Investigator perspectives on recently presented data from clinical trials for HER2-positive localized and metastatic breast cancer (mBC)

DR LOVE: Welcome to Oncology Today, key presentations in breast cancer from the 2023 ASCO meeting; this is medical oncologist Dr Neil Love. For this program, I met with Dr Heather McArthur from the UT Southwestern Medical Center in Dallas, Texas. To begin, Dr McArthur presented and commented on some of the key abstracts on HER2-positive breast cancer.

DR MCARTHUR: Hello, my name is Heather McArthur, and I’m the Clinical Director of Breast Cancer and Komen Distinguished Chair in Clinical Breast Cancer Research at UT Southwestern in Dallas, Texas. And today I’m joined by Dr Neil Love where we’re discussing highlighted abstracts from the 2023 ASCO Annual Meeting.

So we’ll start with the PHERGain study. This is a study that was presented by Javier Cortez. This is the 3-year invasive disease-free survival of the strategy-based randomized Phase II PHERGain trial evaluating chemotherapy de-escalation in HER2-positive early-stage breast cancer. And this is a trend that we’re seeing a lot in HER2-positive particularly this idea of escalation versus de-escalation or optimization of chemotherapy based on risk.

So in this study patients with Stage I or III — Stage I to IIIa HER2-positive disease with a tumor of at least 1.5 cm in diameter were enrolled. They had to have a PET-evaluable breast lesion. Patients were randomized 1:4 to receive either standard of care TCHP, that’s docetaxel/carboplatin with trastuzumab and pertuzumab, in this case were 2 neoadjuvant cycles, versus trastuzumab with pertuzumab for patients who have hormone receptor-positive breast cancer. They also received endocrine therapy.

They received 2 cycles of either the TCHP or the dual HER2-directed therapy, plus or minus endocrine therapy. And then after the second cycle, underwent PET scan. For those who randomized to receive TCHP, they continued to received 4 additional cycles of TCHP before surgery. But for those who had been randomize to the dual HER2 blockage, plus or minus endocrine therapy arm, there was a further randomization after that first PET scan to receive continued dual HER2 blockade with endocrine therapy for 6 cycles if they had a response based on PET, and for those who did not have a response, they received TCHP chemotherapy for 6 cycles prior to surgery.

And then after surgery, patients who had received trastuzumab with pertuzumab and endocrine therapy were randomized again based on the presence or absence of a complete response to continued dual HER2-directed therapy with endocrine therapy or to received TCHP.

So a rather complicated study design but again, speaks to this global effort increasing therapy for those who need it, who are at highest risk, and de-escalating chemotherapy for those who are at lower risk of recurrence.

So there were 2 primary endpoints in this study: pathologic complete response in the PET responders, so that’s called Arm B. And there was a secondary coprimary endpoint, 3-year invasive disease-free survival, also in that Arm B.

So focusing in on the Group B, you can see that almost 80% of patients in that group had a response by PET scan after 2 cycles, and 38% or 37.9% of patients had a pathologic complete response. Again, these are the patients who were randomized after endocrine therapy with dual HER2 blockade. The 3-year invasive disease-free survival for Group B was excellent at only 4.5%. And you can see the Kaplan-Meier curve presented here.

In terms of safety, not surprisingly there were very few Grade 3 or more adverse events in the patients who received trastuzumab with pertuzumab, plus or minus endocrine therapy without chemotherapy. As you can see, very few Grade 3 or more adverse events as indicated by the right most column.

The tolerability or the side effects that you see in Groups A and B who received chemotherapy were consistent with those previously documented with these regimens.

In summary, it met the primary endpoint of pathologic complete response in invasive disease-free survival for this Arm B. Again, that’s the arm that’s randomized to receive endocrine therapy as appropriate, with dual HER2 blockade versus chemotherapy.

The 3-year invasive disease-free survival was 98.8% among the chemo-free Group B who had a response by PET and who achieved a pathologic complete response.

So that indicates that about a third of patients could potentially forgo chemotherapy with significant reduction in toxicity.

Neil, you had a comment?

DR LOVE: Yeah. A couple of questions about that. First of all, the response without the chemo, I guess it’s sort of the PERTAIN type approach, dual HER2 plus endocrine, right?

DR MCARTHUR: Exactly, but only 2 cycles here.

DR LOVE: But 80% response rate?

DR MCARTHUR: So the response rate was defined by prespecified RECIST criteria and also a reduction of 40% or more in SUV uptake on PET. So it was a very specific definition for response here.

DR LOVE: But, first of all, I just wonder, I’m not sure how much people or you, maybe, are using non-chemotherapy in metastatic disease. I don’t think people use it that much but that — I mean, given the response criteria, but very interesting that response.

Is this a strategy, first of all, the non-chemo strategy in ER-positive that you think you would want to use or have used?

DR MCARTHUR: I haven’t used this strategy. And you’re right in that we rarely use endocrine therapy with HER2-directed therapy in the metastatic setting. So, I think we’ve been reliant on that — all the data that we’ve generated now from the metastatic and curative-intent setting, harnessing the synergy between HER2-directed therapy and chemotherapy. So that’s really been our go-to in the curative-intent setting. However, this is hypothesis-generating, indicating that there is a subset of patients who may be able to forgo cytotoxic chemotherapy altogether.

DR LOVE: Could you see yourself offering this to patients as an option right now?

DR MCARTHUR: I’m not sure, based on this modestly-powered study, that it’s sufficient data to garner a change in practice. But it does endorse further exploration and larger randomized Phase III studies.

DR LOVE: The other thing is this issue of paclitaxel instead of carbo/docetaxel, which I’ve heard people already talking about it. Dana-Farber does it a lot. Again is that something you’ve done I the past? And if it hasn’t, is this something you’re going to think about more in the future?

DR MCARTHUR: Honestly, I almost never use docetaxel. I almost exclusively use paclitaxel. I find it much better tolerated. And the initial paclitaxel-based regimen, based on the NeoSphere neoadjuvant study, with excellent PCR rates in that study, endorses that approach. And then we have other data from ECOG 1199, that was for HER2-negative disease, but looked at weekly versus q3weekly paclitaxel versus docetaxel. Paclitaxel seemed to be better tolerated. And there was a trend, although not statistically significant, in favor of efficacy with weekly paclitaxel.

So that has been my preferred partner for HER2-directed therapy.

I just would mention that the ongoing neoadjuvant COMPASS study uses the paclitaxel/trastuzumab/pertuzumab combination.

DR LOVE: The other thing is, of course there’s a chemotherapy shortage going on, particularly with platinums and in a lot of cases carboplatin shortage. So it’s great now this data is out there for people who have that issue. I don’t know if that is an issue at your place. But any broad perspectives on the chemotherapy shortage, particularly the platinums, and how it’s affected your practice? At the recent ASCO meeting, I think we did 10 programs, and this came up almost tumor type, solid tumor type is trying to deal with this.

When you look at breast cancer globally, how has — what’s your take on what to do in situations where you can’t access carboplatin or, for that matter, cisplatin?

DR MCARTHUR: It’s certainly a global issue. Fortunately, in the treatment of breast cancer we’re more modestly impacted. So for hormone receptor-breast cancer, which is the majority of our patients, we typically don’t use platinum-based regimens. For triple-negative breast cancer it has become part of the mainstay for the majority of our patients in the curative-intent setting based on the KEYNOTE 522 chemotherapy backbone, but that’s only about 12% of our patients. And with HER2-positive disease, we have a lot of nonplatinum-based alternative regimens that are very effective.

So fortunately, we’re minimally impacted. But I can tell you that as an institution we’ve made a number of changes from weekly to q3weekly dosing AUC adjustments to sort of the bare minimum for efficacy as clinically appropriate. So we have been making significant adjustments until the shortage is over.

DR LOVE: All right, please continue.

DR MCARTHUR: So next we’ll discuss a Phase II, single arm, open-label trial of T-DM1 or ado-trastuzumab emtansine, an antibody drug conjugate, together with neratinib for HER2-positive breast cancer with molecular residual disease. This is the KAN-HER2 study. This is a Canadian study in which patients receive HER2-directed therapy with chemotherapy as neoadjuvant therapy. They then go on to surgery per standard of care. And patients who do not achieve a pathologic complete response are enrolled. They received adjuvant radiation per standard of care. And then they have a molecular residual disease assessment after 2 to 6 cycles of standard of care T-DM1, which is a global standard for patients with HER2-positive residual disease after neoadjuvant therapy.

And for patients who have molecular residual disease at that stage, they receive neratinib together with their T-DM1 for up to a year of therapy. And then at the end of therapy molecular residual disease is reassessed.

And I can tell you that the study is ongoing and that this is very consistent again with this idea of escalation or de-escalation, particularly for HER2-positive disease, giving more treatment for those who need it versus less for those who are at lower risk of recurrence.

So that data is forthcoming.

Neil. Did you have a comment?

DR LOVE: Yes, I was just going to ask about this last thing — trial, which I thought was really interesting. And I know — I think this comes up with some of the other papers. First of all, is this a tumor-informed cell-free DNA type assay?

DR MCARTHUR: Yes, I believe so.

DR LOVE: Because actually it makes me wonder whether anybody uses that now or whether you use it in the post-neoadjuvant setting when they’re thinking about neratinib? Any thoughts about that?

DR MCARTHUR: Well, neratinib to some degree has gone by the wayside in the curative-intent setting. So the ExteNET study was the study that looked at neratinib for a year after completing a year of adjuvant trastuzumab. And that data was presented, unfortunately, immediately after the practice-changing pertuzumab data was presented. And so, we sort of struggled to find the niche for neratinib in the curative-intent setting, although I selectively use it in patients with hormone receptor-positive, node-positive disease, particularly those who are young because that’s where neratinib performed best in the retrospective exploratory analyses.

So it’s not typically a standard of care in this space. But I think if we saw, with this combination, resolution of molecular residual disease it could potentially be evaluated in a larger study.

Because again, a lot of interest in more biologically-driven strategies rather than strategies that are dependent on cytotoxic therapies although this space is going to be very dynamic with the advance of HER2-directed antibody drug conjugates, which are anticipated to move quickly into the curative-intent setting.

DR LOVE: Right. And it looks like they don’t restrict it to the ER-positive? Because in the ExteNET, most of the benefit was ER-positive. But I don’t know. Is it just ER-positive?

DR MCARTHUR: It is not restricted to any subset.

DR LOVE: Doesn’t seem to be.

DR MCARTHUR: No.

DR LOVE: Really interesting.

DR MCARTHUR: So I think it’ll be hypothesis-generating, but not practice-changing quite frankly.

DR LOVE: I think it’s kind of cool. But the other thing I was going to ask you about, I noticed that you did a study looking at HER2 loss after neoadjuvant anti-HER therapy. And I thought it was really interesting because I know you reported a lot of people went from positive to either negative or HER2-low, which is interesting. But it’s kind of interesting because the other cancers where anti-HER therapy is used, particularly upper GI, like if they lose HER2 they stop using HER2. Whereas in breast cancer once you’re HER2-positive you’re labeled as HER2-positive.

DR MCARTHUR: You’re always HER2-positive, exactly!

DR LOVE: Any thoughts? I’m always asking the GI people whether they have any data and I don’t think they really do. But anything to suggest if you lose HER2 that maybe the benefit of HER2 therapy is lost?

DR MCARTHUR: Well, HER2 testing has been problematic for us for some time. So harkening back to the adjuvant trastuzumab studies, chemotherapy plus/minus trastuzumab, the North AmErikan study and the HERA study, what they showed was that patients who were positive in their local laboratories, a significant number of patients were actually HER2-negative in central laboratory testing, but still seemed to derive benefit from trastuzumab. Which indicated that it didn’t matter where you got a positive result as long as you had one at some point.

And then we saw a subset analysis from the KATHERINE study looking at T-DM1 as adjuvant therapy for patients with residual disease after neoadjuvant HER2-directed therapy.

And they recently presented an exploratory analysis showing a similar story, that patients who were HER2-positive at baseline, a small proportion of the patients became HER2-negative at surgery after neoadjuvant therapy but still seemed to derive benefit from adjuvant HER2-directed therapy in the form of T-DM1.

So I think it’s a complex story, and we saw the same thing in our retrospective study that you’re mentioning, that those patients who became negative stilled seemed to derive benefit from HER2-directed therapy.

So I think there are probably some — a variety of issues that are conspiring in this space, challenges of testing, which we’ll get to later as we’re talking about HER2-low disease, intervariable — or interobserver variability. And then of course, the always challenging issue of heterogeneity especially for HER2-positive disease.

DR LOVE: Really interesting. Also, just 1 other side note. I noticed that you’re doing a trial looking at checkpoint inhibitors in neoadjuvant therapy of HER2-positive disease. and I was kind of surprised. You don’t hear much about checkpoint inhibitors. Any thoughts about that? And are you anticipating it’s going to be a positive study?

DR MCARTHUR: Yes. So this is our neoHIP investigator-initiated trial. It’s a multicenter trial, Phase II trial, looking at THP or paclitaxel/trastuzumab/pertuzumab, plus or minus pembrolizumab. Originally there was a third arm that had trastuzumab without pertuzumab. The overarching idea being that if you administered chemotherapy with HER2-directed therapy and checkpoint blockade, here in the form of pembrolizumab, earlier on in the course of disease that you could really harness that synergy.

There’s a ton of preclinical data demonstrating synergy between HER2-directed therapy and checkpoint blockade. It’s never really been evaluated in the early-stage setting beyond the Impassion050 study, although that was a very high bar in that they took the APHINITY regimen with 3 cytotoxics and 2 HER2-directed therapies. Again, APHINITY with the addition of pertuzumab only conferred a 0.9% improvement in invasive disease-free survival because the control arm performed so well. So it was very difficult to show incremental improvement with the addition of atezolizumab to that regimen.

So we’re taking lessons learned from triple-negative breast cancer, administering this somewhat paired down cytotoxic regimen, together with HER2-directed therapy  and immune therapy earliest on in the course of disease. And yes, I am predicting that this is going to be a positive study.

DR LOVE: Yeah, that really struck my attention. Because again, in upper GI cancer pembrolizumab is part of first-line therapy. And I think like 85% of those HER2-positive people are PD-1-positive. I know PD1 is not a big issue in breast cancer, but is there a higher rate of PD-1-positivity with HER2-positive breast cancer?

DR MCARTHUR: There’s not a higher rate of PD-1-positivity, but there is more innate interaction with immune cells as evidenced by higher TIL levels. And it’s well-described that presence of TILs is higher in HER2-positive disease and predicts for a variety of responses, including to HER2-directed therapy.

So again, I don’t think that we’ve looked at checkpoint blockade in the optimal way previously for HER2-positive disease. and I’m hoping that this study will represent a paradigm change. Again, allowing for less cytotoxic therapy potentially with more rationale biologic combinations.

DR LOVE: Really interesting. How about this paper from Ian Krop.

DR MCARTHUR: So this was an interesting presentation, an age-specific pooled analysis of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer from 3 pivotal trials: DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03.

So as a reminder, DESTINY-Breast01, that was the first study that looked at this novel antibody drug conjugate that’s targeted to HER2, T-DXd, in a heavily pretreated population. In DESTINY-Breast 01, as a reminder, the median number of lines of prior therapy was 6. So this was a very heavily pretreated population.

In DESTINY-Breast02, T-DXd went head-to-head against physician’s choice chemotherapy. In this study, patients had received 2 prior lines of therapy for metastatic disease. and then in DESTINY-Breast03, T-DXd went head-to-head against our standard of care, which, in the second-line was T-DM1 at that time.

So they pooled together the data from these 3 trials and looked at impact by age. And what you can see here, the light blue in patients less than 65. The dark blue is patients 65 or older. And you can see pretty comparable responses in terms of progression-free survival potentially slightly diminished for those aged 65 or older. And then looking at the overall survival table, they haven’t reached enough follow-up from DESTINY-Breast02 or DESTINY-Breast03, but very comparable overall survival for those 2 categories. And if you look at the 12-month landmark survival, you see very similar results.

So the efficacy was very similar in those 2 — sorry — in those 3 studies by those 2 age groups.

And when you look at the individual studies, you look at partial response here in light green, and complete response in dark green, again comparing the younger groups and the older group. Very similar overall response rates. And you see below a delineation of what kind of responses they had. And again, they were very similar.

One of the concerns about these drugs is toxicity, potentially in older age groups and there did seem to be a higher rate of toxicity overall by age group. Here, you can see 11.8% for any grade toxicity in less than 65, a little bit higher at 17.4, looking at the greater than or equal to 65 years of age, and 15.2% in the greater than or equal to 75 of age. Of course the numbers that you’re looking at in terms of patient numbers are getting smaller and smaller. So this is hypothesis-generating. But no Grade 5 ILD issues that were outliers from any of the data we’ve previously seen by age groups.

So they concluded that most ILD across the board were cases of low grade and were very similar for those older than or equal to 65 versus those less than 65.

What did you think of this data, Neil?

DR LOVE: When I saw this data the first thing I thought about was we always do CME satellite meetings at San Antonio, and last year we did sessions where we had docs in practice presenting cases by video. And we had 2 cases of people with HER2-low disease by the same doc, 1, the patient was aged 91; the other 90. And everybody sort of took at deep breath in the audience. They both had great responses and were doing well. But he did pre-emptive dose reduction for both of them. And I’m curious whether or not you do the same thing? Do you ever do pre-emptive dose reduction in frail patients?

DR MCARTHUR: Not for this drug specifically. I will do it as clinically indicated, but not up-front. And there’s no data that exists that shows that we should build up for this patient population specifically. And I think that this toxicity data, again with very few Grade 3 or higher adverse events in the older population, warrants that approach across the board but certainly could be considered for selected patients.

DR LOVE: I think he was thinking more about the chemotherapy type side effects that you see with T-DXd in the older patient, not so much the other issues. And it seemed rational. I think 1 of them, he actually dose escalated the patient. But I had not heard that before. I thought it was pretty interesting.

DR MCARTHUR: I approach it in the same way as my routine cytotoxics, in that I start with the recommended dose and I titrate down as clinically indicated. And I’ve approached these drugs in the same way.

It’s interesting, I have that I inherited from Shanu Modi in New York, who was on the DESTINY-Breast 01 study, who is now almost, I think, 6 years out, still receiving T-DXd which is remarkable, and has had absolutely no side effects whatsoever. And then I’ve had patients who, 1 comes to mind who had 2 doses and said I don’t care if this is the best drug in the world, I never want to take this again because the nausea and vomiting was so challenging to manage.

So I actually find the nausea for some patients, even despite the current recommendation for 3 prophylactic medications, to be more of an issue in this patient population. So I might be more sensitive to that for an older population as well.

DR LOVE: Interesting. Please continue.

DR MCARTHUR: Thank you.

So the next presentation comes from the ECOG-ACRIN Group, E2197 specifically. They did a comparison of HER2 gene expression by RT-PCR across all HER2 IHC groups with recurrence analyses. They previously demonstrated a high degree of concordance between central IHC and quantitative HER2 by RT-PCR. And so they’re building on that by comparing quantitative HER2 gene expression using Oncotype within all the IHC subgroups and looking at risk of recurrence.

This was a study, it’s an older study, that was looking at chemotherapy with endocrine therapy, so there’s no HER2-directed therapy that was administered on that study. And what they show here is evidenced by the curve on the right, is that the 5-year risk of recurrence is a continuous function of quantitative HER by RT-PCR. So, rather than by IHC, I was thinking these sort of lump-sum categories they’re showing continuous risk and they suggest that quantitative expression might be useful for identification of HER2-low breast cancer, which is, of course, a new category that we’re thinking about with the advent of HER2-directed antibody drug conjugates and their success in DESTINY-Breast04 last year for HER2-low disease.

So, again, HER2 testing was designed to look for HER2-positive disease. it wasn’t designed to look for nuanced shades of HER2-negativity, HER2-low specifically, or maybe even ultra-low. So there’s a lot of effort underway to try and identify optimal strategies for identification of patients who might be candidates for these novel treatments.

DR LOVE: It’s certainly interesting tough, about the RT-PCR and the Oncotype. Do you think that that may in the future become the type of assay we’re going to look at when we start talking about HER2-low. Sometimes I wonder if there even is a HER2-low. But any thoughts about whether it’s even worth — do you ever order an Oncotype in a situation where you’re not sure what to do?

DR MCARTHUR: It might become a useful tool, although with the ongoing DESTINY-Breast study that’s including patients with HER2-ultra low cancer, it begs the question of whether HER2 testing is going to become a historical relic if HER2-directed therapy becomes clinically appropriate for all subgroups. So, perhaps there will be more nuanced stories in the future. But I could see a future where indications become HER2-agnostic altogether. But that data is still forthcoming of course.

Racial and ethnic differences in 21-gene Recurrence Score^® and survival among patients with ER-positive breast cancer

DR LOVE: Okay, please continue.

DR MCARTHUR: Thank you.

So the next ... so this is an interesting study looking at racial and ethnic differences in the 21-gene Recurrence Score and survival among patients with estrogen receptor-positive breast cancer. This study came out of Roswell Park.

What they did was they queried the National Cancer database to identify women who were diagnosed between 2006 and 2018 with ER-positive early-stage breast cancer who received surgery and adjuvant endocrine therapy and had a Recurrence Score by the Oncotype assay available. And they looked at racial factors and found that Black women were more likely to have higher Recurrence Scores, that they were more likely to have worsen overall survival, and that there was a statistically significant interaction between race, ethnicity and Recurrence Score.

So this ties into I think very nicely this data that showed here, these Kaplan-Meier showing cumulative incidence plots for overall mortality. You see here that Black patients do worse overall compared with non-Hispanic White or Hispanic White. And then the Asia-Pacific Islanders do better overall, regardless of whether they have Recurrence Scores less than 26 or Recurrence Scores less greater than/equal to 26. So this is very much aligned with some other data that we’ve seen recently. So, as you’ll recall, the RxPONDER exploratory analysis was presented at San Antonio 2022, which showed similarly Black patients had poorer outcomes on that study. That was again a study using Oncotype in node-positive disease. Interestingly, in the RxPONDER, they also showed that Asian patients did better using these same cutoffs.

So it does beg the question whether we need to have different cutoffs for these recurrence assays by race and ethnicity because clearly, the impact is potentially different? What do you think, Neil?

DR LOVE: I was just going to ask you first of all, what you think the reason is that we see these observations as just some kind of genetic thing or do you think there are thoughts out there about sort of the pathogenesis of actually what’s going on? The other thing I was curious about, is this just a prognostic thing or — because, of course, the big thing about Oncotype is predicting benefit of chemo. Any thought, any reason to think that the impact of chemo would be less in these patients?

DR MCARTHUR: Mm-hmm. I think this is purely prognostic in this form, and in the forms that we’ve seen before. I do think it begs the question whether there’s potential predictive impact though if we interrogated different cutoffs for selected populations and understood whether we could pivot and make treatment recommendations based on different cutoffs.

I think biology plays a huge role in these observations. We saw another interesting presentation at San Antonio 2022 that looked at the tumor microenvironment for Black versus White patients after neoadjuvant chemotherapy. And the biology was much more pro-metastatic in the Black population than in the White population. So I really do think that there are unique biologic conspirators here.

DR LOVE: Any thoughts about whether the biology, this relates to the immune response?

DR MCARTHUR: Potentially. I haven’t seen any great race or ethnicity-based data describing presence or absence of TILs, for example, or TIL cutoffs or PD-L1 status by these categories. But that would certainly be very interesting information. Unfortunately, for example in KEYNOTE-522, which led to the FDA approval of pembrolizumab with curative intent for triple-negative breast cancer, only a small proportion of patients participating in that study were Black. And so, it will be very difficult, as it’s been for a lot of these studies, to get nuanced insights from some of our large, randomized Phase III studies. but that would be really important work to do, of course. And more attention, fortunately, is being attended to addressing disparities in enrollment in clinical trials.

DR LOVE: Okay, please continue.

DR MCARTHUR: Next we saw a presentation on behalf of the Oxford Overview or Early Breast Cancer Trials Collaborative Group. This is a study looking at — or a meta-analysis rather, looking at the impact of ovarian ablation or suppression on breast cancer recurrence and survival among almost 15,000 premenopausal women across 25 clinical trials.

So you can see here that 27 trials were identified, and ultimately 23 trials were included, with 14,999 women. Included in the analysis, all women were premenopausal at randomization. There were actually 3 different groups who were captured here. There were patients who had no chemotherapy, which was about 4,000 patients. There’s a group of patients who had chemotherapy prior to randomization who were still premenopausal at the time of enrollment in the study. And then there was a third group of patients who received post-randomization chemotherapy. So a bit of a mixed back in terms of chemotherapy exposure. And of course that third group could potentially, a significant proportion become postmenopausal with the assignment to chemotherapy after enrollment in the trial.

So here you see ovarian ablation suppression versus not in terms of mortality. And you can see a significant impact on breast cancer mortality, in all-cause mortality. Not surprisingly, there’s no difference in death without recurrence, so it has no impact on preventing or incurring any other causes of death.

And then here you see the impact for those patients who received tamoxifen, no tamoxifen versus tamoxifen, and not surprisingly, patients who don’t received tamoxifen are at higher risk of recurrence overall and, therefore, the magnitude of the benefit is bigger in that group, 56.5% versus 39% in favor of ovarian suppression ablation. A significant benefit though in those receiving tamoxifen with a hazard ratio of 0.8, although, of course the absolute benefit in that group is much smaller because they’re starting from the lower-risk position.

Any thoughts on that data.

DR LOVE: Yeah. Actually, first of all, I just had a flashback that I actually attended the 1990 presentation of the meta-analysis by Richard Peto in Oxford where he actually presented it with transparencies, not even slides. Anyhow, that was the one where — incidentally, that was the one that they showed that tamoxifen worked in premenopausal women because before that people didn’t think it did.

But anyhow, the thing I wanted to bring to your attention and get your thoughts about is something that we picked up recently — we do these surveys where we ask investigators what they do in various situations outside a trial setting, and I started to notice something interesting this past year, and I’m curious what your thoughts are about it, which is, in what situations they use ovarian suppression/ablation as, plus whatever, tamoxifen or AI, and in what situations they use tamoxifen alone. Because when you look at guidelines and the editorial that just came out with the SOFT and TEXT trial, they talk about using tamoxifen in lower-risk patients because the absolute benefit is not as great so it’s not worth it, et cetera. And then we started to try to dig out, well, who are these people who are getting tamoxifen alone, at least by the investigators?

So let me ask you, who are the people you would use adjuvant tamoxifen alone in a premenopausal women?

DR MCARTHUR: So lower-risk, so lower stage of disease, closer to the natural age of menopause, which is still about 53 in this country, we often have refined risk for our node-negative subset using tools like Oncotype. So we have a much more refined understanding for that subset of patients which makes it a lot easier to understand or to quantify the magnitude of benefit potentially with different hormone therapy strategies.

So I think Oncotype has really — or those genetic assays have really impacted our ability to offer really refined risk-benefit calculations.

DR LOVE: That’s exactly what we found, which was that node-negative — node-positive they’re going to get ovarian suppression. Node-negative, what we saw is that people were looking at Oncotype. But you don’t see that in the guidelines.

DR MCARTHUR: Right.

DR LOVE: So small, node-negative. Again ultra-low patients, another issue. But we saw investigators are routinely looking at Oncotype and yet, the docs in practice don’t know about that because it’s — I don’t think it’s in the guidelines.

DR MCARTHUR: No. No.

DR LOVE: But anyhow, just kind of an interesting — makes me wonder whether or not tamoxifen monotherapy might be overutilized in the community? I don’t know.

DR MCARTHUR: I don’t know.

Emerging data with CDK4/6 inhibitors for ER-positive, HER2-negative breast cancer

DR MCARTHUR: And it’s further complicated by some of those studies that we’re about to talk about for our higher-risk populations, which are the monarchE study which will segue into here, which is adjuvant abemaciclib for node-positive disease. which includes premenopausal women. And then we’ll pivot to the NATALEE study, which offers ribociclib for node-negative and node-positive high-risk early-stage breast cancer.

So it begs the question do we even need these more complicated hormone therapy backbones if we have better biologic options in the form of CDK4/6 inhibitors?

So I’ll jump into the monarchE update now if I may.

So Erika Hamilton presented this analysis looking at efficacy and safety by age in monarchE. As you’ll recall, monarchE was a study that enrolled women with hormone receptor-positive, HER2-negative, high-risk early-stage breast cancer. As you’ll recall, there were 2 different cohorts. The first cohort enrolled based on conventional clinical and pathologic characteristics. They either had 4 or more lymph nodes or they had 1 to 3 positive lymph nodes plus Grade 3 or tumor size greater than or equal to 5 cm. And then there was a second cohort that included patients that had 1 to 3 positive lymph nodes and a Ki-67 of greater than or equal to 20%. And the reason why that’s an important reminder in the context of this study is that impacted the initial FDA approval because there was a Ki-67 component to that indication, which was later removed. And abemaciclib is now supported for high-risk, node-positive, hormone receptor-positive breast cancer and is now Ki-67 agnostic.

So in monarchE, patients were randomized to receive endocrine therapy alone versus endocrine therapy with 2 years of abemaciclib. And here, we see a breakdown — we have the intention-to-treat population and then a breakdown by age, less than 65 or greater than or equal to 65. And you can see, just scanning across those hazard ratios, you can see a very consistent benefit, all in the sort 0 to 6s, 0 to 7s range, demonstrating a very consistent benefit, maybe slightly less in the greater than or equal to 65, but really a notable clinical benefit in that population. And in scanning across the 4-year disease-free survival, you see benefits in the 80s, indicating that they were very consistent results across age groups.

And when you look at patients in general who get dose adjustments — so here you’re looking at relative dose intensity — and they broke the groups down into 3 different equal groups: those who had relative dose intensity: 0 to 66% versus 66- to 93% and 93% and above, demonstrating that alterations in dose intensity did not negatively impact invasive disease-free survival. The numbers at 4 years were relatively similar: 87- versus 86- versus 84% approximately, regardless of the dose adjustments. So indicating that the therapy is effective even with dose adjustments.

And so the conclusions from this study were really several-fold. They saw that IDFS rates were very similar in those who underwent dose modification compared with those versus not, which we just showed. But they also demonstrated that older patients were less likely to get dose reductions and were more likely to be — were more likely to have their medication discontinued. And those relative dose intensity curves indicate that adjuvant abemaciclib should be used in older patients and that dose reduction should be explored more globally rather than just discontinuation without dose reduction.

DR LOVE: That point about dose reduction to me, came across as 1 of the really important things that’s been coming out recently. We were doing a program with Sara Tolaney and she mentioned that — I guess it was 27% of patients in the monarch study actually had abema stopped, and she said nowadays she almost never has to stop people because she can usually get people comfortable with dose reduction. And I wondered whether or not that’s being done right now routinely in clinical practice. Is that your approach? Or you rarely see a patient, you actually have to stop the abema?

DR MCARTHUR: I had 1 patient who participated in monarchE who had to come off study despite dose reductions due to fatigue. But otherwise, I have found 2 things. Number 1 being really proactive about antidiarrheals in the first 2 months. Once you get people through that 2-month hump at the onset, the diarrhea issue tends to go away completely. So that’s 1 thing to be proactive about. And then with dose reductions, it’s clinically appropriate. Patients tend to do very well. And the vast majority of them are able to complete the 2 years of prescribed therapy. And the importance of dose reductions, including in our patients over 65, is obviously really important.

DR LOVE: All right, let’s hear about the NATALEE study.

DR MCARTHUR: The NATALEE study. So this 1 of the most highly anticipated presentations of the meeting. This is a study looking at ribociclib, so another CDK4/6 inhibitor, together with endocrine therapy as adjuvant treatment for hormone receptor-positive, HER2-negative early-stage breast cancer as presented by Dennis Slamon.

This study enrolled patients with node-negative and node-positive, hormone receptor-positive, HER2-negative early-stage breast cancer. So in contrast to monarchE which only enrolled node-positive patients, this did allow for high-risk node-negative populations. One of the other notable aspects of this study is that the dose was reduced from what we are using in the metastatic setting — typically we use 600 mg daily for 21 days on, 7 days off in the metastatic setting. Here, 400 mg was prescribed with the idea that they could improve tolerability while maintaining efficacy. And the hope was that maybe even QTC prolongation issues and surveillance with EKGs might go away completely with this strategy. Also notably, in this study the CDK4/6 inhibitor is given for 3 years, whereas in monarchE it was prescribed for 2 years.

And here you can see the distant disease-free survival benefit in favor of ribociclib, with a hazard ratio of 0.739, so 88.6% versus 90.8%. This is very consistent with the invasive disease-free survival that was observed in favor of ribociclib, the hazard ratio for invasive disease-free survival was 0.748, with a 3-year invasive disease-free survival improvement of about 3%, 87.1 versus 98.4%. and the benefit seemed to be consistent across subgroups.

In the forest plot, which I don’t think we’re showing here, but the 1 thing to know is in the node-negative population, because there was really a lot of buzz about whether this would be a relevant option for node-negative patients. On the forest plot, the confidence intervals crossed 1. So, although it trended to the side of benefit with ribociclib, it did actually cross 1. So that’s a note here.

The survival, there’s not a lot of follow-up to look for survival for a hormone receptor-positive population. The median follow-up for overall survival was 30.4 months, but there was a trend here towards an overall survival advantage, although further follow-up will be needed to better understand whether that invasive disease-free survival and distant disease-free survival translates into an overall survival advantage.

It did have a favorable side effect profile, very consistent with what we would expect from the metastatic trials. Slightly lower Grade 3 or higher adverse events in this study when compared with the pooled meta-analysis — sorry — pooled data from MONALEESA, 0.2 versus 1.2%, and no unexpected signals.

QTC prolongation did occur in 4.2% of patients on this study. So I don’t think that EKG monitoring will go away when this drug is approved in this setting. I still think we need to be vigilant about EKG surveillance and drug-drug interactions potentially. But I anticipate that this will become another standard of care option for our high-risk, hormone receptor-positive patients. What did you think, Neil?

DR LOVE: Well I was curious, it was interesting first of all the fact that it was 3 years with NATALEE and 2 with the monarch, and whether or not that’s going to carry over in clinical practice. It kind of reminds me in ovarian cancer, niraparib was used for 3 years, olaparib was used for 2 years. But then once they sort of got into it, everything started to be used for 2 years. So do you think that people are going — I mean that’s a big financial and even quality of life potentially, an issue. Do you think people are going to use 3 years?

DR MCARTHUR: I think if they had a high risk node-negative patient, I think it would be a consideration, although for patients who have chemotherapy, they have extended hormone therapy potentially, additional therapy, although relatively well tolerated, does have a side effect profile, will not be palatable for some. But I could see considering this for a very high-risk, node-negative population in whom 2 years abemaciclib would not be endorsed.

DR LOVE: Also I’m curious, based on your clinical experience, and also the data out there, how you compare quality of life with the abema versus ribo in the adjuvant setting?

DR MCARTHUR: Well we don’t really have that data yet. We can extrapolate from some of the quality-of-life data in the metastatic setting. But again, I personally, and this is anecdotal, have found both drugs to be very well tolerated in the metastatic setting. I haven’t used ribociclib yet in the curative-intent setting because we didn’t participate in the NATALEE study, but we participated in the monarchE and the PALLAS studies and have found these drugs very well tolerated for the most part in the curative-intent setting.

DR LOVE: The other question is, as this moves forward how are we going to determine who to use the CDK inhibitor, particularly patients who are lower risk? When I first saw the monarch data, I was figuring, in the past with other forms of hormonal therapy, going back to the meta-analysis, you sort of establish what the hazard rate is, then you apply it to what the absolute risk is. You see what the absolute benefit is. You look at the toxicity and decide whether it’s a good trade-off. But then monarch came out and people were just using very high-risk criteria whether or not to use a drug that really doesn’t have at least life-threatening toxicity.

Do you think we are going to move into that type of paradigm, just to calculate the absolute benefit? Present it to the patient as an option? I mean we use adjuvant endocrine therapy in patients nowadays who are 10% risk of recurrence, pretty low risk. Do you think that’s going to happen with these agents?

DR MCARTHUR: Potentially. As a reminder, almost everyone who participated in monarchE had received prior chemotherapy. So they’re already predefined as being high risk by virtue of the fact that they’ve already received chemotherapy. And that was maybe 1 of the issues with the PALLAS study, which was a negative study with palbociclib, that they didn’t have that same enrichment for patients who require chemotherapy.

So it already is a high-risk population. But, yes, I could see there being predictive tools in the same way that we’re using a lot of tools in other settings that provide sort of clin-risk like estimates for impact of each additional therapeutic option for our patients.

DR LOVE: I’ve got to ask you also because we just did a webinar with Erika Hamilton and Aditya Bardia, and one of the things we were talking about is adjuvant oral SERD trials. Do you think that 5 years from now we’re going to be using SERDs in the adjuvant setting?

DR MCARTHUR: I think so. I think so. So we have — there are a number of studies that are ongoing looking at oral SERDs in the curative-intent setting, both as first-line as for up-front replacement of conventional hormone therapies and then as extended therapy in high-risk populations. So, I would predict, especially based on the favorable toxicity profiles that we’ve seen in the metastatic setting, that these could become part of our biologically-driven arsenal for this disease.

DR LOVE: All right, let’s talk about the circulating DNA study with the PENELOPE study. I feel like we’re talking about circulating DNA in colon cancer, for example, all the time. I was wondering when it was going to come to breast. And we heard a lot about it at ASCO. This ASCO is the first time we really started to hear a lot about circulating DNA. So, how about this study.

DR MCARTHUR: Right. We’ve already heard that study on molecular residual disease, and now ctDNA there’s certainly a lot of attention, again with this idea of escalation and de-escalation with optimization of treatment recommendations for patients.

So this is an analysis from the PENELOPE-B study looking at detection of circulating tumor DNA after neoadjuvant chemotherapy and surgery in ER-positive, HER2-negative breast cancer. As you’ll recall, the PENELOPE study was a study that enrolled patients who received neoadjuvant chemotherapy and then after surgery were randomized to receive palbociclib with endocrine therapy versus placebo with endocrine therapy, in this case for only a year. It was a negative study of course, but still a lot to be learned from this effort.

You can see here that ctDNA analyses were conducted at baseline at cycle 7 and again at end of treatment, so at the end of the year. And not surprisingly, the detection of ctDNA at baseline is prognostic. So patients who had detectable ctDNA, as you can see here, for both invasive disease-free survival and distant disease-free survival had much poorer outcomes than those who didn’t have detectable ctDNA at baseline.

And then what was interesting to me was this analysis of the dynamics over time. So here we’re looking at invasive disease-free survival. Those patients, or the solid green line, is those who were undetected throughout. And you can see that those patients do very well. Those who started out detected but become undetected, that’s the green dash line, they do very well. But those patients who, not surprisingly, are detected throughout do very poorly. And then there’s a subset of patients, small subset, but a subset of patients who were initially undetected who developed detectable ctDNA during the course of palbociclib. And those patients, perhaps not surprisingly, also do extremely poorly.

So I thought this was a really interesting study. What we need, of course, is insight as how to pivot for those patients, both the ones in the solid pink and the dash pink, those who are detected throughout and those who become detected after initially being undetected.

So really interesting data from this study, but again, the predictive impact for these kinds of efforts are really important.

DR LOVE: I was just going to say I think I better let you keep you going here without asking you so many questions. What I’m going to do is write all my questions — because otherwise we’ll never get through here. So I’m going to write down my questions. I’m not going to interrupt you until you get through to the end. Sorry.

DR MCARTHUR: All right!

DR LOVE: I get carried away.

DR MCARTHUR: That’s okay!

DR LOVE: Or we’ll be here all day.

DR MCARTHUR: I know. Well, it’s fun to talk about the data.

So we’ll move on then to the RIGHT Choice trial. This was a really interesting study that came out of ASIA looking at ribociclib with endocrine therapy versus physician’s choice chemotherapy I pre- or perimenopausal women with very aggressive hormone receptor-positive, HER2-negative, advanced breast cancer.

So as a reminder, about 52% of patients enrolled in this study were deemed to be in visceral crisis. So a very poor prognosis population, about 54% of patients in this study were Asian. Those were the groups that drove the study. And perhaps shockingly to many of us, as a reminder the median progression-free survival was double for the ribociclib group as it was for the physician’s choice chemotherapy - 12- versus 24 months — which was a really interesting observation.

So here you see a further breakdown of progression-free survival by age group, those less than 40 versus those greater than or equal to 40. Again, this is a pre- or perimenopausal subgroup. And you see that in both groups there’s a benefit in favor of ribociclib, one that is perhaps magnified in the age less than 40, although, again, you’re looking at very few patient numbers here and few events so it’s really hypothesis-generating. But consistent benefit for the — by each subgroups.

Not surprisingly, the toxicity profile was really favorable for the ribociclib hormone therapy combination versus the chemotherapy combination. And so, it really underscored how effective these CDK hormone therapy combinations can be, even in our very high-risk hormone receptor-positive, HER2-negative populations. And data that was really surprising and interesting to see this subgroup analysis by age less than or equal to 40.

Then move on to the SONIA trial. This is a study that randomized patients with advanced hormone receptor-positive, HER2-negative breast cancer, who had not received any prior therapy for advanced breast cancer. So these are newly diagnosed, pre- and postmenopausal women. They were randomized 1:1 to receive nonsteroidal aromatase inhibitor with or without a CDK, followed by fulvestrant plus or minus a CDK. So the idea is do you need to receive CDK up-front in the first-line setting or is it equally as effective when administered with fulvestrant in the second line? And the primary endpoint for this study was progression-free survival after both lines of therapy.

Notably in this study, the vast majority, over 90% of patients, received palbociclib. And it may be that CDK4/6 inhibitor specifics are important as we consider this study, together with other sequencing studies that we’ve seen so far.

So here we’re showing the progression-free survival after the second line of therapy. It was not statistically significant. There was perhaps, a trend in favor of first-line CDK4/6. As a reminder, the PFS1, after the first line of therapy, was 24.7 versus 16.2 months in favor of first-line CDK4/6, with a hazard ratio of 0.59 from this study. Perhaps a hazard ratio that’s not as good as we have seen in other first-line therapy studies and that may impact the PFS2 analysis.

Here is the overall survival analysis and no significant difference in favor of either strategy.

The safety profile that was observed was characteristic for CDK4/6, predominantly neutropenia, liver function abnormalities, anemia and thrombocytopenia. Again, more than 90% of patients received palbociclib. So that’s a toxicity profile that’s very well described with that CDK4/6 inhibitor — 42% more Grade 3 or more events when used in the first line, perhaps not surprisingly.

Next we have the PALMIRA study. This is a second-line endocrine therapy study with or without palbociclib maintenance in patients with hormone receptor-positive disease. So another sequencing strategy, in this case patients who had had a partial response on first line or some degree of response on first-line palbociclib plus endocrine therapy or had adjuvant palbociclib after at least 12 months of treatment, but no more than 12 months after completing treatment, or no — and no other prior treatment for advanced breast cancer.

So the idea is that if you enrich for patients who have previously demonstrated a response to a palbociclib-based hormone therapy combination, can you continue palbociclib by essentially changing the hormone therapy backbone, and fulvestrant or letrozole were offered here. With a median follow-up of 13.2 months you can see the modest improvement potentially in progression-free survival here, 3.6 to 4.9 months, but was not statistically significant.

And here’s the overall survival curves with really no difference observed with either strategy.

And the treatment-related adverse events are exactly what we’ve seen in numerous other studies with palbociclib to date.

So the next study in this space is the BYLIEVE study. This is alpelisib plus endocrine therapy in patients with PIK3CA-mtuated, hormone receptor-positive, HER2-negative, advanced breast cancer. There are 3 different cohorts here. As a reminder, alpelisib is an alpha-selective PIK3CA inhibitor and degrader. It’s indicated in combination currently with fulvestrant after endocrine therapy. And in this study, patients with PIK3CA mutations, either in tumor or blood, were enrolled. They had to have received a prior CDK4/6 inhibitor with endocrine therapy or chemotherapy or endocrine therapy alone. And they were assigned, based on their most recent therapy.

So Cohort A is patients who received CDK4/6 with an aromatase inhibitor as immediate prior treatment. Then Cohort B is patients who received the CDK4/6 with fulvestrant as the immediate prior therapy. And then everybody else was assigned to Cohort C.

And because there are no real comparators, there wasn’t a randomization within the arms. All I can conclude here is that it demonstrated the combination, the various alpelisib combinations demonstrated clinical activity in all of the sub — in all of the cohorts interrogated.

And demonstrated a toxicity profile, again very consistent with what we’ve seen in other studies. The hyperglycemia is of course, a common issue that frequently requires management with Metformin when these drugs are administered.

Final overall survival analysis from the TROPiCS-02 study of sacituzumab govitecan for ER-positive, HER2-negative mBC; TROP2 mRNA expression and association with clinical outcomes

DR MCARTHUR: And then one of the other potentially big topics or studies out of the ASCO meeting this year was the final overall survival analysis from the Phase III TROPiCS-02 study, looking at the antibody drug conjugate sacituzumab govitecan in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Hope Rugo previously presented the progression-free survival data from this study. Here we go the updated overall survival analyses by Dr Sara Tolaney.

As a reminder, patients in this study had to have received at least 1 endocrine therapy, taxane and CDK4/6 inhibitor in any setting. They had to have received at least 2 but no more than 4 prior lines of chemotherapy and they randomized to receive the antibody drug conjugate, which, as a reminder, is a TROP-2 directed antibody drug conjugate versus physician’s choice chemotherapy. Primary endpoint was progression-free survival. And the study met its PFS primary endpoint as demonstrated here. There was a 1.5-month improvement in progression-free survival from 4 to 5.5 months.

And what was really remarkable to me from the PFS analyses were these landmark analyses as you can see here at 6, 12 and 18 months, demonstrating impressive clinical impact in favor of the antibody drug conjugate.

And there is the overall survival data that was just presented. Hazard ratio, 0.79 with a 3.3-month improvement in overall survival. And again you can see, certainly a 12- and 18 -month landmark analyses, impressive improvements in overall survival.

So the historical bar of just improving progression-free survival of a few months is no longer acceptable. We’re really looking for these clinically impactful improvements in overall survival. And they presented some interesting subgroup analyses from this study. One of the questions is, of course, do we need to use TROP-2 as a biomarker to predict for responses to these therapies?

So here they looked at low versus high TROP-2 expressors, and a very consistent benefit regardless of TROP-2 expression. Hazard ratio of 0.78 and 0.82. So this supports the idea that we don’t need to be testing for TROP-2 to apply these drugs. And then of course with this novel grouping of HER2-low disease, we’re interested in understanding the impact of other antibody drug conjugates in this space. And this I thought was a really interesting analysis too, looking at the impact of sacituzumab govitecan in the HER2-low versus HER2-0, and again you see very consistent benefits for overall survival in both of these subgroups.

So we’re struggling a little bit in our community with ow to sequence these antibody drug conjugates, particularly for those who have HER2-low disease. and trials are planned through the Cooperative Groups to look at that exact question of sequencing in both hormone receptor-positive disease as evaluated here, and triple-negative breast cancer.

Okay, also from the TROPiCS-02 study, we had this presentation from Aditya Bardia, looking at TROP-2 mRNA expression as it pertains to clinical outcomes in the same study. Here you can see PFS and OS by TROP-2 gene expression, TACSTD2 mRNA expression. And you can see very consistent benefit with sacituzumab govitecan regardless of mRNA expression. So the low and the high seem to derive the same benefit from PFS and OS. Very consistent with conventional assays for testing.

The also again looked at HER2 expression correlation and TROP-2 expression was not correlated with ERBB2 expression. So no correlation, it would seem, between TROP-2 and HER2 expression. And sacituzumab govitecan improved PFS and OSS, as demonstrated here regardless of TROP-2 expression and HER2-negtive status, whether it be HER2-low or HER2-0. So very consistent benefits across the board, which are reassuring here by mRNA.

DR LOVE: We kind of caught up a little bit. So let me ask a few question about some of the things that you just talked about.

DR MCARTHUR: Sure.

DR LOVE: First of all, going back to alpelisib, I’m curious — you hear issues that come up with alpelisib in terms of toxicity and I’m curious, are you using the drug? And how do you ameliorate toxicity? And what do you find?

DR MCARTHUR: I actually have found it a difficult drug to administer quite frankly. The blood sugar issue is obviously very common. But that piece is relatively easily managed with drugs like Metformin. It’s the more, sort of sinister issues like fatigue that I find people struggle with the most. And now that we have other options, including oral SERDs potentially intersecting with this space, that are extremely well tolerated, I’m probably using alpelisib even less frequently than I used to. But I find the fatigue and just general malaise with alpelisib has been difficult to navigate.

DR LOVE: Have you been able to — had the chance to use capivasertib, the AKT inhibitor? And if so, what’s you take in terms of toxicity there compared to alpelisib? I know there, they’re using it only a few days week. But any thoughts about that?

DR MCARTHUR: I’ve only used it in the setting of the triple-negative CAPItello study, which hasn’t yet been reported. So I haven’t used it in hormone receptor CAPItello study that was recently reported. We didn’t participate in that study. So I can only speak to the handful of patients that I treated on-study. But from reports that we’ve seen to date for hormone receptor-positive disease it seems to be extremely well tolerated and I think will be a very well received option to add to our arsenal in the not too distant future.

DR LOVE: That’s really interesting. Triple-negative?

DR MCARTHUR: Mm-hmm, with paclitaxel as first-line therapy.

DR LOVE: Hmm. Wow.  Wow.

DR MCARTHUR: Based on the PACT and other studies in the more advanced triple-negative disease. Uh-huh.

DR LOVE: Interesting. Also, in terms of sacituzumab, you were mentioning the data on HER2-low. I’m curious, right now how you sequence chemotherapy or chemotherapy versus T-DXd in HER2-low patients, both hormone receptor-positive, hormone receptor-negative? In both situations you have a lot of debate about what comes first: T-DXd or sacituzumab. How do you approach that?

DR MCARTHUR: Mm-hmm. So, with the triple-negative population, I typically use sacituzumab govitecan first, based on the ASCENT trial, which was dedicated to that specified population. Whereas in the DESTINY-Breast04 study, which looked at trastuzumab deruxtecan in the HER2-low population, only approximately 10% of patients on that study had triple-negative breast cancer. So it’s a much smaller, more modest population in that space. So I look to the Phase III data first. So that’s typically how I sequence. Although, again, trials are being planned through the Cooperative Groups looking at sequencing in these populations because we don’t know the impact of the — the biologic impact of 1 before another.

Hormone receptor-positive breast cancer I’m more nimble perhaps, and it usually requires a conversation with the patient. It depends on risk factors for interstitial lung disease, for example. So it’s worth noting that although there is this misconception that there is a class effect with antibody drug conjugates as it pertains to interstitial lung disease, there actually hasn’t been any interstitial lung disease reported with sacituzumab govitecan. And so if I have a patient who. Has a huge burden of lung metastasis or COPD, for example, I might favor sacituzumab govitecan first.

I also use different monitoring strategies for those drugs. So with trastuzumab deruxtecan, because of the interstitial lung disease where you have to hold drug for Grade 1 ILD or pneumonitis, which can only be identified on imaging, I’m doing imaging much more frequently, every 9 weeks versus any other drug, I typically do imaging every 12 weeks. So a more nuanced discussion happens with our hormone receptor-positive patients.

DR LOVE: Yeah. Actually, when you were talking about your patient on T-DXd for I think 5 years or more, I was curious, are you still doing imaging on that patient?

DR MCARTHUR: We are doing imaging, but relatively infrequently. We don’t have any long-term data, but most of the ILD that was observed with that drug was reported within the first 12 months. And so, we have talked about changing to just trastuzumab potentially as maintenance therapy and we perseverate over those decisions, whether she should actually come off. But I’m not so much worried about the ILD at this point because, again, in the clinical trials to date it really — the cumulative incidence was primarily in the first 12 months.

So, like most long-term responders with metastatic disease, we equivocate about how regularly to do imaging. So for that person we’ve been doing imaging every 6 months.

DR LOVE: So, getting back to sacituzumab, we’re seeing more and more antibody drug conjugates moving up. We just had an antibody drug conjugate plus pembro, enfortumab, approved as first-line therapy in bladder cancer. I’m curious where you see sacituzumab heading. I recently become aware of some neoadjuvant studies with sacituzumab, including neoadjuvant sacituzumab plus IO.

So I’m curious where you see sacituzumab heading in terms of earlier-stage disease?

DR MCARTHUR: Uh-huh. So, I mean, with more targeted therapy and perhaps less toxicity than conventional chemotherapy, you could see its appeal in the curative-intent setting. Through the Alliance Cooperative Group, a study recently opened for triple-negative disease, that’s the optimized residual disease study that Sara Tolaney is leading. That’s enrolling patients who have residual disease after their standard of care therapy, presumably KEYNOTE-522, who haven’t had a complete response to the KEYNOTE-552 regimen or some component of it. Go to surgery have residual disease, and then they get randomized to standard of care pembrolizumab to complete the year, 9 additional cycles, versus pembrolizumab with sacituzumab.

So, again, an escalation strategy for those who are particularly at high risk, about a third of those patients will experience a distant recurrence within 2 to 3 years. And so those are our most high-risk patients.

So I see it moving into that space as an escalation strategy. But I also see it moving into the neoadjuvant space as a replacement, potentially for conventional chemotherapy. And we’re seeing that with the other antibody drug conjugates as well. So, Dado-DXd has moved into the same residual disease space for triple-negative breast cancer, and one could anticipate that it would move into the curative-intent neoadjuvant space as well.

DR LOVE: And speaking of antibody drug conjugates, patritumab, which we hear a lot about in lung cancer, now in breast cancer.

DR MCARTHUR: That’s right. That’s right. We still have Phase I/II study presented by Ian Krop not too long ago, looking at patritumab deruxtecan. This is a HER3-directed antibody drug conjugate. Notably, there are higher levels of HER2 expression metastatic breast cancer as compared to primary tumors. And Ian previously presented some impressive response rates in both ER-positive and triple-negative subsets with this strategy.

So, Erika Hamilton presented Part A from this Phase II study exploring the efficacy and safety of this antibody drug conjugate in advanced disease. And here you could see very consistent responses rates. The total response rate was 35%, but they’re broken down here into groups by HER2 expression, so HER3 expression greater than 75% versus 25- to 74%, versus less than 25%. And you can see very consistent, in my mind, modest numbers of course, particularly in the less than 25% with only 4 patients in that group. But very consistent response rates across the board, indicating that HER3 expression isn’t necessarily enriching for response to treatment, at least from this study.

And the most common adverse events observed in the study were nausea, fatigue and diarrhea, similar to what we’d seen previously in the initial effort. But the majority of events were Grade 1 and 2. So there were no Grade 3 or 4 events in more than 7% of patients, indicating that this could be a very well tolerated future therapy for patients, again in that intersection of ER-positive and triple-negative disease.

So another promising antibody drug conjugate on the forecast.

And I think that might  be our last.

DR LOVE: Right. Sometimes it’s hard to understand how targeted antibody drug conjugates actually are. You showed the data, I think with TROP-2 levels and sacituzumab. Obviously, you have HER2-low and T-DXd. Patritumab, it looked like they had response — they did well even with lower levels. What’s your vision for how ADCs work? With the idea that something like TROP-2, you just see it more in the breast tissue or breast cancer tissue in general compared to normal cells? Or how targeted are these agents, in your mind?

DR MCARTHUR: Well in my mind, most of the drugs that we talked about today, the antibody drug conjugates, have this bystander effect. And I know everybody is talking about that right now. But it does overcome the issue of heterogeneity, and we talked about previously, trastuzumab deruxtecan and HER2-ultra low. So HER2—0, but have the tiniest amount of HER2 expression that doesn’t reach conventional thresholds. And I anticipate that there will be activity even in that subset. And again, the way we’re thinking about it, whether right or wrong, is that at least some part of that is a result of this phenomenon of antibody drug conjugate bystander effect. And that has to do with the new linker technology and the solubility of the drug and some other aspects of these modern ern antibody drug conjugates.

So I think that’s at least part of it. I think that these drugs, as we learned with trastuzumab, which we previously thought of as exclusively binding to HER2 and exerting its effects that way, we later came to understand that it was actually an incredibly complicated drug and could induce ADCC for example, without binding. So it’s possible that there are more broader reaching effects of these drugs rather than target-specific effects.

DR LOVE: So the last thing I wanted to ask you is, we’re kind of heading into the Fall, so we’ll be seeing ESMO and San Antonio. Any data sets that you hope or think might be coming up in the next 6 months you’re looking forward to see?

DR MCARTHUR: There are going to be some great presentations at San Antonio, based on the submissions that I’ve seen to date. There are a number of curative-intent immune therapy studies that are highly anticipated. So I was one of the co-PIs on the Impassion030 study. That was a study looking at adjuvant chemotherapy plus or minus atezolizumab for triple-negative breast cancer, Stage II or Stage III. And we recently announced that we closed the study after almost 2,200 patients of the planned 2,300 patients were enrolled on the recommendation of the IDMC. So, I would anticipate seeing that data sometime in the near future. And that I think will really inform our thinking about the effectiveness of immune therapy and treating micrometastatic disease.

DR LOVE: It sounds like it’s a positive study, from what you’re saying.

Not necessarily?

DR MCARTHUR: Not necessarily.

DR LOVE: I guess it could have been closed because of futility, right. Okay.

But adjuvant IO in triple-negative? Like, who are those — I mean is this after neoadjuvant or straight adjuvant therapy?

DR MCARTHUR: Well, this study was undertaken, going back, it must be about 7 years ago. So it was before the KEYNOTE-522 data was presented and before those health authority approvals. So the vast majority of patients who enrolled on the Impassion030 study were ex-US, where this was potentially the only mechanism for accessing checkpoint blockade.

DR MCARTHUR: I mean, also germane to this conversation is the anticipation of the SWOG-1418 study, which is the study that enrolled patients with residual disease, triple-negative breast cancer, after neoadjuvant chemotherapy and randomized them to the prior standard of care which was no further therapy. It allowed for capecitabine versus pembrolizumab in the adjuvant setting. That’s an event-driven study. That study closed to accrual some time ago and still hasn’t been reported.

So it does beg the question of whether there is a mounting body of data suggesting that immune therapy for breast cancer may not be effective in the adjuvant setting for micrometastatic disease. But we need to see the actual data before we can have those conversations.

DR LOVE: What other trials are coming out that we ought to be having — looking out for?

DR MCARTHUR: There are, not to be focused exclusively on immune therapy, but there are trials anticipated with checkpoint blockade in the curative-intent setting for hormone receptor-positive, specifically ER-positive, breast cancer. So I would be on the lookout for those.

DR LOVE: Hmm, that’s interesting.

DR MCARTHUR: And I think we’ll see more biomarker studies as well, ctDNA type studies because there’s been a lot more attention to those efforts. And again, we need the predictive impact of those studies to help us pivot better treat our patients.

DR LOVE: Actually, I was going to ask you before, do you yourself ever use ctDNA outside a clinical trial setting in breast cancer?

DR MCARTHUR: We do. We do genomics. I mean, we’re looking for ESR1 mutations now after endocrine therapy. They’re acquired mutations in the advanced setting. So we do liquid biopsies. But I’m not looking in the curative-intent setting for ctDNA or evidence of circulating residual disease because at this time I don’t have any data that informs impact on decision-making.

DR LOVE: Do you think that that would be — one of the things about breast cancer that’s so interesting is the delayed recurrence. And how long you can use endocrine therapy? Neratinib, et cetera? Do you think ctDNA would be helpful in that situation?

DR MCARTHUR: I think it could be. The problem, as you point out, is the issue of delayed recurrence, and especially now that we’re seeing improved invasive disease-free survival with the CDK4/6 inhibitors, for example, in the adjuvant setting. We’re going to see the impact of oral SERDs. And you have to follow these patients for decades to really understand the impact. And the field is moving so quickly now with an unprecedented number of FDA approvals in recent years for breast cancer that I don’t think that we will be able to watch patients for 10 years before we make the next clinical decision. So it is a bit of a challenge. So I think we’ll have to extrapolate from ongoing efforts that don’t specifically ask and answer those questions.