ASCO [2022] Breast Cancer In-Depth Slides: MOASC

ASCO [2022] Breast Cancer In-Depth Slides: MOASC

 

Kay Yeung, MD, Ph.D. Delivers Her MOASC 2022 Breast Cancer Presentation

Hello, everyone. Thank you for inviting me. And have the opportunity to really go over some breast cancer (care) updates and definitely a lot of excellent breast cancer presentations and breast cancer abstracts that was presented in 2022 ASCO (this year’s American Society of Clinical Oncology) annual meeting today this year. And I don’t have time to go over all of them, but I hope that the ones I go over will be interesting and important.

 

So this is my financial disclosures, and this is the outline. So I’m gonna start with HER2 low metastatic breast cancer. I’m sure a lot of you have tuned into the planetary session where DESTINY-Breast04 was presented. I will also talk a little bit about the ILD risk factors and in time of onset, which was published recently on a small open.

 

HER2 IHC concordance is an issue now with the HER2 low breast cancer including other, probably cancer subtypes in the future. And then I’ll move on to HR positive (breast cancer) HER2 negative metastatic breast cancer in particular, the PALOMA-2 OS (breast cancer) analysis, the MAINTAIN (breast cancer) study, TROPiCS-02 study, the ABCSG study (studies all about breast cancers), and then I will end up on triple negative, early breast cancer, in particular, talking about the KEYNOTE-522 EFS by RCB exploratory (breast cancer care) analysis. And then jumping into a new area potentially in the future in terms of targeting HER3.

DESTINY-Breast04 Study

So this is the DESTINY-Breast04 (ASCO Annual Meeting) breast cancer (care) study, this is looking at patients with HER2 low or known as HER2 IHC, 1 plus or 2 plus FISH negative. And for these patients, there are limited targeted therapy options, especially for the HR positive breast cancer patient whose cancer care is endocrine therapy-resistant.

 

So antibody-drug conjugate T-DXd has really shown some efficacy in phase 1 and 2 breast cancer studies and therefore, a randomized multicenter open-label phase 3 study was designed in this study.

 

Patients has to be progressed on endocrine therapy, with no prior (not recent) findings of HER2 positive breast cancer or HER2 IHC positive breast cancer or FISH positive disease. And then no prior anti-HER2 therapy treatment (in clinical oncology).

 

They were randomized 2 to 1 to T-DXd at 5.4 milligrams per kg. And then or a physician’s (health care professionals) choice of Capecitabine Eribulin, Gemcitabine, Paclitaxel, and Non-Paclitaxel.

What Was The Primary Endpoint?

The primary endpoint was PFS, the secondary endpoint was PFS, and then intentional to treat arm, and also OS. So, here are the basic characteristics, (estrogen) hormone receptor positive breast cancer patients are composed of the majority of the patient population. And then we do have a small population of patients who are (estrogen) hormone receptor negative (breast cancer).

 

So of note is that most of the patients were HER2, sorry the HER2 positive breast cancer or HER2, 1 plus and 2 plus patients are divided into equally 58% for 1 plus, and then 2 plus is 42%. Most of them have gotten CDK 4/6 inhibitors, and I’ll show you on the next slide.

 

And most of them do have a visceral metastasis. So, liver metastases in 71% of the breast cancer patients and lung metastasis in 36% of patients.

 

So, there is the prior lines of therapy. As I mentioned, most of them (estrogen) hormone receptor positive breast cancer patients did receive CDK 4/6 inhibitor in the prior lines of therapy.

 

The median lines of therapy in the metastatic (breast cancer) setting is 3 the lines of (received) chemotherapy (for cancer care) in the metastatic setting, and here are the results, and this has been published in the New England Journal of Medicine.

 

And as you can see here graphically, I put it right in the middle in terms of comparing T-DXd to chemotherapy.

 

We have a significant and clinically significant improvement in progression-free (overall) survival, 4.7 months, and then also overall survival of 6.7 months with a hazard ratio of 0.5 and 0.64.

 

So this is a very impressive result in probably the past decade for breast cancer patients who have endocrine therapy or endocrine refractory HR positive HER2 negative breast cancer.

 

The first FDA approved targeted therapy for HER2 low disease. It is practice changing. I am using T-DXd for my HER2 low patients after 1 or 2 lines of chemotherapy. And then, this is an exploratory analysis looking at the triple negative or HR negative, HER2 low patients.

 

The PFS on the left and the OS on the right, as you can see, there is an improvement of 5.6 months in PFS, and OS of 9.9 months is a very impressive result for triple negative breast cancer patients. Unfortunately, it’s a small amount of breast cancer patients of 6 N equals 63.

 

Phase 3 KEYNOTE-522 Trial

And then, just to show in terms of cross-trial comparison of another triple negative phase 3 studies in KEYNOTE-522 (breast cancer care) clinical trial at the ASCO Annual Meeting (American Society of Clinical Oncology), where we use Pembrolizumab plus chemotherapy compared to chemotherapy in the first line setting the PFS.

 

A benefit was 4, the absolute benefit was 4.1 months, and then the OS benefit is 11.1 months. So this is quite impressive from T-DXd, and then this also compared to ASCENT (breast cancer) study where Sacituzumab Govitecan was compared to chemotherapy at the three or more line setting, the PFS (progression-free survival or overall survival).

 

In that study was shown to be the PFS benefit was an absolute benefit of 3.9 months, and then OS of 5.4 months. So, this is the subgroup analysis for PFS in the hormone receptive positive (breast cancer) HER2 low patients. As you can see, there is in almost all subgroups.

 

There is a favorable benefit to using T-DXd. There is a small subgroup where there are other races that are non-Asian and non-White unfortunately, it’s a very small number, and therefore it crosses the confidence interval.

 

So nonetheless, it’s very impressive, and I just wanna point out also that in terms of IHT status, 1 plus and 2 plus seems to really derive a very similar benefit with T-DXd and, therefore, should probably not be at a certain point in terms of whether or not you use T-DXd for your breast cancer patients.

 

This is the drug-related adverse event that was reported on the left side in blue is T-DXd, and then on the right side chemotherapy, as you can see, there’s a lot of nausea, fatigue, alopecia, and then neutropenia, especially once there are grade 3 and about 14% of them and then moreover, this was alluded to, before in the lung cancer presentation which is the ILD and pneumonitis.

 

So for T-DXd, the rate of ILD was significant at 12.1 percent for any grade, and then, unfortunately, 3 patients died of ILD.  Compared to chemotherapy, a physician choice, in which only 1 patient had grade 1 pneumonitis in terms of the left ventricular dysfunction.

 

We also saw a good amount higher than expected ejection, fraction decrease at about 4% in all grades, thankfully, no one really died of that.

 

This is actually a little bit higher than what we’ll expect for the general population who get exposed to the drug Trastuzumab Deruxtecan or other TKIs, which usually run around one to 2% TKI less than 1%. So this is something to think about, especially in an earlier setting.

 

When we try to move T-DXd 2, so switching gears a little bit and talking about a little bit about ILD from T-DXd (drug Trastuzumab Deruxtecan), this is a publication that ESMO did a poll analysis of ILD that was seen in all the DESTINY-Breast (breast cancer) studies,  and here they reported that ILD rate is around 15.4%.

 

Most of it is grade 1 and 2, and then, unfortunately, we do see about 2% of grade 5 events. Interestingly most of the ILD did appear in the first year.

 

And this is, you know, becoming the reasoning or rationale behind really closely monitoring your patients, at least with a CT scan every 3 months to look for ILD and then also to really stop the therapy and discontinue the therapy at least momentarily.

 

Even if you only have grade 1 ILD where patients are asymptomatic, then on the right-hand side is the table in terms of looking at risk factors that can lead to ILD. So the risk factors are age less than 65 years old enrollment in Japan baseline oxygen level, less than 95% renal dysfunction lung comorbidities.

 

And then also, higher T-DXd (drug Trastuzumab Deruxtecan) exceeds the dose by more than 6.4%. This was compared to the 5.4 milligrams. Sorry, 5 milligrams. Yes, more than 6.4 milligrams per kg. And this is compared to the 5.4 milligrams per kg that is being used now in and approved in breast cancer. And then also last but not least, the time since disease diagnosis, especially more than 4 years.

 

So next, I want to talk a little bit about this poster that was presented and really try to figure it out. If there are any concordance and differences in terms of IC low calling, here we really, in this situation, now we have this HER2 low disease that we need to figure out which breast cancer patient will benefit from T-DXd.

 

It will be important to figure out how we are gonna call these HER2 low expressions. So in a study with a limited amount of patients, about 2003 patients with HER2 negative advanced breast cancer.

 

Their biopsies were pulled out and then rescored after pathology training to see whether or not they would be different compared to the historical scoring.

 

And interestingly, here on the left side, we first look at the HER2 low prevalence in HER2 negative metastatic breast cancer. And we see that for HR positive breast cancer, 2/3 of the patients do have HER2 low disease, whereas only 40 to 46% of the patients who have triple negative breast cancer have HER2 low disease.

 

And I just wanna point out here that it’s interesting. I don’t know what to make of it, but there is definitely a trend for the increased calling of HER2 low disease. When you look at the metastatic biopsy compared to the primary biopsy. So it might be interesting to really go after repeat testing for some of the patients.

 

And then on top of that, they looked at the different assays of antenna 4B6 was 4B5 was used in the depth destiny breast studies as a companion diagnostic. There are other non-VENTANA assays out there to look for HER2 (breast cancer) expression, so you can see here.

 

Some differences between the calling and particularly in the HR negative (breast cancer) or triple negative (breast cancer) patients where the non-VENTANA studies appear to have a higher call rate.

 

And then finally, the question about concordance between the rescores and historical scores. Do we have to pull out all old blocks and rescoring or ask our pathologist to pull out old slides and look at them? The answer is I think some, for some of your patients, you may want to do this because, for HER2 low or HER2 IHC patients, there are about 20%, 20 to 25% difference in terms of calling.

 

So I think this is pretty much similar to compared to the VENTANA and non-VENTANA assay. So again, I think this really demonstrates that HER2 IHC scoring is really not the perfect test, and in a field.

 

We are really struggling in terms of figuring out who we will give HER2, sorry, T-DXd to and who we would want to try to get, repeat testing, repeat biopsies, and maybe potentially looking for another way to score  HER2 expression. 

 

So looking into the future, as I have mentioned, we used to just think about breast cancer in terms of HER2, as HER2 positive (breast cancer) and negative.

 

Now we have a substantial amount of patients who have HER2 low disease. And now, with the new HER2 ADCs, T-DXd.

 

We really need to go back and probably restate or, I guess, re-phenotype outpatients in terms of whether they are HER2 low or HER2 absolutely negative. However, do we really need to do that?

 

I guess this really comes to the question of HER2 IHC zero. So  in the DAISY study, which is a smaller study where they’ve enrolled patients with HER2 IHC zero. Even though it’s a small number of 38 patients, we did see a response rate of 29% and medium progression free survival (overall survival) of 4.6 months.

 

This really begs the question. Do we really have the right biomarker to pick out our patients to give this novel, and then on top of that, there’s a question of my mechanisms of resistance?

 

I have patients who have HER2 positive (breast cancer) disease and would blow through T-DXd and it’s unclear to me how, in terms of mechanism, how that will happen.

 

However, I think, ongoing studies are looking at some of these questions. And then next is the sequencing of therapy in the metastatic setting.

 

Now we have so many therapy treatment (in clinical oncology) options for patients who have triple negative breast cancer or HR negative and HER2 low patients.

 

Would you sequence T-DXd first, or do the Sacituzumab Govitecan based on the study. And then there’s also the unknown efficacy between subsequent ADCs that are either. Similar targets like the switching between the 2 different HER2 ADCs or the ones with similar payload.

 

So even though you have different targets, but the same payload with the patients still respond And then next, obviously, moving the (clinical oncology) treatment T-DXd and other ADCs to a neoadjuvant admin setting will be and testing them in those setting to really achieve cure rates a much higher cure rates will be important.

 

And then the next question is HER2 mutant tumors. So in non-small cell lung cancer T-DXd is approved in that setting. Only about 2 to maybe 3% of all breast cancer have HER2 mutant tumors. However, I don’t think we know the exact percentage of HER2 mutant breast cancer because we don’t routinely look for them.

TUXEDO-1 Study

So the question is, are that tumor also response would be responsive to T-DXd,  and then finally, there’s a interesting signal from the TUXEDO-1 study, which is a small study where they did see a CNX activity of T-DXd. And this is quite interesting and exciting.

 

And currently many different clinical trial are using T-DXd at a frontline setting or earlier setting to really try to decrease the risk for having CNS disease or disease progression. So then, just going from 1 ADCs to another ADCs, wanna talk about Sacituzumab Govitecan.

What Were the Results of the TROPiCS-02 Study?

And this is the results from TROPiCS-02 study in patients with HR positive HER2 negative metastatic breast cancer. There are endocrine, refractory, and heavily pretreated.

 

So patients needs to be progressed at least on 1 line of endocrine therapy taxings and CDK 4/6 inhibitor, at least 2 but no more than 4 lines of chemotherapy.

 

And these are the randomized one to ones to Sacituzumab Govitecan to chemotherapy. And then the primary endpoint is PFS which was reported. So here, the PFS was presented in the overall population, the medium PFS gain was from 4 months to 5.5 months with Sacituzumab Govitecan and then the with the hazard ratio of .66.

 

When you look at the 6 months, 9. Months and 12 months PFS rate, it appears that it’s about 15% increased. So 15% of the patients did have a better response with Sacituzumab Govitecan.

 

I think the patient selection is always the key end to recent findings a good biomarker to identify these patients who will be sensitive to Sacituzumab Govitecan will be great.

 

There’s also a significant improvement in quality of life with Sacituzumab Govitecan based on their global health and fatigue scale.

 

Importantly, Sacituzumab Govitecan does have more diarrhea, although it is controllable and more neutropenia, so some patients would require those de-escalations or G-CSF support.

 

And then OS was just announced to be clinically significant by the company, with a    presentation will be, I think it’s gonna be presented in next month in ESMO. So we will see, but right now, at this point, I would use Sacituzumab Govitecan as one of the options for my patients with HR positive HER2 negative metastatic (disease) breast cancer.

 

After 2 lines of chemotherapy, so next thing I wanted to talk about is endocrine sensitive, HR positive HER2 negative metastatic breast cancer. As you all may know, the CDK 4/6 inhibitor has revolutionized our (clinical oncology) treatment for endocrine-sensitive metastatic breast cancer, where they are used uniformly.

 

So this is based in addition to endocrine therapy. And then this is based on the PALOMA studies, studies 2, 3 and 7 and also the MONARCH 3 study. And for all of the studies, the PFS were reported. And then for the OS were only reported for the MONALEESA study using Ribociclib.

PALOMA-2 Trial

So at the ASCO Annual Meeting, the OS data was presented for PALOMA-2, which is the Palbociclib study in the first line setting. This is just to remind you how it was done, it was first line. Ribociclib with the combination of Letrozole versus placebo plus Letrozole, the primary endpoint was PFS, and that was significant.

 

And then, right now, we’re looking at the secondary endpoint, the OS. So here, unfortunately, it was disappointing, and for me, it’s personally a little bit perplexing in terms of why we did not see any significant difference in OS benefit even though the PFS was very impressive and is very comparable to other CGK 4/6 inhibitors.

 

So here. There’s some possible reasons for OS difference between this study and the mono Lisa study potentially because of the fact that there’s higher percentage of patients with disease free interval of less than 12 months after adjuvant therapy.

 

So 22% versus one to 7%. And when you take out those patients who have a short interval disease free interval after adjuvant therapy, this is not a planned analysis, but if you look at this the OS curve, this seemed to be separating and favoring additional Palbociclib.

 

There’s also the concern about how the study was under power for the secondary endpoint.  Based on this assumption, the median overall survival is somewhere between 34 to 46 months. As you can see here, even in the letrozole plus palbociclib arm, the median overall survival was 51 months, so there’s a little under power.

 

And then thirdly, there’s also the question of whether or not there, there are true differences between the drugs and the ethic.

 

MONARCH 3 Study

The MONARCH 3 study (ASCO Annual Meeting), which is using a Abemaciclib first line, the OS data is pending and will be reported in ESMO next month. So I’m excited to see what that would tell us.

 

So, for now, this is controversial, but I think it’s practice changing. So I currently will prefer using rib clop. If the patient does not have comorbidities or concurrent medications that will be contraindicated. And I will use that over other CDK 4/6inhibitors in the first line (treatment in clinical oncology) setting until further data.

 

Moving on, also another CDK 4/6 story. This is the maintenance clinical trial where they ask the questions of whether or not it’s beneficial of a continuing CDK 4/6 inhibitor after disease progression by just switching the endocrine therapy partner. So this is a randomized multi central study phase 2, a small study with just 120 patients.

 

And what they did was enroll patients who were. Progressed on endocrine therapy and any CDK 4/6 inhibitor. I have to point out that 87% of the patients did have Palbociclib followed by Ribociclib and 10%, and then Abemaciclib.

 

So the majority of patients do have pail. And then what they did is the majority of the 90, more than 90% of the patients did not have any intervening therapy.

 

And they just basically switched the endocrine therapy. The majority of them have Fulvestrant next, and plus, or minus Ribociclib. And then the disease progression, sorry, progression-free survival (overall survival) is the primary endpoint that was reported.

 

So here, as you can see the a progression-free survival is actually very poor when you just switch the patients to a Fulvestrant only, and this is really what we see in the clinics. 2.7, 6 months of progression free survival. And then with the addition of Ribociclib you have about 2.5 months improvement to about 5.2, 9 months.

 

So this is quite interesting. It really tells us that unless we pair the endocrine therapy partner with a targeted therapy, either CDK 46 and some, which is provocative you.

 

Which, which is what this study is trying to address, or, if for patients who have PI 3 kinase inhibitor or other partners like mTOR, I think the progression-free survival just putting patients on a Fulvestrant is probably not adequate. So right now this is not practice changing.

PALMARIS Study

I am not switching a patient or continuing CDK 46. There are similar studies, pending results, such as the pace and the PALMARIS study, where we look at continuing Palbociclib after Palbociclib. And then, with the addition of Avelumab, there’s also the post Monarch study where you continue Avelumab after disease progression.

EMBER Study

And then the EMBER study used by switching, not just from an endocrine therapy to Fulvestrant, but a new third and then continuing the Ribociclib to see whether or not you gain some difference. It’s an interesting area. I think personally, I like to really maximize the time on endocrine therapy for my patients who are, who still have cancer disease sensitive to endocrine therapy.

ASCO’s Special Article on Bone Modifying Agents

So then next just very quickly, I wanna talk a little bit about the bone modifying agents. And this is basically a table that was published in the. ASCO’s special article looking at the adjuvant bisphosphate and other bone modifying agents in breast cancer was published earlier this year.

 

And basically, long story short, the guidelines did, does not recommend adjuvant Denosumab to prevent breast cancer recurrences. And this is because the studies have not shown a consistent reduction of breast cancer recurrence in any subsets of early stage breast. 

 

Abstract 507

Then this Abstract 507 from the ABCSG 18 study came out with the long term outcomes of adjuvant, Denosumab and breast and early breast cancer and what they did.

 

As I put here in terms of refreshing everybody’s memory is that they randomize patients who are post-menopausal in on aromatase inhibitor to Denosumab versus placebo.

 

The primary endpoint is time to the first clinical fraction. That was significant, that was reported a few years ago. And then the secondary endpoint is the DFS.

 

One of them is DFS and which they reported here in this abstract. So as you can see here, DFS bone marrow of bone met free survival, and overall survival were significant. We improved with the Denosumab. Because of this, I would say the Denosumab can be considered as a (clinical oncology) treatment option for a post-menopausal woman with HR positive breast cancer on, AI therapy.

 

There’s no head-to-head comparison of Zoledronic Acid Zometa versus the Denosumab. So we don’t know how they will compare to each other. And then just so just to point out that DFS OS and BF MFS were all secondary endpoints. I think this is practice affirming.

 

I still opt for Zometa because it has better evidence, more consistent evidence in breast cancer patients in early breast cancer patients.

 

And, I will continue to use Denosumab for some moving on to early triple negative breast cancer where neoadjuvant PD-1 or PD-L1 therapies are being used. This is basically just a summary of those clinical studies that have used immunotherapy and triple negative breast cancer.

KEYNOTE-522

And I want to go over the KEYNOTE-522 in terms of the event free survival based off of RCV analysis. So as a reminder, KEYNOTE-522 is the study where patients are randomized to having chemotherapy neoadjuvant chemotherapy with, or without Pembrolizumab followed by surgery and then adjuvant Pembrolizumab.

 

And what it was found to be significant was the past CRA was in increased by 13% and an absolute 13%. And then the event free survival is also improved.

 

So in this Abstract 502 what the investigator was trying to evaluate is the event free survival benefit of pembrolizumab in patients with past CR versus patients who have residual disease and surgery.

 

So on the left hand side, they show that with the Pembrolizumab in green, you really shift the RCB. A percentage to closer to RCB zero and one, which is not surprising.

 

And then here on the right-hand side, the event free survival is broken down to RCB 1, 2, 0 1, 2, 3.  and then interestingly, RCB 2 is the one that’s particularly benefited from the addition of Pembrolizumab.

 

And then when you see RCB0 patients who got either chemotherapy or pembrolizumab plus chemotherapy that reach RCB0, the event-free survival is very, it’s nothing really significantly different.

 

Even if there’s a difference, that’s very small as 2%. So the patients who actually reach past CR RCP0, the question now remains is do they really need Pembrolizumab, and who will actually benefit from Pembrolizumab to achieve past CR in excellent event free survival?

GeparNUEVO Study

And then another question, it really, remains. Whether not adjuvant Pembrolizumab contributes to this event free survival (overall survival) benefit. And this is because of the GeparNUEVO study, which is another study looking at Durvalumab with chemotherapy neoadjuvant versus neoadjuvant chemotherapy. Followed by surgery and then nothing.

 

So patients did not get adjuvant their Durvalumab, and in that study, they did not see any past CR improvement with the addition of their Durvalumab.

 

However, they were able to see EFS, sorry, DFS improvement with the addition of Durvalumab. So it really begs the question of whether or not adjuvant immunotherapy is needed in this population.

 

There will be a SWOG cooperative clinical trial 1418 (ASCO Annual Meeting) that that address this in details. So then the next thing is to talk about HER3 expressing metastatic breast cancer. I thought this is interesting. Not yet practice changing, but it might be signaling something. Something next to something coming up next.

 

So this is abstract 10033. And I think we all feel of patients with metastatic (disease) breast cancer, we run out of (clinical oncology) treatment options in cancer care (health care) for a lot of them at the end. So HER3 really represent another new target in breast cancer care (health care) particularly in the era of this novel ADCs.

 

So this is a phase 1, 2 study using Pertuzumab, HER3, and DXD in a small number of patients, a 182 patients with HR positive HER2 negative or triple negative disease, but they have to have HER3 high or HER3 low expression. And they were randomized to different dosing.

 

If they have HER3 high HR positive HER2 negative metastatic breast cancer, but then for others 6.4 milligrams per gig were used, and this is the waterfall plot on the right with HR positive breast cancer patients, and then also triple native breast cancer patient with a clinically meaningful and response of about 30% and for HR positive breast cancer and 22% for.

 

Triple negative, and then interestingly, in their dose escalation portion of the study, they did include patients with HER2 positive breast cancer, and they were able to see an overall response rate of 40, 43% and in and I want to point out that’s the duration of responses respectable.

 

It ranges from about 6 to 8 months, I think. This is definitely something to look out for as they move into a later phase of the study. There were, again, ILD issues for this compound, with 6.6% of patients with ILD. There was one patient who unfortunately died of ILD. The other side effects are pretty typical for this DXD. I guess a payload with nausea, diarrhea of normalcy, and neutropenia.

 

So with that, I want to stop and see if anyone has any questions.

 

Kay Yeung, MD, Ph.D. ASCO [2022] Breast Cancer Overview: MOASC Spotlight https://oncologytube.com/v/41282

Kay Yeung, MD, Ph.D., ASCO 2022 Breast Cancer Cancer Question & Answer

https://oncologytube.com/v/41314

Kay Yeung, MD, Ph.D. – About The Author, Credentials, and Affiliations

Her primary area of expertise is in the clinical oncology treatment of breast cancer patients, for which she holds board certification. In order to provide patients with the most effective range of treatment options, she employs a variety of therapeutic approaches, including as endocrine therapy, chemotherapy, targeted therapy, and immunotherapy.

She is also a teacher at the UC San Diego School of Medicine, where she is an associate professor of medicine, where she instructs medical school students, residents, and fellows. Dr. Yeung did both her residency in internal medicine and her hematology/(clinical) oncology fellowship at the University of California, San Diego School of Medicine, where she also served as head fellow during her time there.