Localized Breast Cancer — Professor Peter Schmid, FRCP, MD, PhD

PROF SCHMID: I’m Peter Schmid. I’m a medical oncologist, and I work at Bart’s Hospital in London. It’s my pleasure discussing with you today a few of the most important works from the last year. My focus will be on early breast cancer. We’ll first talk about a few papers in ER-positive early breast cancer and then move on to triple-negative and HER2-positive breast cancer.

2022 was once again a very important year for breast cancer. We’ve had some key new data coming through, and that really helped us to sharpen our understanding of, for example, who benefits best from adjuvant chemotherapy, but also had additional data on some of the new drugs that really will improve long-term outcome of patients.

One of the really interesting data presented at the San Antonio meeting just a few weeks ago was clinical outcomes from the RxPONDER trial, and dependent on the ethnical subgroup that patients belonged to. If you look at the ethnic subgroups in RxPONDER the majority of women were classified as white ethnicity, 6% classified as black, 15% as Hispanic, and 8% as Asian background.

If you look at the invasive recurrence-free survival outcome it is very clear that women with black ethnicity have an inferior outcome compared to women with white ethnicity. Whereas again if you look at Asian ethnicity, or Asian origin, compared to white there’s a slightly improved outcome. If you look at this in more detail in distance recurrence-free survival again we see better outcome of patients from all ethnical groups with the exception of women with black racial background. The hazard ratio of 1.39 is significant in this setting.

And one important parameter seems to be body mass index. In the multivariate analysis, if this was adjusted by body mass index, the hazard ratio was still significant but went down from 1.7 to 1.31.

A second study, again at San Antonio, also looked at outcomes, and this was in the TAILORx trial in patients with node-negative disease versus the RxPONDER, as you are all aware, was in patients with node-positive disease.

And what I found really interesting to see there was that, again, the racial background is important in terms of all outcome parameters for the first 5 years. And if you look at this on the table on the right bottom corner, disease-free survival and overall survival, distant recurrence-free survival, we can see very clearly significantly inferior outcome for black women compared to white women. But interestingly, after 6 to 12 months, that changes, and ethnicity doesn’t seem to be a driver anymore for outcome in terms of later recurrences. And we can discuss a little bit later what factors may possibly be behind there.

So the conclusions of the RxPONDER group was that black women with ER-positive, HER2-negative breast cancer with 1-3 lymph nodes and a recurrence score of less than 25 have worse outcomes compared to white women. And that’s independent of the recurrence score, of the treatment given, age, and grade. But body mass index appeared to be an influencing factor, but the effect persisted even after adjustment for body mass index.

At this time, however, no definite conclusions can be made about racial differences in treatment benefits because unfortunately the number of events was relatively, as only 6% of women in RxPONDER trial were black.

If you look at it, black women were also more likely to accept treatment assignment compared to white women and were just as likely to remain on endocrine therapy at 6 and 12 months. So these data really suggest that the differences in outcome are not driven by lack of compliance within the first year, but may possibly be driven by other factors, including the underlying biology.

A second paper that was published this year is from the West German Study Group, presented by Ulrike Nitz, and that looks, in my opinion, a very clever way at combining the 21-gene expression assay together with the functional assay of endocrine sensitivity. If we go a step back and see where we are at the moment with gene expression assays and identifying who needs chemotherapy for early ER-positive, HER2-negative breast cancer it’s very clear that most women with 4 or more lymph nodes would be recommended to have chemotherapy and endocrine therapy.

For women with 1-3 lymph nodes there’s a slight difference, whether pre- or postmenopausal, but essentially woman with a high recurrence score of more 25 would surely be recommended chemotherapy and endocrine therapy. Whereas women with intermediate risk would only be recommended at the moment, as per RxPONDER trial, to have chemotherapy if they’re premenopausal versus postmenopausal women there’s no benefit.

Similar, in women with node-negative disease with a high recurrence score of higher than 25 we would recommend chemotherapy and endocrine therapy in principle, but only in premenopausal women with an intermediate risk of 11 to 25. There is an ongoing debate whether it’s chemotherapy or just endocrine therapy. In a number of studies we looked at those groups a little bit more in detail over the last year.

So if you go back to the trial of the WSG and the West German Study Group we saw — it was a study that involved about 5,000 patients, ER positive, and node negative or with 1-3 lymph nodes. All women had to have a recurrence score assessed. Cutoffs for this trial were null to 11. There was 20% of women that were immediately offered adjuvant endocrine therapy, and there was a high-risk group of more than 25, and those were offered chemotherapy.

But where the trial was really interesting was in this intermediate-risk group, where we’re not always quite sure what to do. And what the group incorporated was what I would call a preoperative window of opportunity trial phase. So women received, after they had a core biopsy taken to do the Oncotype test, they received 3 weeks of endocrine therapy prior to surgery. And the endocrine response was assessed by downregulation of Ki-67, which were centrally assessed, and if their Ki-67 went to less than 10% patients were classified as an endocrine responder. If it didn’t have the decrease in proliferation they were classified as not having an endocrine response.

And it’s interesting to see that about two thirds had an endocrine response and one third did not have an endocrine response.

And what the trial did is assign those women who had an endocrine response, regardless of what that intermediate risk score was and what the menopausal status was, to endocrine therapy alone. And all other women without an endocrine response received chemotherapy and endocrine therapy.

So the trials allows us now to compare the 3 different groups, the 2 groups in the intermediate-risk group; endocrine therapy, and chemo and endocrine therapy. And there’s an additional control group, a low-risk group, with a recurrence score of 0-11.

And if you look at the outcome data, in the 2 groups of women who received endocrine therapy alone, so this is either women with low-risk, null to 11, or women with 12-25 risk but an endocrine response. And you can easily see those curves that completely superimpose, and the trial statistics show this strategy is noninferior.

So we can identify a group within the intermediate-risk group that is sufficiently treated with endocrine therapy alone and doesn’t need chemotherapy in this context.

If you then look at all 3 groups, including the slightly higher risk of the nonendocrine responsive group who received chemotherapy, you can again see they’re very closely together and shared a relatively similar benefit, suggesting that this strategy is very good at selecting patients who need chemotherapy and improving their outcome and those patients who may not need chemotherapy and are sufficiently treated with endocrine therapy.

As a second publication from the WSG at ESMO, and again for me it was one of the highlights of ESMO 2022, was the data combined from a number of trials looking at the endocrine response by Ki-67 again. And what we’ve known in the past was that in the premenopausal women often see a relatively incomplete suppression of Ki-67. So if you look at the charts, on the left top of the chart, you can see — in postmenopausal women you can see a much more substantial downregulation initially of Ki-67, 81% with aromatase inhibitors. Whereas if you look in premenopausal women it is only about 40% with tamoxifen.

But really interesting, looking at the bars in green, this is the combination of ovarian function suppression over a short period of 3 weeks with aromatase inhibitors. And what I take away from this is if women have adequate ovarian function suppression, even in a preoperative window setting, they have a very similar response to preoperative therapy as postmenopausal women. And that’s something worthwhile discussing because there remains a chance that the biology isn’t as different as we sometimes thought between pre- and postmenopausal women. It is more the treatment that is different, and if you treat those women adequately, not just with endocrine therapy alone, but with combination with ovarian function suppression, we achieve a similar endocrine response, and that can then take them back to the left side of the slide, or to help us stratify women who may or may not need chemotherapy.

So the conclusion from the WSG-ADAPT ER-positive trial demonstrates a guiding systemic therapy by both recurrence score but also endocrine treatment response is feasible in clinical routine and spares chemotherapy in pre- and postmenopausal women with less than 3 involved lymph nodes.

A second attempt in this strategy is obviously trying to reduce or to spare women from having chemotherapy based on gene expression assays. There was an important update from the TAILORx trial group with now 12-year event-free — event rates.

Now if you look at the updated data we see the recurrence score remains highly predictive of outcome. You see Arm D, which is women with higher recurrence score, it’s clearly inferior to the other arms, Arm A, which is low recurrence score, then Arm B and C, the intermediate recurrence score, 11-25, with either treatment with endocrine therapy or endocrine therapy plus chemotherapy.  

So if you look at that intermediate group, which is again the group of interest, it is interesting and clear to see that both were invasive disease-free survival but also for distant recurrence-free survival. There is a difference in the benefit even within the intermediate-risk group. So women who have a very — the lower range of intermediate risk group, 11-15, and there’s practically no difference, whereas in women with 16-20, or then more importantly 21-25, in this age group of less than 50, there’s an increasing benefit from chemotherapy.

And so if you take that back to the data provided from the TAILORx group you can see premenopausal women, women under the age of 50 — now in women above the age of 50 there’s no benefit from chemotherapy in this intermediate-risk group. But women under the age of 50 it’s very clear if their recurrence score is 16-20 there’s possibly a small benefit.

But if you bring in additional clinical parameters, clinical risk, so size of cancer and so on, we can identify a group that still has a 3% absolute benefit from chemotherapy. So patients with high clinical risk, possibly should be considered. Patients with low clinical risk haven’t got a benefit. If you go to the higher end of the intermediate-risk group, 21-25, there is a clear benefit in premenopausal women from chemotherapy, in women with low or high clinical risk.

And so if you bring all of this together, where we are now, I think we’ve got away with what I put in as the amber color, initially, in the node-negative premenopausal, intermediate-risk group there is a benefit from chemotherapy with a recurrence score of 21-25 in women under the age of 50. There’s a benefit in the group of a recurrence score of 16-20 as long as they have high clinical risk factors. And we can obviously also take into consideration the dynamic adjustments based on the results of the WSG.

So the summary of the TAILORx data. With a longer median follow up, now 11 as compared to 7 years, there’s substantially more events now, well 50% more events, essentially, as we saw in the previous results, 1,295 versus 836.

The main study findings are unchanged for women in the intermediate-risk group, recurrence score of 11-25. Endocrine therapy is noninferior to chemotherapy and endocrine therapy for invasive disease-free survival, the distant recurrence-free survival, and recurrence-free and overall survival were also similar between both treatment groups.

Other exploratory key study findings are also similar to the original analysis, that women under the age of 50 with a recurrence score of 21-25 benefit from chemotherapy, but also that some — there’s some chemotherapy benefit for women under the age of 50 who have an even lower score of 16-20, and that’s usually defined by high clinical risk.

New findings of the updated analyses is that late recurrence beyond 5 years, they actually exceed the early recurrences, and again that defines our need for extended therapies and how we can tailor those late recurrence. And the racial disparities for black women are associated with early, but interestingly enough not with late disease recurrences.

If you look at biomarkers for adjuvant endocrine therapy there was an update of the ASCO Guidelines, and I’m not going to read out the whole aspect, but obviously there’s a number of gene expression assays from Oncotype to MammaPrint, Breast Cancer Index, and Endo-Predict, and they can guide the use of adjuvant endocrine therapy and chemotherapy in women who are postmenopausal or over the age of 50 with early ER-positive, HER2-negative breast cancer. There’s also — that’s node negative or has 1-3 involved lymph nodes.

In premenopausal women there’s data obviously with Oncotype in patients with node-negative tumor, but current data suggests that premenopausal women with 1-3 positive lymph nodes benefit from chemotherapy regardless of the genomic assay results. There’s no data on the use of genomic tests to guide adjuvant chemotherapy in women with 4 or more lymph nodes, and at the moment we would not select by biology.

DR LOVE: So before you go on to talk about the monarchE study, just a couple of questions to follow up some of the things you just — we’ll talk more about this when we have the webinar with Joyce, but I just kind of wanted to get some preliminary thoughts from you.

First, do you have any potential explanation or theory about why the differences were seen in the racial ethnic groups in terms of relationship to Oncotype? And am I correct in saying that even though the absolute prognosis or outcome is not as favorable in black women that you still see the same responsiveness or correlation with genomic assays like Oncotype?

PROF SCHMID: Yeah. So it’s a really important and really difficult question, what drives those possible different outcomes between different ethnic groups. And for many years when one thought that maybe access to treatment, later diagnosis, treatment compliance, but actually the data presented here suggests that treatment adherence is very similar between groups. That’s certainly not the main driver of that change.

So it brings it back to is the biology different. There was an interesting presentation at San Antonio that looked into the tissue microenvironment of metastasis and how cancer cells possibly get access to the vasculature, which is the basis for metastatic seeding. And they saw differences in that very early process based on lab results, but also translational results, between black women and white women. And that could suggest that if there’s a higher early metastasis potential that may possibly be one of the — one of the explanations there.

I think the body mass index plays a role, as well, and we know that the efficacy of endocrine therapy can be affected by the body mass index. But as I said earlier, the benefits remain even if this is adjusted by body mass index.

So I think it’s probably a number of factors coming together. Some of them are biological factors, some of them are host factors, or patient factors, and it’s probably not one single factor that drives that disparity.

DR LOVE: Another question is related to the issue of interpretation of specifically the recurrence score in premenopausal women. There’s a lot of controversy about intermediate, but am I correct in saying that still if you have a patient with 1-3 nodes, who’s premenopausal, who has a low recurrence score that they don’t benefit from chemotherapy?

PROF SCHMID: So that is correct. If a low recurrence score, null to 11, for example, that there is no clear benefit from endocrine therapy. And you saw in the different studies the excellent outcomes of women in that group.

I also think it is one possible tool we don’t use enough, and that’s the functional test of endocrine sensitivity, which is very simple to do. If women have their core biopsy we give them 2 or 3 weeks of endocrine therapy. In most countries the average wait from diagnosis to surgery is about 3 weeks, and why don’t we want to learn how Ki-67 does get downregulated. And that’s for me an incredibly powerful, very, very simple, very cheap to do, and therefore we should be able to do this wherever we are. An assay that really guides us, again, in how to utilize chemotherapy or not in this intermediate-risk group. And I think that’s something I would like to see personally be more incorporated into our clinical strategies.

DR LOVE: Yeah. I always thought that that strategy was really interesting also. And the other thing is I’m not sure I remember seeing, maybe it’s been there, and I missed it, the use of ovarian suppression neoadjuvantly. You were talking about it in the ADAPT trial. Has that been looked at before?

PROF SCHMID: So it hasn’t. It hasn’t. It hasn’t been done well enough, and there’s always been some theoretical consideration, is ovarian function suppression working fast enough for that short window of opportunity setup. But the results from the WSG speak for themselves. If we add in ovarian suppression, whether it is complete at that timepoint or not, what is very clear is that women achieve a much higher suppression in terms of Ki-67 and can therefore be, again, easily classified as endocrine responders or not. And I think that’s an important learning.

It's also an important learning, if you think of it, one of the things we still struggle with is to select which women in the adjuvant setting should have combination of ovarian suppression and aromatase inhibitors as long-term adjuvant therapy. The data, again, are relatively clear overall that there is a benefit from AI plus ovarian function suppression compared to tamoxifen/ovarian function suppression compared to tamoxifen alone.

But the side effects are also quite significant. And so if you had better guidance who is endocrine sensitive and responsive and who needs that additional ovarian function suppression or not, that would be — would make a huge impact for patients, especially in terms of quality of life.

DR LOVE: Really interesting.

Okay, let’s finish out with the last paper in this section, the update on the monarchE study.

PROF SCHMID: It was a long-expected analysis. I think everyone is aware of the design of the monarchE trial. And we had data at earlier timepoints. The trial design has been previously described. It’s in ER-positive, HER2-negative, node-positive women with high risk of disease recurrence. And high risk of disease recurrence was defined by 4 or more lymph nodes or by Grade 3 disease or a tumor size of more than 5 cm. And there was a fourth group as a subgroup in Cohort 2 that could also be defined by a Ki-67 of 20% or higher in women who had 1-3 lymph nodes. That Ki-67 group was only about 9%, but I think this is clinically a really important group.

Overall 5,600 patients were randomized between endocrine therapy of choice alone, which is aromatase inhibitor or tamoxifen, or then the addition of abemaciclib to endocrine therapy of choice at a dose of 150 mg twice daily for 2 years.

If you look at the outcome of patients at 42 months now of follow up we see a significant — we see a meaningful improvement in invasive disease-free survival, hazard ratio now 0.664, so a nearly 34% reduction in invasive recurrences.

What I find personally interesting is how those curves are widening. When you look at 24 months timepoint compared to the 36 months or now 48 months timepoint, the delta gets larger and larger over time. The benefit is seen consistently across all subgroups, as you can see on the right side of the slide.

And if you look at the distant recurrence-free survival, which is obviously the most important predictor of long-term outcome, again we see a hazard ratio of 0.65, so again nearly 35% reduction in the risk of having a distant recurrence event.

And really interesting, again, looking at the landmark analysis of year 1, year 2, year 3, and beyond year 3, you can see that both for invasive and for distant recurrence-free survival the hazard ratio gets better year by year. That’s interesting as it suggests there is a possible carryover effect of the benefits of abemaciclib beyond year 2. That’s what’s really important for us to see.

Now there was also, obviously, announced there will be preliminary overall survival data, but with a median follow up of 42 months and knowing that the median survival these days of women with metastatic ER-positive breast cancer is in the range of 4 to 5 years it wasn’t really expected that this trial could show differences at this point in time, and that’s what we see here in the Kaplan-Meier curves.

But I found the analysis on the right side of the slide very helpful in making us understand what is there to expect in the years to come. So you have 3 — you have, on the right side, endocrine therapy alone, on the left side abemaciclib with endocrine therapy. You have 3 groups. We’ve got in dark blue deaths not related to breast cancer. That is very similar. We have then in the lighter blue deaths to breast cancer, small numerical difference, but not significant at this stage.

But important is to look at the 2 green boxes. These are women who are alive but are receiving treatment for metastatic breast cancer. And unfortunately, as we can’t cure metastatic breast cancer at this point time, we’ll be — it’s extremely likely that will lead to an event in terms of overall survival. And the number’s twice as high in patients who have endocrine therapy alone, 249 compared to 125 with abemaciclib/endocrine therapy. So we would expect that these data will lead to a difference in overall survival over time.

The conclusions of monarchE. Now with additional follow up the benefit of adjuvant abemaciclib has deepened in its magnitude with an increase in absolute iDFS and distant recurrence-free survival benefit at 4 years as compared to 2 or to 3 years.

The benefit is still demonstrated across all prespecified subgroups for iDFS and DRFS. What we didn’t show, an important dimension, is Ki-67 remains a prognostic factor but the benefit of abemaciclib is seen similar whether patients have is seen similar whether patients have high or low Ki-67.

The overall survival data remain immature at this time. Fewer deaths were observed with abemaciclib plus endocrine therapy, but of course continued follow up is required and will happen until we have the final assessment of overall survival.

DR LOVE: So I kind of like see things from a macro perspective, and I want to ask you a question about the monarchE data, which is do you think it’s reasonable to — do you agree with the following statement: Even though the trial itself enrolled patients who were high risk, and the approvals that are out there are for patients with high risk, in fact, you could be — again, I’m asking whether you agree with this statement, you could be reasonably confident that if you use this strategy of adding adjuvant abemaciclib in lower-risk patients, including node-negative patients, you would see a benefit, 34% relative reduction, that could be applied to a patient who has a risk of 10%.

The same way that we think about endocrine therapy and chemotherapy in the adjuvant setting. You take the hazard rate, you apply it to the absolute risk, and you get the benefit, and then you decide whether it’s worth it or not. And that in fact the approvals in all the guidelines are based on the perception of whether or not the risk/benefit ratio of treatment is worthwhile. And I don’t know, maybe they even included financial considerations.

PROF SCHMID: Yeah.

DR LOVE: So in other words, what I’m saying is that there kind of was a judgment placed on what the risk/benefit ratio would be as you dropped down the risk. Do you agree with that or not?

PROF SCHMID: So it’s a difficult, but it’s an important question you ask. I think there are 2 points to consider. The first thing is the relative benefit only plays a role if women aren’t already cured. So If you — in a simplistic way, if you’re already cured with the existing therapy a drug on top of it doesn’t provide additional benefit. So we can’t assume the hazard ratio will be the same.

The second thing is extrapolating the results to lower-risk groups would only work if this drug provides exactly the same benefit across all biological groups. And there’s a theoretical consideration too, whether in luminal B type cancers would share partial endocrine resistance, whether that is a group where we see more benefit of a combination of endocrine therapy as compared to luminal A type breast cancers, which are highly hormone receptor sensitive. And that hypothesis hasn’t been tested.

Now by going for higher-risk patients in terms of stage, but also in terms of biology, Grade 3, Ki-67, we enrich for what I would describe as luminal B type cancers. And in that group of patients you clearly see a benefit. So if you have the same biology it is possible that we see that benefit even in lower-risk groups.

But the caveat is, is the benefit consistent across luminal A and luminal B type cancers, and in lower-risk groups you may have more luminal A cancers. So you have those 2 factors coming together. You may already be cured with the existing therapy. Therefore any benefit is smaller. Plus, you may have possibly slightly less of a benefit in a luminal A type cancer, and therefore I would personally not extrapolate those data to substantially lower-risk groups.

DR LOVE: Great. Okay, please continue.

PROF SCHMID: So if you look at triple-negative breast cancer, again, a really important year, where we had updates and final readout of some of the key studies. The developments were in immune therapy. We have 2 important papers with checkpoint inhibitors in early triple-negative breast cancer, Stage II and III disease, and the third important paper selected here is updated data for OlympiA study that looked at olaparib in patients with germline BRCA1 and BRCA2 mutations. Plus we cover the ASCO rapid recommendation update following the release of the KEYNOTE-522 data.

The updated data for OlympiA were presented by Andy Tutt as a virtual plenary and then subsequently published in full paper. It comes back to the question, and for me personally in triple-negative breast cancer we are increasingly moving away from primary surgery. We are — almost all women receive neoadjuvant chemotherapy or should be considered for neoadjuvant chemotherapy because we use this, again, as a functional assay of how well patients respond.

And that is dependent, then, on how valid this is, whether — if patients respond fantastically well they don’t need escalation of therapy. But if patients have residual disease after preoperative chemotherapy can we change and improve their outcome with postoperative, with adjuvant therapy? And the majority of women in the OlympiA trial were in that group.

So the OlympiA trial. While published before in patients with BRCA1 and BRCA2 mutations, with Stage I-IIIB early breast cancer, could be ER positive or triple negative, it is largely triple-negative breast cancer patients who were enrolled in this trial. They could have had either surgery first, followed by adjuvant therapy if they were high risk T2 or node positive, or what the majority received, had neoadjuvant chemotherapy, and if there was residual disease they randomized to olaparib PARP inhibitor for a year or placebo.

And we have previously seen the disease-free survival data showing very clearly substantial reduction in disease-free survival and here presented in distant disease-free survival. And you can see very clearly that the benefit gets slightly more over time. The hazard ratio is 0.61, so about 40% risk reduction.

What we have this year as new is that this is now also leading to a survival benefit, and we see that the curves have started to separate after about 2 years, and when we go to year 3 or year 4 it translates into about an absolute 3% — 3% to 4% benefit in overall survival, with a hazard ratio, again, of 0.68.

And if you look at the benefit within subgroups I would say it is a consistent benefit across all subgroups. There’s a small caveat in patients who had prior platinum therapy. The benefit may not be quite as large, but still it is showing a very strong signal in those patients.

So the conclusions of the OlympiA study are very clear that the benefit in terms of distant recurrence-free survival persists and deepens over time, and also with the time now past is clearly leading to a benefit in overall survival. So it’s an important strategy where we can improve the outcome of patients with residual disease after neoadjuvant chemotherapy if they have germline BRCA1 or BRCA2 mutations and receive adjuvant therapy with olaparib for a year.

The second important study was the full publication of the KEYNOTE-522 trial. This is the second primary endpoint that was presented. Just to remind you briefly of what the KEYNOTE-522 trial evaluated; it was a large, randomized Phase III trial that investigated the benefit of adding immune therapy to neoadjuvant chemotherapy. Patients were 2:1 randomized to either pembrolizumab or placebo and combined with what I would call a most intensive or most active neoadjuvant chemotherapy, 12 weeks of paclitaxel and carboplatin, followed by 12 weeks of AC or EC, then surgery. Patients remained blinded and continued with immune therapy or placebo for a total duration of 1 year.

The trial has 2 primary endpoints. The first one was path CR, and they reported those data 2 years ago. The second one was event-free survival, and this is the updated analysis.

What we had previously shown in the path CR analysis was that the addition of immune therapy led to a significant and meaningful increase in path CR rates from 51% to nearly 65%. We’ve now been able to show that this benefit also translates into a long-term benefit in terms of event-free survival, the hazard ratio 0.63, so 37% reduction of the risk of recurrences, with a median follow up of just over 3 years. And if you look at the 3-year event-free event rates, 16% versus 24%, so about 8% absolute difference.

We also did additional work on who are the patients who benefit from immune therapy. When we presented the first path CR data there was an impression that immune therapy may provide more benefit in patients with node-positive disease. You can see the delta was 20%, so the additional benefit with immune therapy, node-positive disease, in terms of path CR, compared to 6% in node-negative disease.

What was really interesting in this early analysis was if you look at patients in red with chemotherapy alone, we saw what we have always known, that patients with node-positive disease have an inferior path CR rate compared to patients with node-negative disease. But interestingly, when we add immune therapy to this, the path CR rates are identical. So node-positive patients achieved the same path CR rates as node-negative patients. And as was seen in another immune therapy trial, as well, it was probably not just a result of chance.

The second point is that when we now look at long-term outcome in terms of event-free survival the benefit of immune therapy, of pembrolizumab, is the same for the patients who were node-positive or node-negative.

If you look in the little table, the hazard ratio in node-negative disease 0.58, and node-positive disease 0.65. In other words, we shouldn’t — we can’t exclude patients, we can’t select patients, say you’re node positive, you get immune therapy, if you’re node negative you shouldn’t. Those patient groups derive a similar benefit in terms of long-term outcome.

Another analysis that was important in the KEYNOTE-522 trial was the impact of the PD-L1 score on outcome. We are all aware that in metastatic triple-negative breast cancer PD-L1 is an important predictive biomarker for the effect of immune therapy, but in early triple-negative breast cancer it doesn’t seem to be.

If you look on the left side, again, the path CR rates; green is immune therapy, red is chemotherapy alone. What we can see is the more PD-L1 these patients are the higher the response rates to chemotherapy. But the additional benefit of immune therapy on top of this is the same whether the patients are PD-L1 high, intermediate, or negative.

But also, if you look at long-term outcome, event-free survival, you can see patients in the orange box, PD-L1 positive, have the same benefit as patients who are PD-L1-negative.

And this often leads to discussion why do we see that difference. My theory is that the tumors in the early disease seen are much more plastic, the plasticity is high. A tumor that’s PD-L1 negative can be PD-L1 positive after 2 or 3 weeks. We have data where we show that we can convert the PD-L1 score in early disease in about two thirds of patients within 2 or 3 weeks. And that’s probably why we don’t see the PD-L1 as a predictive marker for benefit of immune therapy.

If you look at the summary of the KEYNOTE-522 paper the median follow up now is at this point in time is just over 3 years. The estimated event-free survival rate is about 8% higher, from 76% to 84% with the addition of immune therapy, hazard ratio of 0.63.

The side effects. I didn’t speak about these earlier, but they occur predominantly in the neoadjuvant phase, and they are consistent with what we’ve known about the safety profiles of pembrolizumab or chemotherapy. In patients with early triple-negative breast cancer neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab after surgery results in a significant longer event-free survival than neoadjuvant chemotherapy alone.

DR LOVE: So I’m assuming there’s not much data or any data on the use of adjuvant IO in triple-negative disease. You can enlighten me about that. But how do you approach patients who go to surgery first and then are found to have positive nodes?

PROF SCHMID: So it’s a really difficult situation. Ultimately all we have been able to demonstrate so far is a clear benefit in a neoadjuvant setting, and there are theoretical considerations that you need that primary tumor around to really launch that immune response. And so it’s difficult to know whether patients have the same or less or any benefit from immune therapy if it is starting after the primary tumor has been removed. The studies are ongoing, and I would be very hesitant to give immune therapy in that setting.

It is an open question, and some people may come to a different conclusion and say that the harm associated with immune therapy is truly relatively low, and can we justify not giving a drug that has shown to have an event-free survival benefit. So it just highlights the fact that we need urgently the data from the adjuvant setting.

But also it gets back to the point I made earlier, that it is really important to give patients neoadjuvant therapy in the majority of settings, and we personally in our center give neoadjuvant therapy even in patients who are less than 2 cm and node negative. But it brings an important question around the staging of the axilla, whether we need to do this more carefully before neoadjuvant therapy to avoid situations where we have a small amount of disease in the axilla that become evident later on.

DR LOVE: Please continue.

PROF SCHMID: A second presentation of the KEYNOTE-522 trial was by Lajos Pusztai at ASCO this year, and in this publication we tried to drill it a little bit more into the residual cancer burden, so to work out how much disease is left after chemotherapy and chemotherapy and immune therapy and do we just see a shift in the residual cancer burden or are we possibly actually changing the biology of the disease.

Now if we look at the event-free survival data, and here in the orange box it’s again the distant recurrence data, you can see in practically every of those groups there’s a higher percentage of distant recurrences with the same RCB score. So RCB-0, there’s a just over 2% difference in distant recurrences. In other words, the quality of the path CR is possibly a little bit better if it was achieved with immune therapy. If you go to RCB-2 there’s 15% versus 22% distant recurrences; RBC-3 35 versus 53.

And the way I interpret these data is that the addition of immune therapy doesn’t just work through inducing more responses, but it clearly changed the biology of those cancers, thereby patients with the same amount of residual disease do better if they have received immune therapy before.

So the conclusions here were that the prespecified exploratory analyses show an association of an increased RCB score obviously with worse event-free survival, and that’s independent of the treatment group. Among patients with residual disease at surgery there was a lower percentage of patients in each RCB category, indicating that the addition of pembrolizumab not only increased the path CR rate but also shifted RCB to lower categories. But addition of pembrolizumab resulted in fewer events within each of those groups, in RCB-0, RCB-1, RCB-2. And the effect was most pronounced in RCB-2 — together in the RCB-2 category, and that suggests for us that the EFS benefit extends beyond achieving a path CR, or in other words is probably down to us being able to modify and change the biology of triple-negative breast cancer.

So that led to a rapid communication from ASCO that ultimately stated that for patients with Stage II or Stage III disease, which were the patient groups that were treated within the KEYNOTE-522 trial, the panel recommends the use of pembrolizumab once every 3 weeks, or 400 mg once every 6 weeks, although that wasn’t tested in the KEYNOTE-522 trial, in combination with neoadjuvant chemotherapy followed by adjuvant therapy.

I’ll also comment on whether immune therapy has to be given sequentially or can be given concurrently with radiotherapy, and at the moment there’s no clear guidance. It can be given either way, concurrently or after completion of radiotherapy.

Given that obviously immune-related adverse events can sometimes be severe and permanent, it is important that patients are closely monitored, and there are specific guidelines for the management of immune-related adverse events of immune checkpoint inhibitors present.

So if you look at HER2-targeted therapies there are 2 papers I want to cover. One is the long-term data of the APHINITY trial in what we call classically HER2-positive breast cancer, and then an interesting neoadjuvant study in HER2-low disease, ER-positive, HER2-low disease, with trastuzumab deruxtecan, so HER2 targeting antibody drug conjugate.

The long-term data for APHINITY, 8.4 years median follow up, presented at one of the ESMO Virtual plenaries, and one really has to zoom in to see an overall survival benefit here. If we look at the 2 groups overall there’s 92.7% versus 92% in all patients, hazard ratio 0.83. That is not significant for the overall group of patients.

But if you look at this in a little bit more detail and focus on patients in node-positive disease we see there a separation of the curves, hazard ratio 0.83, so about a 2% difference in overall survival. And that is reflective of what we had seen before, if you look at the right side of the slide, in terms of invasive disease-free survival. The benefits were more pronounced in patients with node-positive disease compared to patients with node-negative disease.

That’s probably not driven by biology, but that’s probably more driven by the overall event rate and the risks, but it clearly shows that patients with HER2-positive breast cancer, if they receive dual HER2 blockade, have already such a good outlook that in the adjuvant setting we achieve relatively little benefit and only provide a benefit in patients with node-positive disease.

So the conclusions here. There were fewer deaths seen with pertuzumab compared to the placebo arm after a median of 8.4 years follow up. The percent of overall survival 92.7% and 92%, a small difference, hazard ratio 0.83, not significant. But there was a trend towards a positive benefit in the node-positive cohort similar to what we have seen in terms of invasive disease-free survival.

The definitive overall survival analysis will take place after 640 events, and that has not happened so far, so we will have to stay tuned and wait for a longer-term outcome.

If you look at the updated descriptive analysis of invasive disease-free survival and safety in the node-positive cohort the absolute benefit is now just under 5% with a hazard ratio of 0.72, and I think that’s an important and meaningful benefit and is in keeping with our standard practice, that we offer pertuzumab to those patients.

The hormone receptor status does not really direct us in whether we should give pertuzumab or not. We see a similar hazard ratio in node-negative compared to node-positive patients, and there are no new cardiac safety issues at this later — it’s still called an interim analysis, but long-term data. The incidence of primary cardiac events remains less than 1% in both arms.

The second study I wanted to cover is not for HER2-positive disease, but it is for HER2-low disease, which is I would call a new subgroup of breast cancer that is emerging. It’s not a biological subgroup, it’s a therapeutic subgroup. So patients with HER2-low disease have pretty much the same biology as patients with HER2 0 disease. There was a number of presentations at San Antonio supporting this.

But we can use trastuzumab deruxtecan as an anchor treatment for those patients with low HER2, and the reason why that works with trastuzumab deruxtecan, in contrast to, for example, previous ADCs such as T-DM1, or just the antibodies like trastuzumab and pertuzumab, is the pronounced bystander effect trastuzumab deruxtecan has. So in other words, if you have 1 positive HER2-positive cell surrounded by a number of HER2-negative cells because of the bystander effect trastuzumab deruxtecan will still tackle those cancer cells and can therefore achieve impressive response even in patients with HER2-low disease.

So if you look at the TALENT study, which was a small study, neoadjuvant setting, in an unselected cohort of patients with ER positive, so hormone receptor-positive disease, but low HER2 expression, and they received treatment with the ADC trastuzumab deruxtecan either alone or with anastrozole.

Now there are 2 things to take away from this. One is the drug works. We clearly have clinical responses here, quite impressive clinical responses. The second thing is there’s no benefit from adding hormone therapy in this setting.

The third possible learning is ER-positive disease remains ER-positive disease. In other words, we don’t see very quick and marked path CRs in ER-positive disease. The biology is just different. So we can’t expect to see a very high rate of pathological complete response rates with targeted chemotherapy, as trastuzumab deruxtecan is, and that’s what the trial also showed. If you were expecting higher rates of path CR in a short treatment with trastuzumab deruxtecan in ER-positive disease you will be disappointed. If you didn’t expect this and were focusing on clinical responses you were not disappointed.

And we see 1 path CR across those 42 evaluable patients here. We see a number of patients with RBC-1, but ultimately it is a good clinical response, and that’s what we expected to see in these patients.

So the conclusion of the group was that neoadjuvant T-DXd demonstrates preliminary efficacy of activity in HER2 low but hormone receptor-positive patients. The toxicity profile is consistent with what we know. The objective response rate is between 58% and 68%. There was only 1 path CR, and the RCB-0 or -1 rate was 15% across both arms.

So ultimately the addition of endocrine therapy did not appear to have enhanced the activity, and dynamic changes in HER2 tissue expression that were clearly seen with treatment of trastuzumab deruxtecan are interesting, and will be used for further learnings.

DR LOVE: My understanding is that T-DXd has not been looked at in a neoadjuvant trial, or at least reported, with HER2-positive disease.

PROF SCHMID: So the studies in HER2-positive disease are ongoing. They are large studies, and there’s a number of studies in early disease. One of the studies I’m most excited about is the post-neoadjuvant study, and if we see what benefit T-DM1 has brought in patients who had residual disease after neoadjuvant therapy with a roughly 50% reduction in recurrences. And if we know that the hazard ratio of T-DXd versus T-DM1 in the metastatic setting is around 0.28 to 0.3 you would expect that study to show an additional benefit and for us to cure more patients.

But the other concepts are looking into replacing part of the neoadjuvant treatment. So we take a whole block out where we would give chemotherapy, possibly with HER2-targeted therapy, and replace it with T-DXd. That’s a different strategy. And again, there’s a very high chance that those studies will also show a patient benefit. And we will then have to work out clinically which strategy is ultimately better or possibly there’s room for both strategies.

Metastatic Breast Cancer — Joyce O’Shaughnessy, MD

DR O'SHAUGHNESSY: Well hello, everyone. Very, very good to be here with you. It’s a pleasure to have a chance to do a Year in Review update from 2022 on metastatic breast cancer. Good timing coming right after San Antonio. I’m Joyce O’Shaughnessy. I’m a breast medical oncologist at Baylor University Medical Center, Texas Oncology, and US Oncology Research in Dallas, Texas.

So it’s always great to have a chance to step back and think about what real progress we’ve made in the last year, and I’ll be focusing on metastatic disease.

So I’m going to start with HER2-positive breast cancer and just update you on the survival data from the Destiny-Breast03 trial. As you know, this was a prospective Phase III trial in the second line HER2-positive setting. Patients already had taxane and trastuzumab with or without pertuzumab, and the randomization was to T-DXd versus T-DM1, head-to-head second-line study. Primary endpoint progression-free survival.

These are the updated data here. Absolutely stunning 4 times longer median PFS; 6.8 months, with T-DM1 and 28.8 months with T-DXd, with a hazard of 0.33, and multiple zeros in front of that 1 with regard to the p-value. So a stunning difference, including a long-term tail on the curve that was quite impressive.

So we saw the survival data at San Antonio. The medians are not reached yet. The landmark analysis at 2 years shows about a 7% absolute improvement in survival. It appears the curves are still pulling apart, with a hazard of 0.64, which is statistically significant. So we do have now a significant improvement in overall survival with T-DXd, which really cements it as the second-line standard of care therapy for our patients in the second-line setting.

These were data that were recently published this year in Nature Medicine. This is a very interesting trial. It’s called the TUXEDO trial. And it looks small, right, but it turns out prospectively in this statistical analysis plan 15 patients were to be enrolled, and these are patients with active brain mets, either newly diagnosed untreated or previously treated and now progressing HER2-positive breast cancer brain metastasis, and they received single-agent T-DXd. And the objective response rate was 73%. The statistical analysis plan said that 61% was the target objective response rate in the brain, in the brain metastasis.

So with just 15 patients enrolled the trial met its primary endpoint. And we can see the survival — the progression-free survival there on the right, which is also quite impressive, these patients having a median PFS of about 1 year or so. So clearly T-DXd is a very active agent in the brain. We have relatively few data, but we have a very well done prospective trial that met its primary endpoint, but it’s just very few patients because it’s very active in the brain against patients in active brain metastases.

We also saw at San Antonio the first data from the DESTINY-Breast02. I think these data will largely end up being historical because the T-DXd is now used in the second-line setting. This is for patients with HER2-positive metastatic disease who’ve already had T-DM1, so it’s after T-DM1. So it’s the randomization 2:1 T-DXd versus either trastuzumab/capecitabine or lapatinib/capecitabine, with PFS the primary endpoint. Again, a strikingly positive result with a hazard of 0.35. Highly significant, as you see here, for both progression-free, as well as overall survival statistically significant as well.

So T-DXd is highly effective following T-DM1, which is interesting. We have very few data of ADC following progression on ADC. So this is helpful to know, although we won’t be utilizing this order. So as I said, it’s more of a historical interest.

So what I can conclude is that T-DXd improves survival and dramatically improves progression-free survival no matter where it’s used in HER2-positive metastatic disease. T-DXd has activity against active untreated HER2-positive brain mets. It’s the definitive second-line treatment for second line based on DESTINY-Breast03.

And also what’s nice about using it early line, it’s less ILD, no fatal ILD second line, but we did see that the incidence of ILD did increase with further follow up on DB03 as patients were on it longer. Longer exposure there was more ILD. ILD mainly occurs in the first 12 months but can occur at any time, so we do have to be vigilant. The key to avoiding serious ILD is not to treat through symptoms. If patients have any shortness of breath, any cough, to immediately stop, investigate, treat, and permanently stop the T-DXd if the investigation shows findings that would be compatible with an ILD picture.

And T-DXd is currently in the first-line DESTINY-Breast09 trial with or without pertuzumab versus the first-line standard, the CLEOPATRA regimen of taxane, trastuzumab, and pertuzumab. So very, very important new development and a breakthrough, basically, for our HER2-positive patients.

We’re all very familiar with tucatinib, the oral HER2 TKI, and in the HER2CLIMB trial tucatinib versus placebo along with trastuzumab and capecitabine. And we know from the HER2CLIMB trial that on the left and the right, progression-free and overall survival were both statistically significantly improved, so adding this very potent, very selective HER2 TKI to trastuzumab and capecitabine improve patients outcome.

Even potentially more importantly and impressively are the data in patients with brain metastasis. For example, if you look at the bottom 2 curves for CNS, PFS, and on the right lower, overall survival, we see big differences in progression-free and overall survival in patients with active untreated brain metastasis with the addition of tucatinib to capecitabine and trastuzumab, with an objective response rate of 47% with this triplet in patients with brain metastasis. That’s intracranial response rate, so a very highly active triplet in patients with a brain metastasis.

I just wanted to alert you that the ASCO Guideline Committee has recently published in JCO their updated algorithm for management of HER2-positive brain metastasis. On this algorithm is covered both local management, as well as systemic management.

And I’ve just summarized here from a systemic standpoint some of the key messages from this updated guideline. So the ASCO Guideline says that for patients whose systemic disease is not progressive at the time of brain metastasis diagnosis systemic therapy should not be switched from their current HER2-targeted therapy regimen. Now that’s long been the guideline and has remained the guideline even though we have increasingly good agents to treat the brain primarily; still ASCO Guidelines say if the systemic disease is not progressing stay the course and manage the brain metastasis locally. For patients whose systemic disease is progressive at the time of brain metastasis diagnosis clinicians should offer HER2-targeted therapy according to the algorithms for the treatment of HER2-positive metastatic disease.

The HER2CLIMB regimen of tucatinib/capecitabine/trastuzumab may be offered to patients with HER2-positive metastatic breast cancer who have brain mets without symptomatic mass effect and whose disease has progressed on 1 or more HER2-directed therapy for metastatic disease. If these agents are used local therapy may be delayed until evidence of intracranial progression. So in other words there’s enough data to support the use of the HER2CLIMB tucatinib regimen instead of radiation therapy because of the objective response rate and the positive impact on intracranial PFS and OS. So we can forestall the utilization of brain radiation therapy.

And the HER2CLIMB regimen of tucatinib plus capecitabine plus trastuzumab may be offered to patients with stable brain mets after local therapy or intracranial disease progression in addition to the option of systemic therapy with T-DXd. So for patients with stable brain mets the committee is endorsing either the tucatinib triplet or T-DXd, but for active brain metastasis the committee has endorsed the tucatinib triplet. So that’s the update on the management of HER2-positive brain metastases.

DR LOVE: Could I just maybe get your thoughts in terms of your own clinical practice outside a clinical trial? First of all, do you line up with bullet number 1? I would imagine you have somebody who has a new brain met on second-line T-DM1, are you going to keep them on T-DM1 or think about T-DXd or HERCLIMB?

DR O'SHAUGHNESSY: I pretty much do stick with bullet number 1, Neil, at least for the first development of brain metastasis. If someone’s doing well with their liver metastasis I will continue their successful systemic therapy and treat with SRS usually, sometimes with resection of a solitary metastasis followed by SRS, I’ll stay the course systemically.

If they then progress again in the brain, still with their systemic disease well controlled, that’s generally when I will consider switching over to a brain metastasis-directed therapy such as tucatinib or T-DXd. It depends on what their systemic disease is doing. I’ve been favoring the utilization of the tucatinib triplet in patients where I think the brain metastasis is going to be their life-limiting site of disease, and particularly if the systemic disease is really not an issue, and we’ve got active disease in the brain. I do try to put off local therapy if they have very small-volume asymptomatic disease I’ll put it off and use the tucatinib triplet because even SRS is not without its — without its toxicity.

So I do tend to use the tucatinib triplet for more active brain metastasis. That’s been my go to and using the T-DXd kind of a backup.

DR LOVE: So the other thing I want to ask you about is your second-line therapy of metastatic disease for patients who get, for example, TCP, who have brain mets. How do you — let’s say asymptomatic brain mets, no mass effect, et cetera, but it’s second line. I know maybe — I’m sure it depends a little bit on what’s the systemic — if there are a lot of liver mets or not, but in general how are you thinking through second-line therapy in patients with brain mets.

DR O'SHAUGHNESSY: If someone had both significant systemic disease, as well as brain mets, I would go with the T-DXd with the survival advantage. However, if someone has really more brain-dominant disease and minimal systemic disease have been doing the tucatinib. So if I really think the brain is likely to be the most significant area of progression and morbidity for the patient I’ve been favoring the tucatinib triplet, but if I really have to balance the effectiveness of the systemic and the brain I have been going with the T-DXd.

DR LOVE: So one other question about T-DXd and screening for ILD. So you mentioned the issue of picking up symptoms, but what about the issue of imaging? I’ve been trying to figure that out, how long do you do it, how often to you do it? I’ve heard there’s ILD that shows up a year and a half later. I hear some people saying I get imaging as much as insurance is going to allow me. Like what do you do?

DR O'SHAUGHNESSY: What I’m hearing from a lot of folks, Neil, is that breast cancer docs, expert breast cancer docs are really wanting to image every 3 to 4 cycles of therapy. That’s about what insurance will cover, even in patients who do not have brain — lung metastasis. You’re going to get your liver CT, throw in the lung CT, so I’m hearing a lot of people’s comfort level is around proactively doing CT scans in the asymptomatic patient to monitor for — here’s the idea. The idea is that if you pick it up early with asymptomatic you can treat it, and then you can reduce the dose, for example, and continue the therapy. The patient hasn’t lost the option, okay? So it’s a way to flush out those patients who are going to have issues, reduce the dose — treat it, reduce the dose, but continue because as you know if they develop symptomatic disease then we have to stop permanently.

DR LOVE: And again, you do this indefinitely? And have you seen ILD like after a year or something?

DR O'SHAUGHNESSY: I have seen it, yes, after a year, but there are patients that go out 2 years and develop it. So yes, unfortunately we have to keep it going indefinitely. But it is such a well-tolerated and effective regimen for patients. It really is in their best interest. The survival impact is huge, and so it is in their best interest to continue on the therapy. So I think it does make sense, Neil, to every 3 or 4 cycles, every 9 to 12 weeks, to do the chest CT scan.

DR LOVE: I mean if it weren’t for the ILD I think people would be really — I mean I’m sure people are thinking about adjuvant therapy anyhow, right?

DR O'SHAUGHNESSY: Oh yes.

DR LOVE: I mean not just first line — not just first-line mets.

DR O'SHAUGHNESSY: Right. No. It’s in the DESTINY-Breast05 trial head-to-head against T-DM1 in the adjuvant setting for patients with residual disease after preoperative therapy. That trial’s enrolling ahead of schedule. So I do think you’re right; it’ll be in the curative setting very soon. And again, the surveillance for ILD will be very important there, as well, I think.

DR LOVE: But I mean when you start thinking about surveillance for ILD in the adjuvant setting, maybe 5 years from now who knows what the face of adjuvant therapy’s going to look like.

DR O'SHAUGHNESSY: Yeah. I mean it may be, Neil, that we simply use it preoperatively. It’s also being studied — the T-DXd is being studied preoperatively, as well. And if you’ve got tumor-infiltrating lymphocytes you may only need 4 cycles of T-DXd to be cured, and then we’re not worrying too much about ILD. So I really do think this is going to change the face of HER2-positive breast cancer.

DR LOVE: Incidentally, I was kind of shocked. Am I correct in saying — there was that paper on neoadjuvant T-DXd for HER2 low, but am I correct in saying there’s no data on T-DXd in neoadjuvant HER2-positive?

DR O'SHAUGHNESSY: I haven’t seen it. I have not seen it yet.

DR LOVE: Yeah because it doesn’t exist. Crazy. I’d love to see that.

DR O'SHAUGHNESSY: Yeah. Right. Absolutely. I’m assuming I-SPY and others are doing it, Neil, but I haven’t seen the data yet.

DR LOVE: Okay, well I always like to do this, so I’m going to ask you, when we ever do get neoadjuvant data on T-DXd in HER2-positive I want you to predict path CR rate.

DR O'SHAUGHNESSY: Oh. Okay. Gee. So in ER-positive breast cancer with preoperative T-DXd — sorry, with preoperative TCHP our path CR rate is in the 40% range, and it’s about 80% in ER-negative, HER2-positive. So I think single-agent T-DXd will come in about the same, Neil. I think it’ll be very similar to the TCHP that we have now. That’ll be my prediction.

DR LOVE: And that’d be amazing if that happened, if you think about it.

DR O'SHAUGHNESSY: Yeah. Wouldn’t that be amazing.

DR LOVE: I mean you could imagine even going in a trial of TCHP versus T-DXd, right, getting informed consent for that experience. 

DR O'SHAUGHNESSY: Yeah. Everybody’s raising their hand hoping it’s 3:1 randomization. Yeah. Because you can scalp cool and preserve your hair, as well, with the T-DXd, which is nice.

DR LOVE: Right, right. All right, please continue.

DR O'SHAUGHNESSY: Alrighty. All right.

So this is a just an update from San Antonio looking at where in real-world evidence tucatinib is being used in HER2-positive metastatic breast cancer. We’re looking at the nationwide Flatiron EMR analysis, and this actually precedes the widespread use of T-DXd, so things are going to change a bit now that we have the brain metastasis data from T-DXd.

But what we can see is the green on the left is patients with brain metastasis, and the purple is patients without brain metastasis. And what we can see is that in the patients in green who have brain mets the tucatinib is being utilized earlier, even in the first-line setting and the second-line setting. And then in patients who don’t have brain metastasis the tucatinib is being used more third/fourth line. So that makes sense, and we can see from the real-world data that median survival from when they start the tucatinib is about 26 months, and median PFS is 9.4 months.

So those data are holding up quite well compared to the clinical trial data, but it’s just an important point that there is a lot of utilization of the tucatinib preferentially for patients with brain mets. Like I said, now we’ve got more T-DXd data. We’ll see how this evolves here over the next year or so.

So let’s go forward here. So again a conclusion. Tucatinib improves survival when added to cape and trastuzumab as second-line-plus therapy, including in patients with active untreated brain mets. ASCO 2022 HER-positive brain met guidelines endorse the tucatinib triplet in patients with asymptomatic, active, untreated brain mets, delaying local therapy is even endorsed.

Real-world evidence shows tucatinib triplet is the second-line choice in patients with brain metastasis. And Phase III, the HER2CLIMB-02 trial, I’m eagerly awaiting that. That’s the T-DM1 plus tucatinib versus T-DM1 alone. That’s underway. And then that same question is currently being asked in the adjuvant setting, as well, in patients with residual disease. So we really have some good trials ongoing for patients with brain metastasis, which is, of course, very sorely needed.

So now let’s just give an update on DESTINY-Breast04. There was an interesting point I wanted to tell you about from San Antonio. So of course DESTINY-Breast04 was the ASCO Plenary presentation 2022, standing ovation, with T-DXd in HER2-low patients. HER2 1 or 2+, IHC positive, FISH negative. And this is the New England Journal of Medicine paper showing improved progression-free and overall survival with T-DXd compared to single-agent chemotherapy of physician’s choice in mainly HR-positive patients, but 60 patients were enrolled who had triple-negative breast cancer. And so whether we look in the HR-positive or in the intent-to-treat population there was a significant improvement in progression-free and overall survival with the T-DXd.

And so these are the only data that we have for T-DXd in HER2-low brain metastasis. This is the DEBBRAH trial from San Antonio. And in the bottom left 2 red boxes we see that Cohort 2 is patients with HER2-low, brain mets, asymptomatic, untreated brain mets, and Cohort 4 is HER2 low, brain metastasis, progressing after local treatment. And on the right in the red box we see the HER2-low patients, only 6 patients from each of the 2 cohorts, and we see that in the untreated brain mets that 4 of 6, so 66% of patients, had an objective response, 83% clinical benefit rate. And then in the previously treated brain met population now progressing we see a 33% objective response rate, 50% clinical benefit rate. So tiny numbers, but these are the only data we have asking the question of does T-DXd work in the brain in HER2-low patients, and the answer is yes. Of course we need much more data, but it’s helpful just to see that little bit.

So T-DXd is superior to single-agent chemotherapy regarding PFS and OS as second-line therapy for HER2-low metastatic disease, both HR positive and triple negative. T-DXd is the second-line standard of care following progression on endocrine therapy and first-line chemotherapy for HER2-low patients. T-DXd has activity against active untreated or treated and progressing HER2-low brain mets.

Some patients can struggle with chronic nausea with the T-DXd, and it turns out that olanzapine 2.5 mg at bedtime is highly effective at eradicating that chronic nausea. T-DXd is being evaluated as preoperative therapy in HR-positive, HER2-low early breast cancer, and the preliminary data from the TALENT trial giving the T-DXd preoperatively to HR-positive, HER2-low patients I thought was quite promising, quite encouraging.

So now I’m going to transition in the metastatic setting to HR-positive, HER2-negative breast cancer, and we’re going to look together at the Phase II Right Choice trial. This is a very interesting trial done in Taiwan and Egypt and Lebanon, kind of a global trial in patients with first-line metastatic HR-positive, HER2-negative breast cancer, no systemic therapy at all for the metastatic disease.

And these were patients — they wanted to enroll patients really in visceral crisis or right on the verge of visceral crisis, so symptomatic visceral disease, rapid disease progression, impending visceral compromise, very symptomatic. They were pre- and perimenopausal women, and they were randomized to ribociclib, letrozole, or anastrozole with goserelin versus combination chemotherapy docetaxel/cape, paclitaxel/gemcitabine, or capecitabine/vinorelbine, with progression-free survival as the primary endpoint.

And what we see, the patients were about 44 years of age, 65% were de novo metastatic, 78% visceral mets, 52% true visceral crisis, 67% symptomatic visceral metastasis. And we can see that the median PFS was twice as long with ribociclib plus AI plus an LHRH agonist, median 24 months, which is what we see consistently in the first-line setting, versus a median PFS of about a year with combination chemotherapy. So I think this is really definitive that endocrine therapy is really highly, highly effective even in patients with very symptomatic serious visceral metastasis. There’s no detriment at all to patients with getting endocrine therapy as opposed to even combination chemotherapy.

So endocrine/ribociclib definitely more effective than combination chemotherapy in patients with rapidly progressive, symptomatic metastatic breast cancer with a doubling of the median PFS. The tempo of response to the endocrine therapy and ribo was similar to that that was seen with the combination chemotherapy. And so chemotherapy should only be used as first-line therapy in patients with significant organ dysfunction, for example impending liver or respiratory failure, and all other patients should receive first-line endocrine therapy plus a CDK4/6 inhibitor. So a very helpful — very helpful study.

DR LOVE: So this also gets into the issue of the effectiveness of chemotherapy in ER-positive, HER2-negative disease. And I’m going to ask you, you were referring to the neoadjuvant T-DXd HER2-low data from San Antonio. Do you have any sense, let’s just say in the neoadjuvant setting, but I think it can maybe apply beyond that, how the effect of T-DXd in HER2 low, ER positive would compare to conventional chemo? In other words, if you did a trial of preop T-DXd versus chemo for locally advanced or patients with ER-positive disease who had a lot of disease, what do you think you would see?

DR O'SHAUGHNESSY: I think you’d see parity with regard to the AC. That’s my guess, Neil. I think that T-DXd, as a topoisomerase I inhibitor, my sense is that in HER2 low, HR positive that it may be able to replace AC.

In the TALENT trial, which was the preoperative T-DXd, they gave 6 to 8 cycles of therapy. So if you gave 4 to 6 cycles versus 4 cycles of AC, for example, I think you’d see parity with regard to your objective response rate and your path CR rates.

I do think that the addition of the taxane is likely to further increase the path CR or the residual cancer burden 0-1 status, because we’ve seen that before in a number of trials, where the paclitaxel or the docetaxel does add in terms of disease-free and in some cases even overall survival. So I don’t know that the T-DXd would completely replace all 3 of the agents in the preoperative setting, but I’d be optimistic that maybe we’d be able to retire doxorubicin, which would be terrific, to use the T-DXd instead.

DR LOVE: Yeah. I mean that — my hope was that maybe it was going to be more effective, but I kind of am thinking maybe it’s not going to be more effective but maybe less toxic. Is that your take?

DR O'SHAUGHNESSY: That’s my take I think, Neil. I think there’s going to be a lot of variability at the end of the day about how much HER2 expression is really there. Right now we can’t discern between the 1+ and the 2+, but our diagnostics are going to get more effective and more discerning, and it’s probably the case if you’ve got 1+ in 10% of cells versus 2+ in 80% of cells that we’re going to see differential effectiveness there. And we have a ways to go, I think, before we can sort that out. And so I think that’s going to play a role in how effective the T-DXd is across the board in the HR-positive, HER2-negative, HER2-low patients.

DR LOVE: Interesting. Please continue.

DR O'SHAUGHNESSY: Alrighty.

So the PADA-1 trial was another very interesting trial from this past year that I think may be showing us a new paradigm that may emerge in our practices with more data.

So this is for patients in the first-line HR-positive, HER2-negative setting. They’re receiving an aromatase inhibitor plus palbociclib. And they’re monitored with circulating tumor DNA for the emergence of a new ESR1 mutation, so a mutation in the estrogen receptor. When that’s found they’re randomized in the PADA-1 trial to continue AI plus palbociclib or to switch over to get fulvestrant plus palbociclib, the idea being that fulvestrant would be more effective against the ESR1 mutation than continuing the AI.

We see that the median progression-free survival was 40% longer in patients who switched over to get the fulvestrant plus palbociclib. But then on the right the question is if we simply waited until clinical disease progression on the AI plus palbociclib and then continued the palbociclib and switched the fulvestrant then, upon real standard clinical progression, do patients still have a longer PFS if they switched earlier with the fulvestrant, at the time of not clinical progression but just an ESR1 mutation. And it turned out that the early switch to fulvestrant gave the patients a 2.7 months longer PFS than putting together the PFS1 from the AI plus palbociclib plus the PFS2, which was 3.5 month with the fulvestrant plus palbociclib. The early switch bought the patients 2.7 months longer PFS.

The question is, is this going to positively impact survival. That’s what we care most about. But very, very interesting paradigm; rather than waiting, clinical progression, imaging progression, try to switch the patients early to see if you can get more mileage out of the therapies by switching at the time of a new mutation, a resistant clone coming up.

And so it turned out that the development of an ESR1 mutation, very common. 50% of patients whose breast cancer progresses on a CDK4/6 inhibitor will have an ESR1 mutation. And PADA-1 showed that PFS is prolonged by switching endocrine therapy from AI to fulvestrant and continuing palbociclib compared with continuing the AI plus palbociclib in patients with a detected ESR1 mutation without evidence of clinical progression.

So will this approach, however, improve survival? And the SERENA-6 trial is a prospective Phase III trial that is evaluating switching to the oral SERD camizestrant in patients with ctDNA detected ESR1 mutations on AI plus a CDK4/6 inhibitor. So the randomization is continue the AI plus CDK4/6 versus switch to the camizestrant plus continuing the CDK4/6.

So this is very, very interesting, and we need to wait for the SERENA-6 data, but I won’t be surprised if this becomes a new standard of care, knowing that ESR1 mutations do arise frequently in patients on CDK4/6. And as we have in hand some of the new oral SERDs that are very highly effective against ESR1 mutations, I suspect we’re going to want to know about that sooner than later and get those agents in there as soon as possible. So that’s what I predict we’re going to be doing in the future, but we’ve got to wait for the SERENA-6 data. So very, very interesting.

The PACE trial is a first-line metastatic HR-positive, HER2-negative randomized Phase II trial from San Antonio looking at the question of patients whose disease is just now progressing on palbociclib and an aromatase inhibitor, and they’re randomized to fulvestrant versus fulvestrant plus continuing palbociclib versus fulvestrant plus palbociclib plus the anti-PD-L1 antibody, the checkpoint inhibitor avelumab. So actually this is second-line therapy in patients progressing on first-line palbociclib plus an aromatase inhibitor.

And you can see the results on the right that there was no benefit to patients progression-free survival wise continuing palbociclib upon progression on palbociclib. There was no benefit versus single-agent fulvestrant. Interestingly the winner here, quite interestingly, with regard to both progression-free, as well as overall survival, was the addition of the anti-PD-L1 inhibitor avelumab. The median survival was about 2 years with fulvestrant plus/minus palbociclib. It was 42 months with the addition of the avelumab, which is really quite interesting. This is important, very practical for our clinic. We don’t want to just continue the same CDK4/6 and change out the endocrine therapy. It just really didn’t improve patients’ median progression-free survival.

We can see in the ESR1 mutant and the PIK3CA mutant cancer — the patients with these cancers, that there there was a suggestion, again, these are hypothesis generating small numbers, that perhaps in these patients, in the red, that continuing the palbociclib and changing to the fulvestrant might be better than single-agent fulvestrant, whereas that was not the case on the left with the ESR1 wild type and PIK3CA wild type. Again, the most interesting finding was the addition of the avelumab, which actually was safe, without liver function abnormalities. You cannot give an anti-PD-1 antibody along with a CDK4/6 inhibitor safely, it’s too toxic on the liver, but avelumab is an anti-PD-L1 antibody, and it was safe. So this opens the door for further development of anti-PD-L1 antibodies with CDK4/6 inhibitors.

So I think the bottom line for our practice is that we don’t want to just continue the same CDK on progression on the same CDK. That’s my take-home message from that trial.

Now that’s a little different than what we saw at ASCO 2022 from the MAINTAIN trial. These were patients, again, they were mainly on palbociclib first line with an AI, and then they were randomized to switch their endocrine therapy versus switch their endocrine therapy and switch from palbo to ribociclib, so 2 changes. And most of the patients switched from an AI to fulvestrant. And here we saw an improvement in median progression-free survival. It went from 2.7 months with fulvestrant alone to 5.3 months with ribociclib plus endocrine therapy. And we can see, for example, the bottom right, clinical benefit rate was almost doubled with switching the CDK4/6 inhibitor from palbo to ribo and also switching from AI to fulvestrant.

Now these are randomized Phase II data. We have 3 Phase III trials going on asking this question of switching to a different CDK4/6 inhibitor. So I don’t think this is the standard of care at this point to switch to a different CDK4/6, although it might be an appropriate thing to consider in some patients.

So switching endocrine therapy and continuing palbo post progression on palbo is not more effective than switching endocrine therapy alone. Switching both the endocrine therapy and the CDK4/6 inhibitor from palbo to ribo prolongs PFS modestly versus endocrine therapy switch alone.

But the question is what’s the clinical relevance now of the MAINTAIN trial now that we’re going to be giving ribociclib preferentially first line. So does switching to palbo make sense? Or would be switching to abemaciclib? I think probably the latter. We have some data from a case series that switching to abema after progression on palbo is also effective for patients.

Can ctDNA post progression on palbo identify patients who may benefit from switching CDK4/6 inhibitors, for example lack of a loss of function RB mutation. So if the cancer is picked up a loss of function RB mutation perhaps they’re not going to really benefit from switching to another CDK4/6 inhibitor. Adding the PD-L1 inhibitor avelumab, palbo, and endocrine therapy is safe and further trials would certainly be of interest. And abemaciclib’s being evaluated in 2 Phase III trials post progression on palbo or ribociclib in the EMBER-3 and post-MONARCH trials.

DR LOVE: So we could talk more about this in the webinar, but I am just curious, clinical relevance now that ribo is first-line therapy of choice. That’s a pretty strong statement. Is that in general what you’re doing?

DR O'SHAUGHNESSY: Yes, yes. With the 3 first-line ribociclib trials, MONALEESA-2, -3, and -7, all showing substantial improvement in overall survival I really do feel obligated to offer this as the first line therapy to most patients with HR-positive, HER2-negative breast cancer. Some patients have cardiac comorbidity, and then I would favor palbociclib for those patients. And then some patients have super aggressive disease, and the Right Choice study notwithstanding, which is very encouraging in this very aggressive group, I do find, Neil, in my own experience, that abemaciclib with the continuous treatment for very aggressive liver metastasis still remains my first choice. We await the final survival data from the MONARCH 2 trial. We have seen the — excuse me, MONARCH 3, the first-line trial, we have seen the interim analysis of MONARCH 3, so AI plus/minus abemaciclib. We’ve seen a very encouraging hazard ratio for survival that’s almost statistically significant.

So in 2023 we’ll get the final data. I suspect it’ll be positive. So unfortunately palbociclib in the PALOMA-2 trial did not show an improvement in overall survival, so I’m utilizing that less now first line. But yes, I’m hearing this too, Neil, from my colleagues that most docs are going over to ribociclib as the preferred first-line choice.

DR LOVE: Yeah. Because we constantly ask people what are they doing, and up until recently I would not say most investigators were that strong. Maybe since San Antonio that’s changed. I mean have you — how long have you felt that strongly now?

DR O'SHAUGHNESSY: I think since the PALLAS data were presented — I’m sorry, not the PALLAS, excuse me, the PALOMA-2 data were presented at ASCO I think that’s really been the watershed time, was the lack of survival first line with palbociclib. That was the big switch I think, Neil, so just in the past few months.

DR LOVE: Interesting. Please continue.

DR O'SHAUGHNESSY: Sure.

So we saw a very, very important trial at San Antonio. I really, really look forward to having this agent for practice, capivasertib, the oral AKT inhibitor, very positive trial, the CAPItello-291 randomized trial, Phase III, in patients with HR-positive, HER2-negative breast cancer who’s breast cancer’s progressing on first-line AI with or without a CDK4/6 inhibitor. And there was a coprimary endpoint, the intent-to-treat population, and then about the 40% of patients whose breast cancers had a molecular alteration in the PI3-kinase AKT pathway, either a PIK3CA mutation or an AKT mutation or genomic loss of PTEN.

So patients were randomized to fulvestrant/placebo versus fulvestrant plus capivasertib. And capivasertib is given 400 mg twice a day orally, 4 days you take it, 3 days you’re off, and you need to take the 3 days off because of usually GI toxicity, diarrhea. And so coprimary endpoints, PFS in the intent-to-treat population, as well as in a separate coprimary endpoint of in the altered population.

And so the demographics were that patients were primary endocrine therapy resistant 38% of the time, 68% visceral mets. Prior CDK4/6 inhibitor for metastatic disease was 70% of the patients.

And you can see on the top the intent-to-treat population, down the bottom the AKT pathway altered population. We see about a doubling of PFS in both groups, a little bit better hazard ratio in the altered population, 0.5. These are both statistically significant, so yay, this is terrific, a positive trial for these patients with — progressing on CDK4/6 and who have pathway altered disease as well.

And you can see in the top left, these are the patients whose breast cancer was not known to be altered. So they did not have a mutation in PIK3CA, AKT, or PTEN, but there was a small group that was unknown. So we can see in the top the Kaplan-Meier for patients who did not have altered breast cancer, including the unknowns. And then down the bottom left we can see that the hazard was 0.79, not significant, but again it was a small number, in those whose breast cancers were known not to be altered in one of those 3 mutations.

So there was some activity in the non-altered because you can have activity of the AKT pathway without having a mutation in PIK3CA or AKT or PTEN. There’s other ways, such as heregulin and signaling down, for example, through HER2/HER3 heterodimer, for example. You can have activation of that pathway. So we do see that capivasertib can inhibit that pathway but just not as dramatic as we saw in the intent-to-treat population and in the altered population.

I love the 2 subsets on the top right, liver metastasis and prior CDK4/6. These are impressive. It’s great to see this level of activity in patients with liver metastasis, yes or no, and also the objective response rate. If we look, for example, bottom right at the AKT altered population the response rate was about 10% with fulvestrant, almost tripled, up to 28.8%, with the capivasertib. So really nice to see these positive data.

And so capi plus fulvestrant improved PFS over fulvestrant post progression on an AI plus/minus CDK4/6 inhibitor in both the overall population and in patients with PIK3CA or AKT pathway altered cancers. Efficacy in the subset of patients with the non-altered tumors is still a bit uncertain because of small numbers.

GI tox, primarily lower-grade diarrhea is manageable with the 4 days on, 3 days off, because it stops in the 3 days off. Much less hyperglycemia than with alpelisib, and they allowed patients on the CAPItello-291 who had hemoglobin A1cs up to 8%, so that was pretty good. Capi may be the PIK3CA/AKT pathway inhibitor of choice following progression on a CDK4/6 inhibitor once FDA approved, and the data are in fact being considered for FDA approval. So I personally look very much forward to having this agent available in practice.

I wanted to update you, as well, on the EMERALD Phase III study. We’re hoping for FDA approval of this agent in February. And this was a later-line therapy in patients whose breast cancer had progressed on a CDK4/6 inhibitor, HR positive, HER2 negative. And they were randomized to the oral SERD elacestrant 400 mg daily versus single-agent endocrine therapy of physician’s choice, either fulvestrant or an AI, most patients received fulvestrant, with coprimary endpoints of PFS in all patients or PFS in the ESR1-mutant population. And the patients were able to have progressed on 1 or 2 prior lines of endocrine therapy.

And we saw progression-free survival in the intent-to-treat population on the left, and in patients whose breast cancers had an ESR1 mutation, which was over 50%, we saw statistically significant improvement in PFS in both groups. So this trial met both its coprimary endpoints. We can see the data are even more impressive in those with an ESR1 mutation. Very, very interesting. These remain endocrine therapy sensitive patients if we have an oral SERD to give those patients. And we had seen that, as well, in the AMEERA-3 trial, as well as in the acelERA, trial with giredestrant on the left, and amcenestrant in the middle, that it was the ESR1-mutant population that really got the differential benefit from these other oral SERDs, as well, with regard to PFS. So the story is really shaping up that the oral SERDs are really bringing something new and effective to the treatment of ESR1-mutant metastatic breast cancer.

And what we saw at San Antonio was a breakdown of the effectiveness, the duration of PFS, of elacestrant versus endocrine therapy based on how long the patients had been on their antecedent CDK4/6 inhibitor.

What we’re looking at here first is the intent-to-treat population, and what we see is that as patients had more and more endocrine therapy sensitive breast cancer they had been on the prior CDK 12 months, 18 months, their median PFS on the elacestrant improved up to 5.4 months, for example, if they went at least 18 months on the prior CDK4/6. But in the ESR1-mutant population it was even more impressive. Those patients who were on the antecedent CDK at least 12 months, they were up at 8.6 months median PFS with the elacestrant.

So our patients who do well on the CDK4/6 inhibitor, they have an ESR1 mutation, we can expect a median PFS of around 8.5 months or so. So it was quite interesting that this agent, the elacestrant, will end up being aimed at patients that we think have endocrine therapy sensitive disease, either because they have an ESR1 mutation or because they did well on their prior endocrine therapy for a goodly period of time. So very, very helpful to us as we hopefully move towards FDA approval.

So elacestrant is effective post progression on CDK4/6 inhibitor in patients with endocrine therapy sensitive disease. The hazard ratios for improved PFS versus endocrine therapy are similar in patients who receive at least 6 months or longer prior CDK4/6 inhibitor. That is not those patients whose cancer is primary resistant to the CDK4/6 inhibitor.

The benefit of elacestrant is definitely more marked in patients with an ESR1 mutation, especially those who had at least 12 months of prior CDK4/6 inhibitor therapy. And then the next steps are to combine the elacestrant with other targeted therapies that we commonly use in HR-positive, HER2-negative metastatic breast cancer. That’s going on in the ELEVATE trial, and an adjuvant trial is also planned.

Another important update that we had from San Antonio was the SERENA-2 trial. This is a randomized Phase II of the novel oral SERD camizestrant versus fulvestrant in the second-line setting in patients whose breast cancer was progressing on an aromatase inhibitor with or without a CDK4/6 inhibitor. And the patients — 50% of patients in the SERENA-2 trial had had a prior CDK4/6 inhibitor, and they were randomized to 75 mg daily of camizestrant versus 150 versus fulvestrant.

And you can see the primary endpoint on the right. Both of the camizestrant arms were superior to fulvestrant alone. And so this trial met its primary endpoint. These are statistically significant improvements in PFS, about 7-ish months with the camizestrant versus 3.7 months with fulvestrant, so definitely more effective.

And then this was just — the blinded independent central review also agreed with that assessment. We’re seeing now patients who had prior CDK4/6 inhibitor therapy. On the top left we see that the differential benefit with the camizestrant over the fulvestrant was more impressive in those whose breast cancer progressed on CDK4/6, which is fine because of course that’s the vast majority of patients in practice.

And also interestingly we see on the bottom left in the ESR1-mutant population again this story that the oral SERDs are differentially more effective than fulvestrant in patients whose breast cancers harbor an ESR1 mutation. Interestingly here the curves were on top of each other for fulvestrant. Fulvestrant did a lot better in patients whose breast cancer was not ESR1 mutation.

So there are several Phase III trials going on with camizestrant right now, and whether patients had liver metastasis or not there was still this differential benefit with the camizestrant compared to the fulvestrant.

The safety was actually very good with the lower dose of the camizestrant, the 75, which is the selected dose for the Phase III development. Photopsia, which is flashing lights, occurred in about 12% of patients. Sinus bradycardia, which was really asymptomatic, only occurred in 5% of patients with the lower dose. So I think really very, very good tolerability of camizestrant at the 75-mg dose.

And so we can conclude that camizestrant has improved PFS over fulvestrant, including in patients post progression on CDK4/6 inhibitors. More data are needed with regard to the efficacy of camizestrant in the ESR1 wild type population. It’s highly effective in the mutant population. And at the chosen dose of 75 there’s a low incidence of sinus bradycardia and photopsia. And the first-line SERENA-4 Phase III trial is ongoing with CDK4/6 inhibitor versus an AI plus CDK4/6 inhibitor, so we await the results of SERENA-4.

So sticking with the theme of HR-positive, HER2-negative breast cancer we saw updated data from the TROPiCS-02, the Phase III trial of sacituzumab govitecan, the ADC with a topoisomerase I payload aimed at the TROP2 antigen, which is ubiquitous in metastatic breast cancer, versus single-agent chemotherapy of physician’s choice as third line or later therapy for HR-positive, HER2-negative breast cancer.

And we can see in the bottom left that both PFS and OS were significantly improved with the sacituzumab compared to single-agent chemotherapy. Just as we had seen in triple-negative breast cancer patients in the ASCENT trial, now we’re seeing it in HR positive. But this antibody-drug conjugate with a topo I payload is very effective and improves survival over single-agent chemotherapy by a median of 3.2 months as later-line therapy.

And what we saw at San Antonio was breaking down the effectiveness of sacituzumab compared to single-agent chemotherapy in patients who had very high levels of expression of TROP2 in their cancer versus lower levels, and there was really no impact on survival of the level of expression of TROP2. It basically worked — as we saw as well in triple-negative breast cancer patients, it worked as well in the high expression, intermediate expression, and low expression of TROP2, so that’s good.

We do not have to select patients based on TROP2. We don’t have to test for TROP2 in the practice. And so there’s a randomized trial going on now in the first-line setting for — with sacituzumab versus chemotherapy of physician’s choice called the ASCENT 07 trial that is going on right now.

And then we saw another very interesting antibody-drug conjugate at San Antonio, again targeting TROP2 with a topoisomerase I inhibitor payload. It’s called datopotamab. These data here are in HR-positive, HER2-negative patients. And this is patients who had had a median of 2 prior chemotherapy regimens for metastatic disease, so similar to the TROPiCS-02 population, and this was a single-arm trial. There is a randomized trial called the TROPION Breast01 trial going on in this HR-positive population with datopotamab versus single-agent chemotherapy of physician’s choice.

And we can see in this initial Phase II trial there was a response rate of 27%, a clinical benefit rate of 44%, median PFS of 8.3 months; very, very good. The safety is good. The toxicity is stomatitis that’s actually helped by prophylactic use of steroid mouth rinse. But not much at all here in the way of myelosuppression, for example, that we see more with sacituzumab. So this is also a very promising antibody-drug conjugate for HR-positive, HER2-negative patients. Again, we don’t have to select — just like we don’t have to select for sacituzumab we don’t have to select patients for datopotamab because it too targets TROP2.

This is given IV once every 3 weeks. The sacituzumab is given day 1, day 8. So there’s some differences between the ADCs, but this is also a very, very promising agent.

And so we can conclude that sacituzumab improves survival compared with chemotherapy as late-line therapy in HR-positive, HER2-negative metastatic patients post progression on CDK4/6. It’s a Category 2A preferred therapy on the NCCN Guidelines following progression on 2 prior cytotoxic regimens, and we’re awaiting FDA approval. ASCENT 07 is underway for first line with sacituzumab in HR-positive metastatic patients, and datopotamab is also a very potent active anti-TROP2 ADC as late-line therapy for HR positive, with stomatitis being the most common toxicity, ameliorated by steroid mouth rinse. So new agents in this HR-positive, HER2-negative space that’s really supplanting single-agent chemotherapy.

And then just to finish up with some updates on triple-negative metastatic breast cancer, I just wanted to mention to you the KEYNOTE-355 published this year in The New England Journal of Medicine by Javier Cortes, and this is the first-line trial, metastatic TNBC in patients who were randomized to single-agent chemotherapy with paclitaxel or nab-paclitaxel or combination gemcitabine/carboplatin with or without pembrolizumab. And they had coprimary endpoints in the intent-to-treat population, as well as in those patients with PD-L1-positive, triple-negative breast cancer. And the bottom line, down on the bottom left, we see statistically significant improvement in PFS in patients with PD-L1-positive breast cancer, defined as a combined positive score of 10 or higher.

And most importantly, on the right, an improvement in overall survival, about a 7-month improvement in median overall survival with the addition of pembrolizumab to chemotherapy in patients, 38% of patients whose breast cancer had a combined positive score of 10 or more, making it absolutely standard of care to test our patients’ breast cancer for PD-L1 by the combined positive score in the first line metastatic population.

I show this just because this really nailed it for me, both on the right PFS and on the left overall survival. The bottom point estimates, if you’re going to see improvement in PFS and overall survival the patient really has to have the cancer have PD-L1 CPS 10 or higher. It won’t work for 1-9. So it’s CPS 10 or higher to get improvement in PFS and OS in the first-line metastatic setting.

So this is the established standard of care for our PD-L1-positive patients. It doesn’t work if the CPS is less than 10, and what we don’t know is will first-line pembrolizumab still improve survival in our metastatic patients in the first-line setting if they already had neoadjuvant and adjuvant pembrolizumab in the curative setting. We don’t have data yet, but most of us would utilize it if at least there had been a year intervening between ending the adjuvant pembrolizumab and beginning the first-line metastatic treatment.

Just an update on the ASCENT trial. That has been updated this year with regard to its final survival analysis. This was in the second-line and later metastatic TNBC population. Patients were randomized to sacituzumab versus single-agent chemotherapy of physician’s choice for their triple-negative breast cancer, and we can see down at the bottom, for example, the clinical benefit rate was extremely poor with single-agent chemotherapy, just 9%, and went up to 45% with the sacituzumab, dramatically more effective than single-agent chemotherapy, and we saw really impactful improvement in progression-free and overall survival.

I don’t think I realized how poor our single-agent chemotherapy was in this pretreated metastatic TNBC population, with median survival of only 6 months with chemotherapy, going up to doubling to a year. And so these are really, really important data for our second line and later population based on these Phase III ASCENT data. So clearly Category 1 preferred regimen, NCCN Guidelines, second line plus therapy.

The treatment-limiting toxicities are myelosuppression and diarrhea, manageable with dose reduction. I really think it’s important to start with a lower dose of the sacituzumab in heavily pretreated patients or those who have impaired hepatic function. We really do have to watch out. I do hear about some hospitalizations in these patients, and so I always start with the reduced dose myself. I just think it’s important for us to all know about that. And now sacituzumab is being evaluated as first-line metastatic TNBC therapy with or without pembrolizumab in the first-line setting, TNBC, ASCENT 03 and 04 trials.

Now there is a competitor to sacituzumab in the metastatic TNBC population, and that again is the datopotamab, another ADC that targets TROP2 and has deruxtecan, the topoisomerase I payload. And we’ve seen now from San Antonio the first data with regard to datopotamab in pretreated metastatic TNBC patients. This is given IV once every 3 weeks. 42 patients enrolled in this pretreated population.

And the objective response rate was 32%, very, very good. In topoisomerase I inhibitor naïve population who had not seen prior sacituzumab the objective response rate was really impressive at 44%. Median PFS 4.4 months, topoisomerase I inhibitor naïve patients 7.3 months. Survival 13 to 14 months. And again the most common adverse events are stomatitis, nausea, vomiting; again can be ameliorated with steroid mouth rinse. Very impressive late-line data.

We also saw datopotamab now move into the first line metastatic TNBC population in this Phase II study, the BEGONIA trial, in combination with the anti-PD-L1 antibody durvalumab. Very impressive responses here of 73%, highly durable. You can see many patients going out well over a year. You can see in the bottom right that regardless of PD-L1 status, so the yellow is PD-L1 high, and the blue is PD-L1 low, we see this combination’s highly effective regardless of the degree of PD-L1 staining. This is a really, really effective combination in the first-line metastatic population.

And so dato-DXd has really promising activity, late-line single-agent, and in the first line with durvalumab regardless of PD-L1 expression. Every 3-weekly dosing’s convenient, with less neutropenia and diarrhea than sacituzumab, but with stomatitis. Dato-DXd’s being evaluated as first-line therapy in metastatic TNBC with or without the checkpoint inhibitor depending on the PD-L1 expression. It also will be evaluated as adjuvant therapy for residual TNBC following neoadjuvant therapy, as well as preoperative therapy in Stage II/III TNBC patients.