SECTION 1: KEYNOTE-522: neoadjuvant pembrolizumab in TNBC

HEATHER MCARTHUR:
– Welcome to Breast Cancer Sessions with VJOncology. My name is Dr. Heather McArthur, I’m the Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Cancer Research at UT Southwestern in Dallas, Texas.

KEVIN KALINSKY:
Hi, I’m Kevin Kalinsky, I am the Director of the Glenn Family Breast Center at Winship Cancer Institute at Emory University in Atlanta, Georgia.

HEATHER MCARTHUR:
So why don’t we start off talking about the KEYNOTE-522 data that was presented just yesterday?

KEVIN KALINSKY:
Yep, so even just to review just the design of KEYNOTE-522, which has really, I think, been a game-changing study for patients in the optimal setting. These are patients who had a T2 greater positive breast cancer who received carbo could be weekly or every three weeks along with weekly taxol and then followed with an anthrocyclin and cytoxin, which is given every three weeks. And then patients also got pembrolizumab in the neoadjuvant setting, went to surgery and then continued on said therapy, meaning either got pembrolizumab alone or continued if they were randomized to not get pembrolizumab, they continued with that. And we’d seen previous data suggesting that there was this improvement in PCR, also showing this event free survival, this was approved. And then this led us to see these updates here at San Antonio.

HEATHER MCARTHUR:
Right, so about two years ago, we first saw the initial analysis showing an improvement in pathologic complete response in favor of the addition of pembrolizumab to chemotherapy of about 14%. So a massive delta. At that point, the event free survival data was really immature. There was only about 15 and a half months of followup. So there was a deferral by the FDA regarding the approval. And since then we’ve seen the updated analysis, diminished delta in pathologic complete response. So about a seven and a half percent now with further follow-up. But what was really exciting was the more mature event, free survival data with more than three years of follow-up, there was a delta of almost 8%. So 7.7% at three years in favor of the addition of pembrolizumab to chemotherapy. So I agree with you that that was a game changer and in the United States at least, became a standard of care for our patients with high-risk triple-negative breast cancer.

KEVIN KALINSKY:
Yeah.

HEATHER MCARTHUR:
And so at this meeting we saw some further analysis. We saw an analysis looking at various subsets to see if those findings really held up across subsets. They look specifically at the node positive population versus the node negative stage two versus stage three, for example, and really the benefit with the addition of pembrolizumab was seen across the board, or at least that was my take. I don’t know if that was your interpretation.

KEVIN KALINSKY:
Yeah, I think the same take, I think also, you know, no additional unexpected toxicities. I think that this is a profile that we’re increasingly familiar with thyroiditis and then some of the rare side effects that we can see with pneumonitis and things like that, but that were uncommon in this study. So I think that’s right across all, the additional analysis, it just continued to this theme that the patients who were eligible for the study were across these different subsets were benefiting.

HEATHER MCARTHUR:
And I think you touched on a really important point, which is toxicity because a lot of these checkpoint blockade, immune drugs are new to us in breast cancer, are new to a lot of people in breast cancer. And there have been concerns about immune-related adverse events. And what we saw in the updated analysis this week was really the majority of toxicity issues arise from the chemotherapy backbone in the neoadjuvant setting. There are relatively few adverse events in the adjutant setting, looking at the immune related adverse events, specifically in the adjuvant setting, interestingly 6% approximately in the placebo arm versus approximately 10% in the pembrolizumab arm. So a very small increase in the adjuvant setting, but it is important still to be vigilant about delayed toxicity. Since there have been reports of immune-related adverse events even a year after last exposure. So it really requires multidisciplinary vigilance in ensuring that our patients aren’t experiencing what can sometimes be devastating and lifelong adverse events.

KEVIN KALINSKY:
Yeah, I fully agree with that. Some of those toxicities can be really subtle and really nuanced. And sometimes even when patients are getting chemotherapy can be hard to discriminate really what’s giving that particular patient, whatever the side effect is, whether it’s fatigue or something else. So it was always important I think, just to be mindful of that, so that we can appropriately treat them if this is a immune-related adverse event.

HEATHER MCARTHUR:
But a really exciting time to be treating breast cancer and triple negative breast cancer specifically, because these are really unprecedented improvements and cure rates. And I think the tasks going forward will be to try to figure out or tease out, who needs more and who can get away with less. So can we further optimize the chemotherapy backbone for patients who are at lower risk? There are a lot of questions around patients who achieve a pathologic complete response. Do they need to continue the adjuvant pembrolizumab? Of course this study was not designed to ask and answer that question. So we certainly have our work cut out for us in the future.

KEVIN KALINSKY:
Yes, completely. If you look at those curves and you see the patients with a PCR, whether without pembro, you know, they look similar to each other, but that’s the way this study was designed. And this was asked during the question answer session and right now the standard is just to continue the full year of pembrolizumab, but it is a question about whether we can deescalate in that particular population. And I also think, you know, in terms of the chemotherapy that patients are getting also this continued question about which patients need carboplatin, do they need full escalation of the chemotherapy that they’re receiving, but this was the way the study was designed. And really in the U.S as you mentioned, has become a bit of a standard of care.

HEATHER MCARTHUR:
Right, and in those high-risk patients who do not achieve a pathologic complete response, we’re gonna struggle to figure out whether we should be co-administering olaparib and a germline BRCA patients, and capecitabine for residual disease, which was also a standard of care. And of course those drugs were not permitted on the KEYNOTE-522 study. And so again, a lot more work to do, to figure out the most biologically rational strategies for these high risk patients.

KEVIN KALINSKY:
That’s right, yeah. It would be interesting to see also in this residual disease setting, just kind of looking ahead, other questions that will be answered, you know, the role of antibody-drug conjugates, where that will come into play. We’ll have ctDNA, later on this meeting we’ll see some of those initial results from Nick Turner and his group. So I think there are lots of things that are still yet to be answered in this.

HEATHER MCARTHUR:
Absolutely.

KEVIN KALINSKY:
It’s ever evolving field.

SECTION 2: KEYNOTE-355: pembrolizumab + chemo in untreated mTNBC

HEATHER MCARTHUR:
Absolutely, so an exciting time to see those data in the curative intent setting, we also saw some data from the metastatic setting in the form of an update from the KEYNOTE-355 study. That was a study in which patients with triple negative breast cancer were treated in the first-line setting with chemotherapy plus pembrolizumab versus placebo, as you’ll recall, the chemotherapy backbone options were paclitaxel, nab-paclitaxel, or combination of gemcitabine with a platinum. So it was physician’s choice chemo do with pembrolizumab or placebo. We previously saw progression-free survival data. At this meeting we saw an update in the form of overall survival data. What was your impression of that, Kevin?

KEVIN KALINSKY:
Yes, so I think the data remained consistent with what we’d seen previously, you know, the utilization, at least in terms of the FDA label and the approval has been for those patients with a combined positive score of greater than equal to 10% as the assay, we utilize for pembrolizumab, as opposed to, for instance, SP142 for tislelizumab but again, in the frontline setting in the U.S, it’s just approval for pembrolizumab. So it was nice to see this continued benefit of OS, where we saw this benefit of about seven months or so. And the patient population who had CPS score that was greater than equal to 10%. And then also the data that we saw here was the breakup by those who had CPS of 10 to 19, versus those who are 20% or greater. And what was nice to see is that the hazard ratio was similar between those two subgroups. So really it looks like those patients are benefiting in terms of their survival, which is meaningful for our patients with triple negative breast cancer.

HEATHER MCARTHUR:
So beyond a combined positive score of 10 consistent benefit, no matter what specific range was interrogated. And really exciting to see again, overall survival advantage of seven months, which is very consistent with what we’d seen in the IMpassion 130 study, a very similar overall survival benefit. Of course, that indication was withdrawn by the sponsor due to some post-marketing issues. And so pembrolizumab is currently the only checkpoint blockade drug that’s FDA approved for the treatment of metastatic triple negative breast cancer in combination with chemotherapy. But I agree with your point that there has been tremendous consistency and historically in a population with a median life expectancy of 12 to 18 months to see a seven month improvement in overall survival is really unprecedented and exciting.

KEVIN KALINSKY:
Yeah, I mean, I think the other thing that discriminates as we’ve been talking about the IMpassion 130 study was just this difference about allowing some of the early relapses in there, right? So patients from completion of their therapy to starting on KEYNOTE-355, must’ve been at least six months or greater. And did in terms of previous reports seemed, if you look at that forest plot, when you look at the taxanes versus the carbo-gem that maybe those patients who got carbo-gem, maybe they were doing a little bit worse, but also that was being enriched for those patients who were early relapses. So as you mentioned previously, the drug is approved with either a taxane or with carboplatin gemcitabine.

HEATHER MCARTHUR:
That’s right. And it seems that you still derive benefit with that chemotherapy backbone, even if you’d received it previously in the curative intent setting, which I agree is an interesting observation.

KEVIN KALINSKY:
Yeah, I think one of the questions that was asked during that session is, what to do if now we’re giving pembrolizumab in the operable setting, and then what would we do if a patient then recurs? Whether we have data and this is really kind of a data free zone and whether we would use that cutoff of about 12 months or so, just to make sure they weren’t relapsing quickly within completion of their operable checkpoint inhibitor. But I think it also just kind of demonstrates how, like the field just moves very quickly. And we just try to catch up from other data to help inform what to do.

HEATHER MCARTHUR:
At the present time we don’t have any data that change in the chemotherapy backbone where we reinvigorate a response to checkpoint blockade or a change in the checkpoint blockade antibody administered can reinvigorate chemotherapy. So a lot of work to be done because those immune therapy resistant patients will be presenting in the not too distant future.

KEVIN KALINSKY:
Yes, yep.

SECTION 3: NIMBUS, BEGONIA, PEARL & future directions in IO

HEATHER MCARTHUR:
We did see another study in the metastatic setting that I thought was interesting. The NIMBUS study that was a study that took patients with both hormone receptor-positive and triple-negative breast cancer, who had a high tumor mutational burden. So greater than or equal to 10 with the idea that those patients, were more likely to have antigens presented to which the immune therapies could respond. And those patients were treated with nivolumab and the CTLA4 directed therapy in the form of low dose ipilimumab. What was your impression of that data?

KEVIN KALINSKY:
Yeah. Small study, but still met its primary endpoint. I think the other thing that was interesting about that study is when you look at those patients who had TMB that was greater than equal to 14%, that that response rate was high. It was almost 60% range, right? Which is really notable. And that included for those five responses, right? About, I think it was three of those head hormone receptor positive HER2-negative disease, which we think, okay, historically this is a subtype that’s not terribly responsive to immunotherapy, but it shows that TMB, we can really see some nice responses. So I think it was quite an interesting study, albeit small, but I think there are other questions that kind of remain of, how would this perform if we were to be looking at just giving checkpoint inhibitor? How should we best define TMB? Then I think they have some other translational medicine efforts ongoing, including circulating markers. But that was interesting. What did you think?

HEATHER MCARTHUR:
Very interesting. So those five responders had very durable responses in the swimmers plot and you know, it is a chemotherapy-free regimen. So hearkening back to those early monotherapy checkpoint blockades studies, where when administered in the first line setting atezolizumab or pembrolizumab conferred responses of about 25% in the first line setting, indicating that there is a population of patients who can derive benefit from immune therapy alone. And as we talked about earlier in the context of KEYNOTE-522, the majority of the toxicity comes from the chemotherapy backbone. So this was, again to me, a reminder that if we give rational combinations of checkpoint blockade in selected populations, that those could be very effective strategies. So very provocative, very hypothesis generating and provocative. But you’re right. This issue of cutoff point for tumor mutational burden is an ongoing challenge in the field.

KEVIN KALINSKY:
So other things at this meeting that you’re looking forward to some other smaller studies that are kind of on your radar, anything else that’s of particular interest to you?

HEATHER MCARTHUR:
Absolutely, so tomorrow we will be seeing the results of some of the arms of the Begonia study. This is a study with multiple arms looking at paclitaxel together with checkpoint blockade in the form of durvalumab, plus various other combinations. And we’re going to see some of those results tomorrow and I think that will be very interesting. I’m also very excited to present our own data, looking at combination of pembrolizumab together with radiation prior to neoadjuvant chemotherapy for triple negative breast cancer. And the idea was that we would essentially borrow the boost dose of adjuvant therapy and administer it earlier on in the course of the disease. So while the tumor is still in situ, radiation of course causes inflammation, but it also causes physical destruction. So the idea is that by breaking down a tumor into tiny fragments, that might be more easily digested by immune cells and co-administering immune therapy, that you would have a more robust antitumor response. So we’re gonna be very excited to present the results of that study called the PEARL study tomorrow.

KEVIN KALINSKY:
Yeah.

HEATHER MCARTHUR:
What about you?

KEVIN KALINSKY:
Yeah. I think this question of AKT inhibition and whether or not incumbent, you know, there’s some good preclinical rationale for that. So we’ll see how that study kind of bears out. And in the context of having some toxicity that we can see with AKT inhibition. So we’ll see some data with that. Also we’ll see some updates from iSPY2 study there from our German colleagues, just in terms of giving in a HER2-positive population, HER2-targeted therapy with IO. So there’s a lot of interesting things that are there, but as we’re speaking, I can’t help but think about how a couple years ago the breast cancer field was really in its infancy in the context of IO compared to other solid tumors, and here we are now where we have approvals in the metastatic setting, in the early stage setting that really has been a shift that’s happened relatively quickly.

HEATHER MCARTHUR:
The pace is really exciting and it’s really an exciting time to be treating breast cancer, especially those triple negative breast cancer patients for whom we relied on cytotoxic chemotherapy until a couple years ago. So now to have options for them that actually improve life expectancy is really exciting.

KEVIN KALINSKY:
Yeah.

HEATHER MCARTHUR:
Well, it’s so great to sit down and talk with you, Dr. Kalinsky, and thank you for joining us with VJOncology and Breast Cancer Sessions.

Heather McArthur:

Dr. McArthur reports no disclosures.

Kevin Kalinsky:

Dr Kalinsky reports no disclosures.