Testing for ESR1 mutations after disease progression in metastatic breast cancer.

, “Expanding Treatment Options for Metastatic Breast Cancer.”

I’m Dr Hope Rugo from the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. Joining me to today in this virtual discussion are my excellent and expert colleagues:  Dr Claudine J. Isaacs from the Lombardi Comprehensive Cancer Center at Georgetown University; Dr. Priyanka Sharma from the University of Kansas Cancer Center; Dr. Tiffany A. Traina from Memorial Sloan Kettering Cancer Center; and Dr John Fox, vice president of Clinical Transformation at Spectrum Health.

We have great experts on our panel today, and are excited to have John Fox, MD, MHA, as well to give us a different perspective on treatment choices for patients with metastatic breast cancer. Today we are going to highlight a number of topics pertaining to the systemic treatment for breast cancer and the impact of recent clinical trial data on clinical decision-making.

Let&#39;s get started on our first topic which is treatment after progression on a CDK4/6 [cyclin D/cyclin-dependent kinases 4 and 6] inhibitor plus endocrine therapy. One of the big questions that comes up, Tiffany, is whether or not we routinely re-biopsy or reorder molecular testing at disease progression in patients with hormone receptor-positive metastatic breast cancer, and whether you actually test and decide on treatment for

mutation status. Also, if it&#39;s positive or negative do you retest in the future since it might impact your treatments? Then of course attached to this is what we know now about mechanisms of resistance to CDK4/6 inhibitors.  Can you tell us a little bit about those areas?

Sure. I think there is a lot in there to unpack, but to start with, I think having tissue material for biomarker assessment in the setting of metastatic breast cancer is important. We know in the first-line setting to never assume, to recheck your ER [estrogen receptor], PR [progesterone receptor], and HER2 status so that we’re not missing the opportunity to use appropriate targeted therapy. Together with that, I think in the first-line setting, although while often using a CDK4/6 inhibitor, it is a nice opportunity to start your molecular testing for PI3K [Phosphoinositide 3-kinase] status knowing then that you may have an opportunity in later lines of therapy to use a PI3 kinase inhibitor.

I do find that often in first-line metastatic breast cancer routinely we’re doing a biopsy, sending those hormone receptors again, and beginning the molecular profiling. To your question about

mutations, many of our women have had an adjutant aromatase inhibitor which drives the development of an

mutation. There’s a great rationale for thinking that fulvestrant and SERDS [selective estrogen receptor degraders] may be better in the setting of an

mutation. Often, I will use the clinical circumstances to help guide me in what that first-line choice may be for an endocrine therapy backbone, and the

That&#39;s really interesting. That that is a question that I think is of interest to everyone’s patients, but would you serially test for

, for example, with ctDNA [circulating tumor DNA]?

It is an option. Over time, we have considered doing cell-free DNA testing more looking for an actionable mutation like the PI3 kinase alteration. In my experience for

, I haven&#39;t seen it crop up in later-line endocrine therapy, but it may just be that I haven&#39;t seen enough of that. I&#39;d be curious to hear what other people think in that setting.

mutation as well, but we&#39;re starting to do that. I think the other question is what the difference is in ctDNA versus tumor biopsy, and might you be seeing differences between those. We&#39;ve tried. We&#39;ve had a few patients who are trying to be on top of things and say “Okay, looking forward to the next thing. I&#39;m on a CDK4/6 inhibitor. Do I have a PI3 kinase mutation?”

Some of what we&#39;ve heard is that the optimal time to test is when a patient really has disease progression and not while they&#39;re having response to the treatment they&#39;re currently on. I’d also be interested in how people think about doing this because we like to be organized and thinking ahead, but at the same time testing while somebody is responding to their current treatment might not be the best time to do it.

I think it is a good point, and we&#39;ve seen that

mutations come and go. We may not have even been getting a very accurate representation of what&#39;s going on. Personally, I don&#39;t serially test but I could see a situation where you might. Also, it does appear that

mutations are conserved so that you gain a few in the metastatic setting and with progression but not a lot so that you could probably safely test while you&#39;re doing treatment. I usually test when they&#39;re starting to look like they might be progressing sometime in the near future.

Treatment After Progression on CDK 4/6i in mBC

The SOLAR-1 trial data in the second-line setting in metastatic breast cancer are examined as well as the use of alpelisib and everolimus.

mutations is because of the SOLAR-1 data and our use of alpelisib. Priyanka, tell us a little bit about the use of alpelisib in the SOLAR-1 trial. What did that study show?

SOLAR-1 was a trial for women in the second-line setting after progression on the first-line aromatase inhibitor therapy, and it showed the benefit of adding a specific PI3K [phosphatidylinositol 3-kinase] inhibitor to a backbone of fulvestrant. There was improvement in progression-free survival that was clinically meaningful, almost a 6-month improvement. That led to the approval of the drug last year.

Now it&#39;s available for us to use in clinic, and that obviously has driven the clinical necessity to look for PI3 kinase mutations. In this trial, the benefit of alpelisib was noted primarily in patients who harbored a PI3 kinase mutation in the specified domain, and about 40% of the patients had a PI3 kinase mutation when tested on tumor tissue.

It&#39;s an interesting question. The real question is what are we seeing in the population at large in terms of

mutations, but then what do you do with the patients who either don&#39;t have a mutation or they have already progressed or can&#39;t tolerate alpelisib for whatever reason?  How are you using everolimus now, Tiffany?

It’s still one of the drugs in our armamentarium, and so it depends on what the toxicity and concern was, like you mentioned if somebody wasn&#39;t able to tolerate alpelisib. I’d want to be sure patients aren&#39;t having difficulty with pneumonitis as I&#39;m thinking about using everolimus, but I still see it has a place. It just has moved down quite a bit in the lines of potential options for endocrine therapy partnered with exemestane.

There is evidence for partnering it also with tamoxifen even. Sometimes in someone who’s had a small level of progression but needs a change of therapy, has sequenced through all of our other available endocrine therapies and perhaps they’re PI3 kinase wild-type, I would see that as an option with the steroid rinse to make the mucositis more manageable, if you will, as an alternative to moving onto chemotherapy.

Priyanka, where do you tend to use everolimus, and what&#39;s your preferred partner with everolimus?

I agree with Tiffany that especially the patients who have a PI3 kinase mutation and cannot tolerate alpelisib maybe because of diarrhea, or a small proportion who develop significant rash, this is a useful drug. For patients who haven&#39;t had fulvestrant, obviously that makes for the most rational partner. I see a role in later lines of therapy as well combining with Aromasin [exemestane] or tamoxifen.

I agree with the pneumonitis aspect. Obviously, patients who have had pneumonitis with alpelisib are probably at higher risk for having it with everolimus, but diarrhea and rash sometimes are one of the reasons we can&#39;t give alpelisib. Also, our patients who have hemoglobin A1C [glycated hemoglobin] above the threshold that SOLAR-1 used or have uncontrolled diabetes.

I think it&#39;s a great question. Claudine, when you give alpelisib to a patient with fulvestrant, how are you managing their blood testing and managing toxicity?

Obviously it’s one of those drugs that makes us be better internists again, for some of us who are old and forgot some of this stuff.  We need to manage and follow their glucose carefully on this and be monitoring their hemoglobin A1C, and I tend to follow the algorithm that&#39;s out there for what we should be doing in terms of metformin dosing and a variety of things by monitoring there carefully for that.

It was interesting, we just presented data at ESMO [the European Society for Medical Oncology] in 2019 about the time course of toxicity with alpelisib on SOLAR-1. What we saw is that if you&#39;re going to be hyperglycemic, you usually peak in the first 15 days and the same with rash. We actually have encouraged people to use preventive antihistamines, and the non-sedating antihistamines seem to play a big role.

I&#39;ve actually doubled the dose in the first week or so for patients, and we stopped seeing rash. It was interesting that when we were doing the phase 1 studies, we saw tons of rash, and then we stopped seeing it. I think this is something like the steroid mouthwash that we used for everolimus stomatitis, that we can really minimize that toxicity. For the hyperglycemia, it’s been interesting. I don’t know if any of you talk to patients. There are a lot of patients who have hemoglobin A1Cs that are slightly elevated. We know they are at higher risk. I’ve actually found the insulin-dependent diabetics easy because they just modify their insulin. But for the other patients, do you talk to them about a low carbohydrate-type diet? Tiffany?

We do. We check a baseline hemoglobin A1C and talk about generally having a low carb diet as well as having a finger stick monitoring, glucose monitoring. As Claudine mentioned, it&#39;s just been a new world and having to relearn diabetes management. It’s something we haven&#39;t had to do for a long time.

By the time I get past metformin, I&#39;m usually getting my endocrinologists involved, and I’m guessing most of you guys are too. But there are new classes of drugs that we learn about on the television that we may have some guidelines for recommending, and that will help us a little bit because our endocrinologists are also busy. So it&#39;s interesting. Then there&#39;s also some interest in combination therapies and how we&#39;re giving other alternative agents in the hormone receptor-positive setting. I don&#39;t know if you have any perspective on where we&#39;re going to go with this moving forward. Priyanka?

Obviously, we&#39;ve seen the efficacy of AKT inhibitors in this setting with fulvestrant, and capivasertib, which is in a phase 3 trial right now in the second-line setting after progression on first-line AI [aromatase inhibitor] therapy. For that trial, it’s enrolling regardless of PI3 kinase mutation status, so patients who don&#39;t have a mutation and are otherwise a good fit, we’re recommending that trial to patients. Among the second-line space, I see that as one of the other promises that hopefully will bear fruit.

SOLAR-1 Trial in Metastatic Breast Cancer

The role of PI3 kinase inhibition in various settings in metastatic breast cancer and a payer perspective on differentiating breast cancer at various stages of disease progression.

There have been some studies looking at combinations of PI3K [phosphatidylinositol 3-kinase] inhibitors and other treatment, CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors, and so forth. It seems as though most of those have met with too much toxicity, so we&#39;ll see where that goes, but there is interest in using PI3 kinase inhibitors in other settings too. Priyanka, I know that you&#39;ve led some of the work in that area.

Yes, we evaluated the specific PI3 kinase inhibitor with nab-paclitaxel in metastatic HER2 [human epidermal growth factor receptor 2]-negative breast cancer. It also has encouraging efficacy in the phase 2 trial. Like Hope said, we recommended prophylaxis with an antihistaminic for most of our patients, and that led to a really low-grade manageable rash situation. We also asked our patients to have diabetic education right up front, at least in the context of that trial. I think that helped quite a bit.

If we can teach patients ahead of time how to control the carbohydrates that&#39;s helpful, and we also have some preclinical data that suggest that some type of ketogenic diet, low carbohydrate intake, might add to the efficacy of these inhibitors. Of course, we don&#39;t know that from clinical trials, but certainly in terms of being able to tolerate the drug, that helps.

I know there is some concern that giving insulin might abrogate to some degree the effects, and certainly that&#39;s for PI3 kinase inhibitors, and although seen in animal models, we really don&#39;t have any idea about that in the human setting, I would say. You have to treat the diabetes, but there is interest in the oral agents like the SGLT2 [sodium-glucose cotransporter 2] inhibitors as well, so that&#39;ll be interesting to see. We want to get John involved and his comments in this area because it’s so important for all of us, and also some feedback from all of you when we hear what he has to say.

From a formulary or medical policy perspective, John, how are you differentiating breast cancer at various stages of disease progression? For example, how do you decide on CDK4/6 inhibitors, first in everybody, for

mutations? What evidence is needed to support the use outside of the label? Also, when you have multiple agents in the same class like CDK4/6 inhibitors, how do you decide which one is OK to use?

There are a lot of questions in there. Let me first step back and say that I think most payers have agreed that they&#39;re going to follow NCCN [National Comprehensive Cancer Network] guidelines in choosing which therapies to cover. There are some payers in some states that don&#39;t follow NCCN guidelines, but most payers have agreed to use these guidelines. Almost 30 states have mandates to cover FDA-approved cancer therapies. Certainly Medicare and Medicare Advantage Plans have to follow the NCCN guidelines or another compendium.

Their drugs are in a protected class. Cancer drugs are in a protected class. So I think the question more commonly is not whether to cover therapies, but under what circumstances. I think the advent of molecular diagnostics has really helped us and increased the probability that patients get on the therapy that is most appropriate for their cancer type. One of the common questions is, can you get paid for doing molecular diagnostic testing? And interestingly, in patients who need IHC [immunohistochemistry] testing, for example, nobody&#39;s evaluating those, and most commonly payers aren&#39;t looking at single gene mutations.

If you&#39;re looking for a single gene mutation like a

mutation, those are covered. It’s typically when you get into these very costly next-generation sequencing tests, for example, if you have to do a liquid biopsy because you don&#39;t have tissue and have to use a Guardant laboratory test or a Foundation Medicine test, those tests are prior authorized to determine that they&#39;re medically appropriate. Interestingly, I work in a regional delivery system. We don&#39;t perform these tests locally.

I think everyone here probably does tests in their own institution and may or may not be concerned about getting testing covered. But I think that&#39;s a significant issue and one that we have been on the forefront of trying to ensure that people get tested so that we can make sure that they&#39;re on the therapy that&#39;s most appropriate given their tumor mutation status and stage of disease. To come back to your questions, I think for patients who are PR [progesterone receptor]-positive, if a provider chooses to use a given CDK4/6 inhibitor, that&#39;s their prerogative to use, and it&#39;s also their prerogative in most delivery systems which one to use.

There was an indirect analysis performed last year published in

that compared all 3 CDK4/6 inhibitors, and it showed that they had equal efficacy in the first-line and second-line setting. So a priori, we as a plan don&#39;t have a preference over which one is used. There are some differences in the toxicities. I think abemaciclib had higher diarrhea rates, and Kisqali [ribociclib] has higher rates of QTc [corrected QT interval] prolongation. In those circumstances it would be hard to tell a provider that you can’t use palbociclib first line when the others have toxicities.

There are many health plans today that have incentive programs or prior authorization programs around these drugs to try to steer providers to a select drug, but there aren’t many circumstances that I&#39;m aware of where a provider is precluded from using their preferred CDK4/6 inhibitor. With that said, in the traditional Medicare population, which many of these patients are traditional Medicare beneficiaries, a provider is free to choose whichever regimen they prefer.

That&#39;s actually really great to hear. Of course, we do know that there aren’t head-to-head data on the CDK4/6 inhibitors yet, and I hope there never are because I hope that money is put into studying new agents in new settings rather than to comparing the different agents. I just think that that would be such a huge study.

The cost of doing the study would be prohibitive. I agree with you that the findings may not change providers&#39; opinions around which therapy is best. There can be real-world data that are examined. That has some challenges in the coding accuracy, but that might be the best place to identify toxicities and overall survival.

I think that it may be for toxicities. I think it&#39;s really hard to look at clinical end points in real-world data in terms of overall survival, though it certainly had been a great interest. I think on the clinician side we&#39;ve seen a lot of issues with that data.

Payer Perspective of Coverage on Cancer Therapies

Testing patients who have received CDK4/6 inhibitors in metastatic breast cancer as well as testing patients with ctDNA upon disease progression with a single gene test versus NGS.

Priyanka, do you want to comment a little bit on how we&#39;re testing patients who have already had CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors versus not in the SOLAR-1 trial and then next steps?

One of the things that always happens in our field is that new drugs and data come along, but where we put it in our patients in clinic today doesn&#39;t match the trial design. In SOLAR-1, the majority of patients did not receive a CDK4/6 inhibitor in the first-line setting with aromatase inhibitors, which would be considered current standard of care. And we&#39;re applying alpelisib to the second-line setting. We need studies that mimic the population that we&#39;re treating in clinic, and I believe one of the trials is looking at CDK4/6 inhibitor progression and the efficacy of PI3 kinase [phosphatidylinositol 3-kinase] inhibitors.

mutations early on in the first-line setting on a CDK4/6 inhibitor just because as we know it&#39;s a fairly conservative mutation, so I&#39;d rather have that information available when I need to make this change. But we do need the data of how efficacious this combination is when patients have received contemporary first-line endocrine therapy plus targeted therapy.

We&#39;re really looking forward to the data from the BYLieve trial to try to help us understand benefits, although it&#39;s a single arm trial in patients with

mutations who&#39;ve had CDK4/6 inhibitors. There is one other question that&#39;s probably of interest to our audience and to all of us. John, if a patient has had ctDNA [circulating tumor DNA] testing and you don&#39;t find a

mutation, how do the payers approach them getting NGS [next-generation sequencing] from the tissue?

Your question is if they do a circulating tumor DNA and don&#39;t find a

mutation, would we pay for a repeat tissue biopsy and a solid tissue? I know that&#39;s an issue, but I think the important thing there, at least in my understanding, is to test people with circulating tumor DNA when they&#39;re progressing. If there is no evidence of progression, there may not be circulating tumor DNA being sloughed into the blood stream for sampling. But if the guidelines indicate that a patient might be appropriate for a therapy and the only way to get that would be through a repeat biopsy, we’d pay for it. I think the big question though is how many markers do you need to look at?

If you just need 1 marker, it could be a single gene test as opposed to next-generation sequencing where you&#39;re sequencing hundreds of different genes. The other time that we would pay for a next-generation sequencing panel, whether it be through ctDNA or through a tissue biopsy in solid tissue, would be if a patient was eligible for a clinical trial. Payers differ there. Certainly Medicare would cover a test in that situation, and they would certainly cover the clinical trials. Not all payers cover testing to determine whether patients are appropriate for a clinical trial. But we’ve said if we&#39;re going to cover a trial, we need to cover the tests that are appropriate to determine whether a patient is eligible.

I think that&#39;s a good summary of what we are thinking about and what the payers are thinking about on both sides in terms of what you can do. You mentioned single gene testing on tumor tissue. We generally only get that when we send it to a sponsor rather than when we send it on our own. Claudine, have you sent single gene testing?

I tried, and maybe the last time I tried was about 6 months ago, so I recognize the world changes. But I couldn&#39;t get single gene testing&#151;it’s hundreds of genes or nothing when you’re sending off this next-generation sequencing.

I think that cost relatively is similar for some of our sponsors in terms of our partners in the laboratory testing area. The cost is relatively similar to getting 1 gene versus many actually.

Well, in fact, the cost of the testing itself compared to the cost of these drugs&#151;I try not to remember the cost of the drugs—but the CDK4/6 inhibitors are $10,000 or more a month, so the cost of single test, either circulating or solid tissue, is on the order of $2400 or $3000. It pales in comparison to the additive cost of treating the patient month over month with an expensive therapy, so it&#39;s a good investment to make to make sure that the patient is appropriate for a given therapy.

Great. Thanks very much for your participation in this discussion. It was really interesting, and I think is an area that is changing on an ongoing basis. It&#39;ll be interesting to see what happens in the next year with more data.

Payer Coverage on Repeat Biopsy in mBC

A discussion on a phase 3 trial using oral paclitaxel and encequidar for treatment of metastatic breast cancer.

 In this segment we're going to talk about oral taxanes, how oral therapy might play a role for us in terms of treatment, and what are the advantages of oral therapy. I'm going to talk a little bit about the Oraxol study that was presented at the San Antonio Breast Cancer Symposium. But first, I'd like to ask our panel what the advantages of oral therapy are to our patient population, and what they’re thinking about in terms of wanting oral agents. Here we're focusing on chemotherapy. We know that most of our endocrine therapy is oral on 1 IM [intramuscular] administration, but for chemotherapy we're stuck with this IV [intravenous] therapy. Tiffany, do you want to comment on that?

Often the perception has been that oral therapy would be simpler and easier for our patients, although I say that's perception because we've found that in the space of targeted therapy that's not always the case. Certainly having the option of oral therapy gives a woman more freedom away from the clinic, perhaps not needing central access. It depends on the adverse effect profile of the oral therapy to help in decision making over what adverse events we would otherwise see with intravenous therapy, which is sometimes really well tolerated.

 I think this is an issue, with IV access being an issue as well. Claudine, any other comments on that in terms of what your patients think about IV therapy and frequency of dosing—IV versus taking oral therapy?

Absolutely. Of course you need to take the toxicity of the given agents into consideration, but I think the default from a patient perspective is that people tend to prefer oral therapies. Where we are right now in the world it’s clear that the more that we can get people away from our infusion units, and the more we can have them have the liberty of getting their treatment at home, that is clearly advantageous. But I think we need to balance that against the toxicities. The default is if we could give the same therapy orally, that would obviously be a tremendous advantage for our patients.

 Coming from the area that I am in, which is very rural, for us, oral therapy also has an added advantage. A lot of our patients are traveling 3 to 4 hours from where they are to come to the infusion center. From that aspect, it’s also preferable as long as the toxicity profile isn’t prohibitive.

 That’s interesting because now we'll be able to talk to them by telemedicine visits, given our experience with COVID-19 [coronavirus disease 2019]. Let's talk a little bit about the data that were recently reported from a phase 3 trial about an oral taxane. This study was conducted in Central America and South America using used a drug called Oraxol, which was compared to IV paclitaxel. Patients who had metastatic breast cancer were randomized 2 to 1 to OPE [oral paclitaxel with encequidar] or IV Taxol [paclitaxel]. The primary end point was the tumor response by week 19 that was confirmed 1 month later, so a little bit different from what we've seen in other registration trials.

In this situation they had to show that they were at least as good as IV paclitaxel, so that was a reasonable end point with tumor response by week 19. There was a total of 360 patients who were randomized in this trial, and many had received some other prior treatments for their metastatic disease. It’s important to understand what Oraxol is, and it's actually oral paclitaxel. It comes in a little gelatin capsule, so you need several of them together. Most people took 10 or 12 tablets each time. Then one of the problems with oral paclitaxel and with any oral drug is actually that you don't get absorption because you have the pump, the P-glycoprotein efflux pump is pumping it out as quickly as you get it absorbed.

They actually used another agent called encequidar, which is designed to try and prevent the P-glycoprotein pump from pumping out the chemotherapy as quickly as it is absorbed. It actually also enhances absorption, and it doesn’t have a lot of toxicity on its own. This drug is called encequidar. Basically the way people took this medication is a single tablet of encequidar, and then they took several little capsules of the oral paclitaxel. They took it for 3 days in a row every week for 3 weeks in a row, followed by 1 week off. This was compared to 175 mg/m2 of IV paclitaxel given every 3 weeks, the original way that IV paclitaxel was approved.

A lot of these patients had received some prior treatment. About a quarter had received prior chemotherapy, about a third had received prior taxane exposure in any setting, and of course quite a number had visceral disease, so they were our standard patients. They saw an improved response rate of about 15% difference favoring the Oraxol, and that showed a 40% response versus 26% response rate. They didn't see big differences in terms of subset analyses. They had the smallest number of patients who had triple negative disease, so it was a little bit harder to assess in that specific population.

They saw that the responses were quite durable with about three-quarters of the patients staying on treatment for more than 100 days, about a third of patients more than 200 days, and the follow-up is still ongoing. They did look at progression-free survival as well, and it was relatively equivalent at the first evaluation, but they have further evaluations ahead. Then overall survival actually favored the Oraxol with a hazard ratio of 0.68. Although this wasn't their primary objective, the 

 value is .03, and it is intriguing that you could see this improvement in overall survival.

I think one of the things that we were impressed with for these data was a difference in neuropathy. If you looked at the grade 2 or greater neuropathy, there was significantly less neuropathy over time with the Oraxol compared to IV paclitaxel—a clinically significant difference in terms of developing neuropathy. If you just looked at the total incidence, it was 31% for IV paclitaxel and only 7.6% for the Oraxol, which is very different. So it's quite intriguing, and the first encouraging data we've seen in this area. I'm interested in what everybody thinks about this. Tiffany, what do you think? What did you think about the data that were presented, and what would be a reason for you to use this over IV paclitaxel? Did you have any concerns about the study design?

Hope, I think you've raised some of the challenges of the design in and of itself—the control arm not being our traditional control arm, dosing, and schedule of intravenous paclitaxel, not having clarity on the different subgroups and who these patients are. But with all that being said, it does appear to be favorable in terms of that neuropathy profile. We have many women who have long-lasting neuropathy as a result of their adjuvant taxane, and that can be a limiting factor then when we need to treat them serially in metastatic disease. To be able to have a taxane that's active, that has less neuropathy, that perhaps could even partner nicely with some other oral targeted therapies and have a doublet oral regimen, and that enables women to stay out of the infusion suite, could be really advantageous.

It is a large pill burden from what you described, and so I think it will be a matter of finding the right patients for whom this is suitable. The other point that I didn't raise when we were talking about advantages of oral therapy over intravenous is a bit of a concern, that we know practices are spending a lot of time trying to get approvals and authorizations and access for oral regimens for our patients. I would love to hear some of John’s thoughts on how oral anticancer therapies such as this, how this would compare with simple IV paclitaxel.

 That's an important point that you bring up because the share of cost not just for capecitabine, our current oral drug in the United States that we have as chemotherapy, but also for CDK4/6 [cyclin-dependent kinases 4 and 6] inhibitors has been prohibitive. These are patients who have Medicare and not secondary insurers.

Advantages of Oral Taxanes in mBC

The importance of patient education in managing toxicities on therapy in metastatic breast cancer.

 Claudine, what are your thoughts about this? Who would you decide to use Oraxol for? What do you think about adherence and the share of costs for patients?

Those are all critically important points, and I think we’ve already raised a number of the points that we think about with oral therapies versus IV [intravenous] and managing some of the pros and cons. One of the things I don't think we've gotten to quite yet are some of the issues regarding compliance and adherence to therapy. We know that that's a big issue with adjuvant endocrine therapy for instance, and it might be different when you're talking about the metastatic setting in terms of adherence to therapy.

There will be different factors pushing people one way or the other, but with complicated drug regimens there is a lot of continuing education that needs to happen for patients, not only in terms of how they take the drugs and when they're supposed to take them, but also this question about managing toxicity being very clear. One of the things that we have traditionally been very good at is if we're giving IV therapies, that the patients are coming into the infusion unit, they get a toxicity check by virtue of showing up, and often the infusion nurses are excellent at this.

They call us, page us, and they have us come by. Different groups have different systems for it, but you lose that when someone is on oral therapy, so I think it underlines the importance of careful patient education, how to reach out, how to manage the toxicities, and what to do about this. Obviously having more options is great, but just because these drugs are oral, it doesn't mean they don't have toxicity. It's really about balancing on an individual basis what's best for a particular patient.

Absolutely, and I think that's well said. Priyanka, you mentioned that you're in a rural situation. People did have nausea. Although the neuropathy was impressively better to me because neuropathy is such a big issue for us in long-term paclitaxel, they did have nausea, but our colleagues in Central America said that it was easily controlled with antiemetic therapy.

 For our patients, not needing to come to the infusion room every week would certainly be a plus, but the complexity of taking the medication would also have to be considered. You have to wait a certain number of hours after you take 1 aspect of it, and take multiple pills, and then fast for more hours. That would raise concerns with some patients where we don't know whether they would be able to comply with that complexity.

One of the advantages of this particular formulation is lack of need for steroids. A lot of patients are concerned about needing to take weekly steroids for weekly paclitaxel, especially those who have diabetes that's not that controlled. We talked about potentially combining with other drugs, so a lack of need of steroids would also make something like this more appealing to be able to combine with other drugs. For example, this could be PI3 [phosphoinositide 3] kinase inhibitors or AKT inhibitors that cause hypoglycemia.

 That's a good point, the steroids, and also the point that you brought up about fasting is important too. This is because interestingly, capecitabine doesn't have those. But this oral medication, as many have in the past, has very strict criteria in terms of fasting before and after taking the pill. You do that 3 days in a row every week for 3 weeks out of every 4 weeks, so it's a big issue. They are studying whether they can have more food closer together and studying to understand the food effect. But that will be a big question for us in how we are able to use this in different patient populations.

Compliance and Adherence to Therapy in mBC

A payer perspective on coverage of IV versus oral therapy in metastatic breast cancer taking into consideration cost and patient survival outcomes.

 One of the issues for us is always how payers deal with this. We talked about share of cost and how you decide what payers think about IV [intravenous] versus oral therapy in terms of invasive delivery as well as the concerns about the different treatments. Paclitaxel is now generic, but it’s IV. This drug will be new and oral, and not generic. John, can you tell us a little bit about what your perspective is on this?

 Just to clarify, is it 2 drugs? You did describe the pill taking, but is it 2 drugs?

 It’s 2 drugs combined. The product Oraxol includes oral paclitaxel, which is poorly absorbed because of the P-glycoprotein.

 No, actually. It’s a bunch of pills. There’s a little blister pack with 1 pill with the encequidar and then another blister pack with several gel tablets that have oral paclitaxel in them.

 OK. So for the patient, another consideration, as you alluded to, is going to be the patient cost. IV paclitaxel, as you note, is generic, and even if patients don’t have cost coverage with a Medigap policy, they’re going to be paying a small amount of money. But for an oral therapy, if they have a Medicare Advantage plan or traditional Medicare, they’re going to be paying 25% coinsurance up until they hit their catastrophic coverage. Then they’ve got 5% after that. The cost of this, depending on what it is, may be prohibitive for some patients.

Even if patients have Medicare Part D coverage, they’re still going to have significant costs. For us as a plan, what we observe all the time is simply that if there is only an oral therapy, everybody thinks that the new IV is the cat’s meow because we can ensure adherence, and if there is only an IV therapy, everybody thinks that the new oral therapy is the cat’s meow because it will improve patient convenience. I think there is a mixture of both. I agree with Claudine that it’s nice to have an option. I think that fundamentally, though, Medicare is going to require that we cover this drug if it’s FDA approved.

Then we’ll have to allow that oral therapy. One exception is I don’t know how many of your practices or how many of your institutions are involved in OCM, the Oncology Care Model, through CMMI [Centers for Medicare & Medicaid Innovation]. Most of these patients who are on IV therapy can be coached through the toxicities, and if you’re in an OCM practice and now these dollars are coming out of your pocket instead of the federal government’s, it may be in the institution’s interest to try to coach those patients through the IV therapy.

There are a lot of private practices that are in OCM, and I’m confident that if they’ve got a generic paclitaxel IV compared with a drug that might cost $10,000 a month, they’re going to work very hard to try to get that patient to tolerate the IV paclitaxel.

 Do you see a situation where the payers might—outside Medicare—say, “We would approve IV paclitaxel, but unless there’s a demonstrated superiority, we don’t want to pay for this expensive drug.” What about the difference in neuropathy? What types of differences would influence a payer to pay for the more expensive drug?

 I suspect that if patients develop neurotoxicity on the IV paclitaxel, that would be an indication for covering them. I just want to clarify. As I read the abstract, it looked like in the modified intention-to-treat analysis that the overall survival was 27.9 months versus 16.9 months. Do you think that may be inaccurate because of the study design?

 No, I don’t think so. Overall survival is one of those hard end points, so it’s pretty good in general. They have a modified intention-to-treat population, which are patients who took at least a certain amount of drug and is unusual for intention to treat in general. But it was based on the fact of where they did the study and the fact that it was also oral, so I think that is an impressive difference. Of course, survival differences—that’s what you were referring to—might motivate a payer to pay for the more expensive drug.

 Yeah. With that said, in practices that are in OCM where the money is coming out of their pockets, what would they do in that circumstance? I think everyone that I know of in the 5 or 6 practices in OCM would err on the side of giving the drug that produced the longest survival. But this study is also interesting because it highlights the importance of doing phase 3 trials. If we were just to have done a phase 2 trial or just looked at progression-free survival [PFS] as an end point, the difference was about a month…between the 2. We would have made a beta-type error and concluded there was no difference when in fact there really was.

I think there are a few frustrations we have as the payers, especially with the 21st Century Cures Act and that the FDA’s approval of a lot of drug is based on phase 2 data alone and often single-arm phase 2 trial data. Our frustration is that we don’t know at the end of the day whether there is a patient meaningful end point that’s been achieved. I think this study’s results showed that it was important to look at overall survival because the difference in PFS was very modest.

 I think the neuropathy might also be a way that providers will be able to go back to the payer and say, “I know you want us to use paclitaxel, but this patient already has underlying neuropathy.” It will be interesting because I think that may be very motivating data with the overall survival still relatively early for this trial. Claudine, I know that there has been a question, and Tiffany brought this up a little bit earlier, too, that the control arm wasn’t our standard control arm for this trial with every-3-weeks paclitaxel. How much does that impact your assessment of overall survival versus the neuropathy or other end points?

I think it makes us a little bit less enthusiastic to jump on that huge overall survival benefit. CALGB [Cancer and Leukemia Group B] quite a while ago did a randomized trial looking at weekly versus q3 week [every-3-weeks] paclitaxel and showed that the weekly was superior. I don’t remember the differences off the top of my head, but they weren’t as marked as the differences in overall survival that were seen in this trial.

I think it makes us a little less likely to scream off the rooftops that this is associated with this huge overall survival difference, but it makes you think that it’s unlikely to be inferior and might be a bit superior. There may be a lot of reasons associated with that in terms of how adherent people were or what was going on and what was their access to therapy after. So I think we need to integrate all those things when you’re thinking about survival benefit. I do think we need to be a little cautious to remember that this is not compared with what we would think of as the standard paclitaxel to use in this setting.

 I think that that’s an important point, and I think what’s interesting is that in some settings, weekly paclitaxel around the world is not feasible to give, so it’s going to be interesting to see what happens with the further analyses of these data and what people think about them. The issue of more expensive and less expensive will also play a role, as well, in the rest of the world. There are other oral taxanes that are being studied, tesetaxel, which is another type of oral taxane being given in combination with capecitabine versus capecitabine alone.

In the initial trial, which was in patients who’d received taxanes in the adjuvant setting but not in the metastatic setting, of course, and then in another trial, which is going on now in patients who are taxane naïve, so that will be very interesting. That’s an oral agent that’s given every 3 weeks. Then there’s another oral taxane called Liporaxel [oral paclitaxel], which is an emulsion from Korea that’s being tested in a phase 2 trial compared with weekly paclitaxel in the United States now. Priyanka, what are your perspectives on some of these newer studies looking at oral taxanes?

 All these formulations are different in terms of how they’re being delivered, some pills, some emulsions. We do have experience with Liporaxel, which is an emulsion given once a week. It’s liquid that the patient drinks twice a day, and for the most part, it’s relatively well tolerated. The main issues have been with diarrhea and bad taste in mouth. But it doesn’t require the extensive timing of fasting and number of pills. From that aspect, that makes it easier, and you take it only once a week, so there are not multiple doses spread over multiple days. This drug is approved in Korea for gastric cancers. I think we will see more of these agents and formulations, and probably the one with the best efficacy and the one that’s easiest to deliver in clinic might be the winner.

 It’s interesting because tesetaxel is being tested in combination with capecitabine, so that’s a little bit different, a little bit harder to separate out the toxicities of that combination therapy. But that first trial, contested trial, has completed accrual, so we hope to see results in the next year or so. Who knows?

It’s interesting. I think we’re entering a new era, where our threshold for thinking that a new drug is good has increased as we’ve had a lot of targeted agents, but I think having oral therapy for us in the United States would be a tremendous advance. We never got the oral vinorelbine approved, so it would be nice to see some additional options for our patients. Thanks very much for everybody’s participation. This was a great discussion.

Payer Coverage of IV Versus Oral Therapy in mBC

Typical outcomes for patients who have progressed after 2 lines of therapy in HER2+ metastatic breast cancer and a review of trastuzumab deruxtecan as seen in the DESTINY-Breast01 trial.

 We’re going to go on to our next section, and we’re going to talk about relapsed and refractory HER2-positive metastatic breast cancer. This is an area where we’ve had enormous progress over the last year, but overall, we’ve made huge advances over the last couple of decades. First, we want to hear from Tiffany a bit about what we see in patients who’ve progressed after the 2 lines of therapy in our classic treatments in HER2-positive breast cancer. What’s the typical outcome, and what are you thinking about in those patients?

 I think we’ve had so many new exciting agents. To set the landscape of where we’ve been traditionally, if we’re looking to phase 3 data, we’ve got the original capecitabine-lapatinib trial that we could perhaps extrapolate from in thinking about a later-line setting. This is where the median time to progression to just take lapatinib was measured in a few months, perhaps an improvement from 5 months to 7 months.

Overall survival in that trial was about 17 months to 19 months with the addition of the HER2-targeted therapy. If we look at the EMILIA study, which as you remember was capecitabine-lapatinib versus T-DM1 [trastuzumab emtansine], there the median progression-free survival [PFS] was still just measured in months in the third-line setting, an increase from 6 months to 9 months on average for median PFS and overall survival perhaps stretching out to about 2.5 years with T-DM1. That’s the evidence we had in the third-line setting and later of what our expectations were for the time to progression or PFS, which was really about 6 to 9 months or so. That puts into context what we’ll talk about, many of the new agents we have for HER2-positive advanced disease, and how much better we can do.

 CNS [central nervous system] metastases are a big challenge in that setting also.

Absolutely. Often these patients of progressing CNS metastases are excluded from the typical randomized phase 3 trials that we’re looking at for new novel agents in this space, so that is also an exciting changing moment for HER2-positive advanced disease in patients with brain metastases.

 We have, as you pointed out, seen a lot of really interesting data in the last year with several different agents. Claudine, could you tell us some about the sort of top-level results from some of these trials that we feel are going to impact our clinical practice?

Absolutely. It’s been a really exciting time, and beyond second-line therapy for HER2-positive breast cancer. First of all, we’ve had trastuzumab, which came on for the first-line setting that showed us a survival advantage, then the CLEOPATRA trial, with adding the pertuzumab for the first-line setting. It became our standard therapy there, and second line became TDM-1. After that, as Tiffany mentioned, there were a number of options, but there was no clear winner.

We were often just cycling out different chemotherapy drugs with trastuzumab, but in the last year or so, we’ve seen some results of some pivotal trials, most of them randomized phase 3 trials, but a couple of phase 2 trials that have really changed the landscape for us entirely. These drugs typically fall into classes. Most of the newer drugs that we’re seeing are tyrosine kinase inhibitors, but the trastuzumab deruxtecan is a new antibody-drug conjugate [ADC]. That’s a study that was just presented at the San Antonio Breast Cancer Symposium whose results showed the most phenomenal waterfall plot that many of us have seen in a trial. Just to give you high level on these, just to remind you what’s different about this drug, it’s an ADC just like TDM-1, but the payload is different.

The payload with this drug is a TOPO1 [type I topoisomerase] inhibitor, and there is a very high drug-to-antibody ratio. There is also some bystander effect with it easily crossing the cell membrane. It has a relatively short half-life, so the thought is that it can get to neighboring cells but doesn’t hang around for very long. What was seen in this study was that this was a heavily pretreated group of patients. They had a median of about 6 prior therapies for HER2-positive disease. They had to have had prior trastuzumab. The patients also had to have had prior T-DM1, and about two-thirds of patients had had prior pertuzumab. The objective response rate was about 61% in the study, and it was impressive, as I mentioned, for the patients.

There were very few patients who progressed. Most patients had a response, but 61% had an actual objective response, and if you think about the median number of prior therapies, that was very impressive. The adverse effect that was seen that is the one that we need to think about most and that was the most concerning is that a subset of patients had interstitial lung disease [ILD] that developed. Any grade was about 13.5%, but there were about just over 2.0% of patients who had fatal ILD with this drug, which is obviously a very concerning adverse effect. It seemed like, if the drug was continued when you had just abnormalities on x-ray, that could progress very rapidly.

That is something for us to keep in mind. This drug did get FDA approval, so it is available. Some institutions have it available already. I think one of the things that we might want to talk about is how we think about these drugs in this era that we’re in with the COVID-19 [coronavirus disease 2019] pandemic, where we’re really worried about preexisting lung disease and what that might do to increase risk. But this drug is an exciting drug. It has very quick activity in patients. Most patients had some degree of response, and the duration of response was also very long with this drug. I think it’s a really exciting drug for us to have available for our patients.

Evolving Treatment Landscape of R/R HER2+ mBC

Insights on the HER2CLIMB and phase III NALA trials as well as data on pyrotinib for the management of relapsed/refractory HER2+ metastatic breast cancer.

 That's really interesting, Claudine. Could you talk a little bit about the other data we saw at the San Antonio Breast Cancer Symposium in 2019 about the oral tyrosine kinase inhibitor tucatinib?

That was another exciting presentation. Those were the results from the HER2CLIMB study, which were published recently in 

. Tucatinib is a tyrosine kinase inhibitor. It's irreversible, and it targets HER1 [human epidermal growth factor receptor 1] and HER2. This trial was a randomized phase III study, and the key on this is eligibility. In the United States, this looked at the group of patients that we would be thinking of in the third-line setting. All patients had to have had prior trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine], and the randomization in this trial was that all patients got Xeloda [capecitabine] and trastuzumab.

They either got tucatinib with that, it was placebo controlled, or they received a placebo. What they saw in that study were impressive findings looking at comparing what we achieved with the addition of tucatinib in this setting. Probably the highest level thing, 1 of the 2 things that are the most worthwhile end points to retain from this study, is that there was an overall survival benefit again. It was not negligible. It was about a 4.5-month prolongation overall survival for the group of women who got the tucatinib on top of the capecitabine and the trastuzumab in the setting.

The other thing that was really interesting is this trial specifically allowed patients with brain metastases. It actually required patients to have an MRI [magnetic resonance imaging] prior to going on study. Just under half of the patients had brain metastases, and that group got benefit from the addition of tucatinib. I think what's important to note is it's not just the group of patients who had brain metastases who derived benefit. It was both patients who had brain metastases as well as patients who did not have brain metastases. The progression-free survival [PFS] benefit was very similar in both of those groups.

If you looked at PFS overall there was a benefit. If you looked at PFS in patients who had brain metastases and who didn't, there was a very similar degree of benefit, and the same thing for overall survival. I think this is something that we can consider for our patients who have brain metastases, but I think it's a very definitive type of trial in a group of patients where we would really be considering this agent today in the United States in terms of how we practice.

 It’s a really fascinating study, and of course it was great to have the data published at the same time and see the reduced rate. Although people get diarrhea, the rate is much less than others. We saw data at ASCO [American Society for Clinical Society] this last year, in 2019, about the NALA trial and also a trial done in China with pyrotinib and capecitabine, other oral tyrosine kinase inhibitors. Priyanka, can you tell us a little bit about that?

The NALA trial was also a third-line trial in patients who had received prior 2 lines of therapy and randomized between capecitabine and lapatinib versus neratinib plus capecitabine. Unlike the HER2CLIMB trial, where 100% of patients had received what we would consider traditional first-line and second-line treatment, pertuzumab in first-line and trastuzumab emtansine second-line,in NALA I think it was about 50% who had received trastuzumab emtansine in second-line and much less first-line pertuzumab. There was no difference in median PFS, but per the trial design, which allowed them to do analysis looking at means, if the separation of curves was a little bit later, which is what was seen in the NALA trial, they noted a difference of 2 months in the mean PFS.

Also it was noted that a smaller proportion of patients needed intervention for CNS [central nervous system] disease on the neratinib arm compared to lapatinib arm. They did not put any data in terms of responses in the brain per se, and actually neratinib plus capecitabine was approved last month by the FDA to be used after failure of 2 prior lines of HER2-targeted therapy. The approval doesn't specify which types of prior lines of HER2 therapy needed to be delivered in the first-line and second-line setting. One of the toxicities of this combination is diarrhea, and we've seen that with other trials, with neratinib, especially when you combine with capecitabine.

In spite of anti-diarrhea prophylaxis, patients had significant grade 3 diarrhea; I think 20% to 25% of patients in the neratinib arm had grade 3 diarrhea. This has been one the limiting factors in terms of utilization of this drug, which has been available to us to use in the adjuvant setting. The other trial with pyrotinib came out of China. During the time this trial was conducted, China did not have approval of pertuzumab and just barely got approval of trastuzumab emtansine.

Even though this was a third-line trial, patients hadn't received pertuzumab and trastuzumab emtansine. The addition of pyrotinib to capecitabine did show improvement in progression-free survival, so from that standpoint the trial met its primary end point. The median PFS was prolonged from 4 months versus 11 months in this trial. Again, the caveat was that the competitor arm wouldn't necessarily be considered standard in regions where we have pertuzumab and trastuzumab emtansine available.

 I think this is really interesting because the pyrotinib trial has this huge PFS benefit, more than what we've seen with other oral tyrosine kinase inhibitors, and also a benefit in patients with brain metastases. The key with that trial is that some of the patients hadn't actually ever received trastuzumab so, they were a relatively treatment naïve group of patients who didn't have access to other therapies. Regardless, having additional agents available to patients who don't have access to other therapies in other countries where the drugs are effective is a great thing.

I don't know that pyrotinib will really have a role in what we are looking at right now.

HER2CLIMB and NALA Trials: R/R HER2+ mBC

A review of the phase III SOPHIA trial on margetuximab vs trastuzumab for the treatment of relapsed/refractory HER2+ metastatic breast cancer.

 I wanted to mention the other phase III trial that was presented at ASCO [the American Society of Clinical Oncology annual meeting] 2019 and also updated at the San Antonio Breast Cancer Symposium. This was the SOPHIA study, and it looked at a novel HER2 [human epidermal growth factor receptor 2]-targeted antibody with chemotherapy versus trastuzumab and chemotherapy in patients who had received prior pertuzumab. About 90% of these patients had received prior T-DM1 [trastuzumab emtansine]. Margetuximab is an Fc engineered antibody. There are different IgG [immunoglobulin G] Fc gamma receptors, and the Fc portion of the antibody binds to the receptor.

Some have more affinity for the antibody, some have lower affinity for the antibody. This particular engineering was designed to try to increase the binding for the low affinity activating Fc gamma receptor, which is CD16a, and decrease affinity for the inhibitory Fc gamma receptor. It's actually interesting because it’s an engineering of an antibody to try to activate the immune response, and that's been shown in preclinical studies. SOPHIA randomized these patients who had heavily pretreated disease to receive margetuximab or trastuzumab with a chemotherapy. The central blinded analysis progression-free survival was significantly longer, but the difference was only 0.9 months with a 

You meet an end point, but the difference is very narrow in terms of the clinical impact. We actually had updated the investigator assessed progression-free survival as of September of 2019, and in that, the difference was a little broader with an absolute difference that was more than 1 month. But it's still pretty narrow. The hazard ratio was a little bit better. The drug is very well tolerated, but the greatest interest in margetuximab was looking to see what happened in patients who had this low affinity IgG Fc gamma CD16a genotype, which is called F, the allele F. Either you would be homozygous or heterozygous for F. If they looked at this group of patients for progression-free survival and overall survival, it looked like you really widened the gap.

In other words, the improvement of margetuximab appeared to be primarily in this group of patients who have a low affinity F genotype. They are very interesting data, but difficult to understand exactly how it's going to play a role in terms of all of these other therapies. It still may play a role in the later-line setting. Then there is a lot of interest in setting the antibody specifically in patients who have the F allele, which is actually a large majority of patients, so it’ll be interesting.

One of the things that you're alluding to there is up front, looking at the patients who are less likely to respond to trastuzumab because their tumor has the allele that makes them less sensitive to that therapy. So instead of trying in the later line setting like the SOPHIA trial was, perhaps moving this up earlier, we might actually see greater benefits.

That is a proposed trial, actually, from Dana-Farber Cancer Institute by Ian E. Krop, MD, PhD, to look specifically at patients who have the F allele and randomize them to margetuximab or trastuzumab because we’ve certainly learned that margetuximab was as good. In a phase I trial some patients stayed on margetuximab for over 4 years, and they were heavily pretreated with refractory disease. I think it's worthwhile pursuing and looking more to try to understand where to place this in our armamentarium for HER2-targeted therapies, and of course we're still waiting for the final overall survival analysis from that trial as well.

SOPHIA Trial in R/R HER2+ mBC

A discussion about which agent to choose and in which setting for the management of R/R HER2+ metastatic breast cancer, including what drugs payers will defer to for reimbursement.

 One of the questions is the order of therapy and how we would choose different treatment options. Let’s briefly hear from you how you have put these in. Assume that tucatinib and margetuximab are approved, and we've given pertuzumab in the adjuvant or neoadjuvant setting, or somebody's in the de novo metastatic setting and they've gotten both pertuzumab and T-DM1 [trastuzumab emtansine]. Of course there are patients who will have received both pertuzumab and trastuzumab emtansine in the adjuvant setting now who will get to the metastatic setting. How would you choose 1 agent to use and what sequence? Then we'll hear how the payers actually look at that. Tiffany, do you want to briefly comment on that? Why would you choose which agent in which setting?

From Claudine’s presentation and from what I've been thinking about, we should be looking at the tucatinib data. Obviously, we'll need to see what that label looks like and what line of therapy we'd be looking at. But the fact that there is benefit to using tucatinib and it's an overall survival benefit not limited to patients with brain metastases—there could be benefit for anybody with that prior exposure HER2-positive disease at least in the third-line setting—I lean toward the tucatinib. Although, we have to remember that’s in combination with capecitabine, in combination with trastuzumab. Despite the fact that the DS-8201, trastuzumab deruxtecan, has such a beautiful waterfall plot, it is really a single-arm, nonrandomized presentation.

I think there's great activity there, but that is balanced with the ILD [interstitial lung disease] concerns. So with the available drug before me, recognizing many of these women will have seen pertuzumab and likely trastuzumab emtansine, I lean a bit toward that overall survival advantage from tucatinib. It would be wonderful to see a time when perhaps tucatinib is able to minimize the development of brain metastases even more so than being able to treat it once they're present.

 That's a good point, and I think that was very clever of them to add trastuzumab to the combination, which my guess is it really made a difference in their ability to see large differences in overall survival with an antibody component. Priyanka, how about you? How would you use these and in what order?

 Assuming that we're making a choice in third-line setting and we have all the drugs available, another factor that would come into play would be oral versus intravenous administration, multiple drugs versus single agent, and previous risk of interstitial lung disease with other drugs in the past. That would play into the decision-making; presence of brain metastases even if they're controlled. But having a phase 3 trial that shows a survival advantage obviously makes a difference in that choice. The other factor is the DESTINY-Breast01 trial included patients that were heavily pretreated, so I would feel comfortable using the tucatinib combination in third-line setting and save trastuzumab deruxtecan for later lines of therapy since the trial population included heavily pretreated patients.

I do. I feel exactly the same as my esteemed colleagues here. And I guess the only thing that I would add now is occasionally we have those patients who for reasons that we don't understand have blown through all of these other treatments very rapidly. I think one of the things that really impressed me with the DESTINY-Breast01 trial was the responses that were seen in patients who’d had a lot of prior treatments and the rapid response.

In those patients where we feel we need to slam the brakes on and we don't have much time, that might be a patient population where I might move this drug up. But otherwise I think based on the phase 3 data, the survival, the benefit with brain metastases or not, I would use tucatinib as my third-line drug for the vast majority of patients.

 There are always those patients who don't tolerate capecitabine for a variety of genomic reasons. John, now we're coming back to the same area again about the oral therapy versus IV [intravenous]. This is in regard to share of cost and how we decide. If there are a lot of different treatment options available, where does the insurer fall in in terms of trying to help us and also decide what's going to be reimbursed?

 First of all I'd say, especially in these late-line therapies, that the number of patients who are going to receive these therapies is relatively small in comparison to first-line therapies. Certainly, we'd prefer regimens that are replacement therapies versus add-on therapies, so instead of a 3 drug versus 2 drug, a 2 drug versus 2 drug. I was particularly interested in the HER2CLIMB study with tucatinib. This is very reminiscent of the non–small-cell lung cancer space where osimertinib, which was a second- and third-generation TKI [tyrosine kinase inhibitor] for patients who had 

 mutations, not only treated brain metastases but also reduced the likelihood of the development of brain metastases and was subsequently approved as a first-line therapy. 

We'll see if tucatinib makes that same progression from third-line to earlier-line therapies. Interestingly and just by way of analogy, in our OCM [Oncology Care Model] practices when providers are presented with that data and shown the prices of osimertinib versus erlotinib, they said, “This drug is so much better that we're going to use this even though it's costlier.” But another example is in a 

 mutation in non–small-cell lung cancer when comparing crizotinib and ceritinib, they said, “There is a cost difference, but we don't think there is an outcome difference, so we’re going to use the lower cost therapy.”

That’s how providers are reacting to some of these data. To go back to your question, as long as it's being used consistently with the FDA label and the NCCN [National Comprehensive Cancer Network] guidelines, there is going to be access to these therapies especially given the fact that most of these drugs, because they're new, don't have long-standing data. So we're going to defer to the oncologists in deciding which ones to use.

Frankly, we can't even pronounce the names of most of these drugs, let alone decide where to use them, so I think we’re going to defer to the NCCN guidelines. Unlike most guidelines, the NCCN guidelines are kept very up to date.

 This has been an interesting discussion. I think it highlighted some of the tremendous advances that we’ve seen in HER2-positive disease. And of course we're all very interested to see how this moves into the early stage setting, and how some of the very active drugs move earlier in the course of therapy to try to reproduce what we saw when we first started using trastuzumab, where we were curing patients with incurable disease.

That still remains an expansion area. And of course trastuzumab deruxtecan is being tested in patients who have a previously undefined subset of disease or HER2-low, IHC [immunohistochemistry] 1+ and IHC 2+, mainly ER [estrogen receptor]-positive but a small subset of triple-negative disease, in an ongoing randomized phase 3 trial. That's going to also provide us with a lot of interesting data in another group of patients all together for the first time.

Sequencing of Therapy in R/R HER2+ mBC

A review of the IMpassion130 trial data on atezolizumab for the treatment of triple-negative breast cancer and the impact on PFS and OS for patients with PD-L1+ tumors.

 With that general idea of trying to pick out treatments based on what type of disease somebody has, so HER2-low disease, how are we personalizing medication for patients? Of course 1 area where we really want to focus on personalizing medication—not that we don't want to do it for everybody—is triple-negative breast cancer. We've been hit by the poor options available to patients in the metastatic setting and for patients who don't have a great response in the early stage setting.

We have such limited options, and we have a very clear idea of what the outcome is for the majority of patients. We were excited to see data from the IMpassion130 trial with a checkpoint inhibitor, atezolizumab, added to nab-paclitaxel, but this only benefits a relatively small group of patients in the metastatic triple-negative setting. Tiffany, do you want to tell us a little bit about the IMpassion130 trial and what patients might benefit from atezolizumab?

Sure, I'm happy to. I was thinking back that it looks like we're right around probably the 1-year anniversary of when atezolizumab was FDA approved for this very indication based on IMpassion130. If you remember, that’s a study of about 900 women with triple-negative breast cancer, or metastatic disease, or locally advanced unresectable, and it was a first-line trial for these patients. The backbone was chemotherapy of nab-paclitaxel with a randomization to atezolizumab or a placebo.

If you recall, that primary end point for the study was both PFS [progression-free survival] and OS [overall survival], and what we saw in results was interesting. For the intention-to-treat population there was an improvement in progression-free survival, but what was most compelling was seeing the subset of patients with PD-L1–positive tumors. We’ll come back to how that PD-L1 was tested, but in that subset of patients who were PD-L1 positive, the difference in progression-free survival was more substantial, about an absolute difference of say 2 to 3 months, and about a 40% or so improvement in PFS.

When you move onto looking at the overall survival data, this is where things became a little bit more exciting. In the intention-to-treat population there wasn't a statistically significant difference in OS. However, just comparing in the subset of patients with PD-L1–positive disease, the group that received atezolizumab had about a 40% improvement in overall survival, with an absolute difference on the most recent analysis of almost 7 months. While that didn't have the power for a formal statistical analysis, it looked compelling and of interest for these patients.

Talking a bit about the PD-L1–positive definition is important. In IMpassion130, the assay used to establish PD-L1 positivity was the Ventana SP142 assay, and the definition of positivity was based on the percentage of immune cells positive. That is in contrast to PD-L1 testing in some of the other solid tumors where different assays were used, and different scores were used, such as combined positive scores [CPS] with assays such as the SP263 or 22C3. Hope, I know at ESMO [the European Society for Medical Oncology annual meeting] you performed an ad hoc analysis from the IMpassion130 data looking at other PD-L1–positive assays. In your data, from what was presented, the proportion of patients on IMpassion130 who had PD-L1 positivity using an SP142 assay was about 40% of those 900 patients.

In the analysis that you and your colleagues reported using SP263, another antibody and assay, there was about 75% PD-L1 positivity by that definition. I think with the 22C3 assay this was about 60% or so, maybe even more. Even higher than that, maybe 80% or so, were considered positive. There was concordance between SP142 and these other 2 antibodies, but only about 40% of overlap. When we try to define which patients are more likely to respond to the addition of atezolizumab, my preference based on the data I've seen is to stick with the SP142 assay as the predictive biomarker, if you will. I’m curious to hear what others think, and they are your data, Hope, so please elaborate on that if you think that there is other important biomarker nuance that we should be aware of.

 You did a great job of discussing that, and the information was in the biomarker evaluable subpopulation. We've all been very interested in the press release in February of this year from KEYNOTE-355 that suggested in an important population, patients who relapsed 6 months or greater after adjuvant or neoadjuvant therapy versus 12 months, that those patients benefited from the addition of pembrolizumab to gem [gemcitabine], carbo [carboplatin], paclitaxel, nab-paclitaxel as the options, but only if they had a CPS score of 10 or greater.

As you were talking about, when we were looking at this in the ESMO analysis, CPS scoring is supposed to be positive at 1 or greater, and that was this huge population compared to SP142. It is interesting. It does seem like you have to have more positivity, and CPS looks at tumor and ICs [immune cells] and looks at a ratio. Perhaps in the metastatic setting you really need more of the PD-L1 expression on immune cells, and you're seeing that with this higher CPS score. It's hard to know. We haven't seen the data presented yet from KEYNOTE-355 but will this year, so that'll be helpful.

It is a shame in some in some ways that it's only 41% in IMpassion130. People have found different percentages looking at their populations of patients, but it's clearly not everybody, and we still want to improve outcome for those patients.

IMpassion130 Trial Data on PD-L1+ Tumors in TNBC

The use of PARP inhibitors and I/O therapy is examined for the treatment of triple-negative breast cancer, and the MEDIOLA and SWOG S1416 trials are reviewed.

 Now that we have PARP inhibitors approved for patients who have 

-mutated metastatic disease, there’s been a lot of interest in combinations of therapy with PARP inhibitors and checkpoint inhibitors. Priyanka, do you want to comment a little about the hypothesis behind combining these agents?

 As you said, for PARP inhibitors, we’ve had them available to treat our patients with HER2-negative metastatic breast cancer—that is, in the setting of germline 

2 mutation. There are robust preclinical data to suggest combining a PARP inhibitor with a checkpoint inhibitor might help improve on the patient population that’s eligible for PARP inhibition, beyond those that carry a germline mutation. Several postulated mechanisms have been proposed perhaps by increasing antigen load and increasing PD-L1 expression. Maybe having a PARP inhibitor on decreases the capability to repair damaged DNA. That damaged DNA might induce some local lymphocyte infiltration, some type of innate immunity, so several mechanisms. Based on that, there are a couple of trials that looked at the combination.

The first cohort of the MEDIOLA trial looked at patients with a germline 

 mutation and combined a PARP inhibitor olaparib with durvalumab. You’ve seen several presentations on that over a period of time. The last 1 I think was in San Antonio Breast Cancer Symposium in 2019. MEDIOLA included patients who were in the first line and beyond settings. It reported impressive response rates, about 70%. When you looked at the patients who were first line and second line, it was a little bit lower as you went further along. But we’ve seen that individually for both PARP inhibitors and checkpoint inhibitors, the further along we get for a metastatic timeline, the decreased the response rates. Again, this is a single-arm study. I understand that they have an expansion cohort ongoing, but what would be needed would be a randomized trial.

 Yes, it is interesting. There is a randomized phase 3 trial called KEYLYNK-009, which is looking at patients in the first-line triple-negative setting regardless of 

 mutation or HRD [homologous recombination deficiency], so not stratifying based on HRD. Patients receive gem-carbo-pembro [gemcitabine, carboplatin, pembrolizumab] and then are randomized to either continue with that or to receive olaparib and pembro [pembrolizumab] as a maintenance approach based on some of this idea that you might upregulate the immune response. Whether that will be changed based on the data from KEYNOTE-355 remains to be seen.

It will be interesting to understand that based on when we finally see that data presented in a setting. Another question that comes up is, how do you decide whether to start with the I/O [immuno-oncology] or a PARP inhibitor? If you have a patient who has PD-L1-positive disease, who has metastatic triple-negative breast cancer, what do you choose? Claudine, what do you choose in that setting?

Expanding Treatment Options for Metastatic Breast Cancer