed from her data. She showed the dip in the PROs around the time that you're getting chemotherapy for both groups, and then improvement. The only difference that teased out was the role and showing that people who went on to get further immunotherapy, they didn't bring their resumption of roles back up to where the other group is, likely because they were going every three weeks for an infusion and going to the infusion chair. I think a really robust conversation about, "Are we using the right PROs? These are the standardized ones that we've been using."

First of all, I'm a huge proponent for PROs. I think they're really important to be part of all of our phase III randomized trial and really maybe we need to also be further thoughtful about what are the PROs that maybe we need to ask specific questions in the era of immuno oncology that may be different that we developed in the time of chemotherapy alone.

Rugo: That's really interesting and I think it's great to see PROs being highlighted on the plenary platform at San Antonio, and it's so incredibly important as we launch into the questions about using immunotherapy for early-stage triple-negative breast cancer.

I thought it was interesting also that in these two trials it looked as though the effect was greater in node-positive disease -- which is, who knows, immune activation or something -- but also that PDL1 itself might be predictive for chemotherapy benefit outside of the use of checkpoint inhibitors in terms of the pathologic complete response. Really interesting.

Just a quick question to both of you as we close is based on these data now, are there patients who you would use a checkpoint inhibitor for outside of a clinical trial? We come from centers where we have a lot of trials going on, but most of our colleagues don't, and so is there a situation where you would use a checkpoint inhibitor? Would you give it for a year, if you would give it? Jennifer?

Litton: Oh, sure. In the early-stage setting, at this point I do think that we have to wait for the data to mature and to have the FDA approval. This can be a huge financial burden for our patients without the approval. I think that we are likely to see this move forward, given the improvement in PCR, if the event-free survival matches that. Just given also, I think, the importance of the PROs that we didn't see that people were doing a lot worse.

The one thing I just want to make sure we said during this is for the biomarker, for the PDL1. I think from work you've done, it's really important when we're talking about this that we're using the right biomarker for the right drug. I do think SP142, if you're going to use atezo, don't try to use the 22C3 and go back and forth. If you're going to use pembrolizumab, then using the 22C3. I think that the biomarker in this case, so far, from the data, is important which one you choose.

Rugo: Yeah. For metastatic disease, although it could have an impact in...

Litton: For metastatic disease, yeah.

Rugo: ... early-stage breast cancer. I think that's a really important point because we've seen a lot of overlap but not complete overlap. Somebody could have disease positive for one or the other. What we don't know is the overlap if you use CPS of 10 or more.

Litton: Right.

Rugo: We'll see more data on that. Jo, would you use a checkpoint inhibitor in the early-stage setting?

Chien: Yeah. I agree with Jennifer in that we definitely need to wait for the approval and the EFS data. However, I will say that I have given it off study in certain select patients who cannot go on study for one reason or another and I have done this in very high-risk patients.

I think we've now seen a number of studies showing improved PCR rates and I think it's a big question as well, what is the role of immunotherapy in relationship to carboplatin with taxane, anthracycline-based neoadjuvant chemotherapy? It may be that with immunotherapy carboplatin has less of a role based on IMpassion031, which was nab-paclitaxel and atezo showing PCR rates that were fairly comparable to those seen in KEYNOTE-522.

I think there is value for triple negatives in particular to achieve PCR. There are certain very high-risk young patients where we know the relationship between PCR and survival to do our best to achieve that. So, yes, to answer your question. I think we are still waiting for the EFS data and I think that's really important. But in the meantime, while we're still waiting, I do think there's value in trying to achieve PCR in these high-risk patients.

Litton: You do. One last thing. I do think that the new trials that are looking at, actually, de-escalation, the chemo backbone just like you're suggesting, Jo, with using the immune checkpoint inhibitor in the right patients are really intriguing. I'm looking forward to those going forward.

Rugo: Yes, although NeoTRIP, which gave a docetaxel-carboplatin regimen, did not show benefit from atezolizumab, although very small, and I think we have to keep that in mind. We'll have to wait and see. This has been just such a great conversation and I think helps us all put this data into perspective. Thanks so much for discussing immunotherapy from San Antonio and over the course of 2020.

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