This has been a lovely discussion. Really great talking to you. We covered the waterfront on a lot of these topics. Let’s go around—if you have 1 final thought you’d like to leave folks with. Neil, I’ll start with you. Anything you’d like to leave us with?

We’ve just brushed the surface in terms of where the field is going for hormone receptor–positive advanced disease. What’s most exciting is biologically speaking, we’ve all known for a long time that ER [estrogen receptor]–positive or hormone receptor–positive disease is a basket. It’s like triple-negative, perhaps a little more narrow, but it comprises several molecular subtypes. The challenge was translating that understanding into the clinic and acting upon it. We’re starting to do that, with not only next-generation sequencing but also understanding resistance mechanisms. Understanding how just watching the natural history can translate into categorizing the molecular subtype. Most importantly, having drugs, some of which are already available and many of which are coming down the pipeline, that we can match to our better understanding of the molecular biology of the breast cancer that we’re dealing with. What we’re seeing is a shift away from this sort of broad-basket treatment to a very precise approach to treating the subtypes of hormone receptor–positive breast cancer.

So true. You see change, but there’s a lot more ahead. Hopefully, in our lifetimes we’ll see it all sorted out. How about you, Sarah?

The body of literature surrounding ribociclib has been interesting lately. I implore folks to take a look at those data before reflexing to prescribing palbociclib in the first line. We don’t have head-to-head trials, but we have a compound that, if offered in the first line, is leading to a median survival of over 5 years, and that survival benefit seems to consistently get better as the years go on. Also, CDK4/6 in the first line improves quality of life, prolongs survival, and prolongs time to chemotherapy. All considerations that CDKs should be used in the first line. The body of literature surrounding ribociclib is looking quite promising.

Thanks, Sarah. How about you, Gabe? Have the last word for us.

The first paper I wrote, in 1974, was about metastatic breast cancer. It showed a median survival of about 24 months. At that time, we didn’t know about subsets. In the intervening years, we haven’t shown, in any individual clinical trial, a prolongation of survival in the hormone receptor–positive population until we got to the CDK4/6 inhibitors. Yet the control arm of the MONALEESA-2 trial shows a median survival of 51 months, so we’ve made progress. We’ve made significant progress in those 3 to 3½ decades. Now we’ve broken the ceiling of 5 years. What we’ve discussed is that this is the first step, the first of many exciting paths we can take. I’m confident we’ll continue to make great progress in this, as in other types of breast cancer.

Thank you so much. Thanks for your thoughts and for participating. It’s really great talking with you. I want to thank our viewing audience as well for participating. I hope this has been informative and interesting for you and will be helpful in your practice. Bye-bye.

Videos

Final takeaways from a discussion on best practices treating HR+/HER2- metastatic breast cancer with CDK4/6 inhibitors and PI3K therapies based on data presented at ESMO 2021.

Treatment Advances in HR+/HER2- MBC

Sarah, what are some of the other agents being looked at to help address some of the mechanisms of resistance that may be driving progression on CDK4/6? What are some of the other hypotheses going on?

Endocrine therapy in CDK4/6 inhibitor resistance has been studied extensively at this point. We have the circulating tumor DNA data from PALOMA-3. Those data showed us that emergence of 

 mutations that lead to functional loss of RB1 may be 1 of the areas implicated in resistance. We’re also seeing some upregulation of CDK2, some upregulation of CDK7. There are some clinical trials with new CDK inhibitors that target CDK2, specifically target CDK7. Those are ongoing. A crowded space right now is the oral SERD [selective estrogen receptor degrader], SERM [selective estrogen receptor modulators], SERCA [sarcoplasmic reticulum calcium-ATPase] area. 

 mutations are implicated in endocrine resistance in about 40% of patients. Unlike PI3-kinase mutations, these mutations do evolve over time in patients who are on aromatase inhibitors [AIs] and patients on fulvestrant and CDK4/6 inhibitors.

Fulvestrant, we know from retrospective series, seems to work better than aromatase inhibitors for 

 mutations. However, its single-agent efficacy in 

-mutant breast cancer is still not great. There are 

 mutations, like Y537S, that seem to be resistant to 

 mutations. Preclinical data are showing that oral SERDs and SERMs, like lasofoxifene, seem to have much better efficacy in 

-mutant breast cancer than fulvestrant and then aromatase inhibitors. There are many oral SERDs out there. Elacestrant, amcenestrant, giredestrant are some of the ones in later-phase clinical trials. We saw the first neoadjuvant study that Sara Hurvitz presented with giredestrant vs AI in a neoadjuvant setting, and it seemed to lead to fairly robust cell cycle arrest, which was exciting. There are many ongoing phase 3 trials going on as well.

Thanks a lot. The oral SERDs really are interesting, aren’t they? The SERCAs and the SERMs for the 

-mutant patients in particular. It’d be nice to have a better single-agent endocrine therapy to offer patients post-CDK4/6. We can still do it, but as you said, we have limited effectiveness with fulvestrant post–CDK4/6. We saw that in VERONICA, the failed trial of venetoclax with fulvestrant post–CDK4/6. It was just shy of 3 months, or right around 3 months, median PFS [progression-free survival] with fulvestrant as a single agent. We need some improvement, clearly. Hopefully the oral SERDs, SERCAs, and SERMs will do that for patients. Gabe, what other agents, what other novel strategies, are hopefully going to come into the HR [hormone receptor]–positive, HER2 [human epidermal growth factor receptor 2]–negative metastatic space to make the next big advances for patients?

These are very exciting times and arguably the most exciting times since I’ve been in oncology, which is more than a few weeks. First, an area we haven’t mentioned is that a number of other CDK inhibitors are under development: CDK2, CDK7, CDK9, CDK12. Some of them are in clinical trials. Some of them were developed to address CDK4/6 resistance. There’s hope that some of them will turn out to be of great interest.

We haven’t touched on the area of DNA repair. Of course, some of the hormone receptor–positive breast cancers have 

 mutations. We have the entire field of PARP inhibitors making progress finally. You were 1 of the early investigators involved in this field, so you have followed that very closely. And there are some exciting things happening. The OLYMPIA trial has shown some advantage in the metastatic setting, and recently it was reported to show that olaparib prolonged relapse-free survival in the primary 

-mutated population. That’s very exciting. In the wake of olaparib, there are, of course, other PARP inhibitors. Talazoparib is arguably 1 of the more exciting ones. There are some newer ones, like pamiparib—it’s reported to be about 16-fold more potent than olaparib.

We’ll have to see how this field evolves, but it’s very exciting. The area that’s relatively novel, even though it’s relatively very old, is the area of androgen receptor [AR] inhibition. We’ve ignored that to a large extent because we didn’t quite understand what androgens and androgen receptors were supposed to do. But there’s some emerging understanding of that. The Breast Cancer Research Foundation is funding a multiproject program to address this issue, to understand the biology of androgen receptor, and to understand the activity of androgen receptor–active agents. Many of the early clinical trials are based on enzalutamide, but of course there are other AR inhibitors that are of great interest. This is relevant not only to ER+, HER2- breast cancer but also to the triple-negative population.

Finally, the most exciting part for me, and something that was underlined at this ESMO [European Society for Medical Oncology Congress] presentation, is the area of antibody-drug conjugates [ADCs]. While many of the antibody-drug conjugates focus on the HER2+ population and, to a lesser extent, the triple-negative population, some are clearly focused on the HR+, HER2- breast cancer. Sacituzumab govitecan is 1. We already have data that suggest that about a third of the patients with HR+ breast cancer benefit from this drug. Then there’s the low HER2, ER+ population where the trastuzumab deruxtecan data suggest there might be extension of the activity of that ADC beyond the HER2+ data. There are many more, but there’s not enough time to talk about them. This is a very exciting field because the technology gives us the possibility of developing many more of these, having identified many relevant and worthwhile targets.

As soon as we get great data in the metastatic setting, we get them right into the curative setting. There’s a superhighway from metastatic to the curative. It’s really good. We have to pat ourselves on the back about how quickly and courageously we bring things from the metastatic into the curative setting.

A panel of breast oncologists highlight exciting treatment strategies being explored in clinical trials to help address treatment limitations in HR+/HER2- metastatic breast cancer.

Novel Agents Under Study for HR+/HER2- MBC

Let’s turn to how we sequence therapies in the metastatic setting. We said we’re almost always starting with the CDK4/6 inhibitor. That’s the easy part, but then it comes after that. With the 

 mutation, in an appropriate patient who doesn’t have uncontrolled diabetes, we’re probably going to, when we can, alpelisib. Sometimes patients need chemotherapy. It’s a minority, but we’re utilizing that. There are a little data, not much, for CDK that’s getting traction in the community, although we’re light on the data. Yet some folks are sequencing the CDKs or coming back to 1 later on.

Let me start with you, Neil, if you don’t mind. Generally speaking, what’s the big picture? How do you think about sequencing the various subsets of patients after CDK?

I agree that sequencing therapy after exposure to CDK4/6 inhibitor is certainly an evolving landscape. We do have some data to help guide us. A lot of those data are extrapolated, but we could look back a couple of years ago to the MAINTAIN trial that was presented at ASCO [American Society of Clinical Oncology Annual Meeting]. That was a small study that was a little over 50 patients or so. That was our first clue that perhaps there’s activity of continuing a CDK4/6 inhibitor after prior exposure.

They used abemaciclib specifically in the post-CDK4/6 exposure setting. I know that a lot of my colleagues in the community are doing this. It’s a patient-by-patient decision. I’ve thought about and have done this in patients who perhaps have a minor progression of disease and aren’t dealing with large-volume disease, or they have a mutational profile. The data are evolving and mutational profile may not be consistent with known resistance mutations or mechanisms. But in terms of strong evidence, we’re not there.

In the post CDK4/6 space, moving on to alpelisib in someone who has a PI3 kinase mutation is warranted now that we have some data from BYLieve. But it’s an evolving space. For those who don’t have a PI3 kinase mutation, that’s where we’re struggling with that decision-making. Everolimus and exemestane have been extrapolated from BOLERO-2 as a potential use, but biologically, mechanistically speaking, this may not be an efficacious approach. We do have some data from the EVERMET study, where the use of everolimus mTOR inhibition after prior CDK4/6 inhibition wasn’t particularly effective. I’ve done this occasionally in patients with minor progression of disease, but I’m doing it less and reaching for a clinical trial in this space.

Thank you, Neil. Sarah, how do you think through what to do after CDK4/6 progression?

That’s where our next-generation sequencing comes in handy. If the patient has a PI3 kinase mutation and they’re fit, I’m reaching for alpelisib with an endocrine therapy backbone. If they don’t have a PI3 kinase mutation, and I don’t have a clinical trial for them to go on, if they’re fit, I still reach for everolimus. I haven’t reviewed the data that Neil just spoke of but, we have data with everolimus with the fulvestrant backbone. We have data with everolimus with the tamoxifen backbone. I’ve had patients who have meaningful clinical benefit on everolimus combinations after CDK4/6. So I’m looking for a clinical trial, looking at their next-generation sequencing, and everolimus combination.

Do you ever use or go back to a second CDK? Have you used palbociclib or ribociclib? Would you use abemaciclib?

We were just talking about that today. The most data that we have is mostly retrospective. There are ongoing prospective studies. But the data that we have suggests that abemaciclib might be fairly effective after progression on palbociclib or ribociclib. In my practice in the last week, I had a patient who very clearly had developed 2 new bone metastases but no visceral disease. We changed the endocrine therapy backbone, and we changed the palbociclib to abemaciclib to see if we could get some longer benefit out of his CDK4/6 combination. I’ve done that, and data are evolving in certain circumstances.

I was part of that retrospective analysis. It was a case series from 4 or 5 institutions. It’s data light, no question. The clinical benefit rate was about 36%. Some of the patients had quite a bit of time between the CDKs. Mostly it was palbociclib first line and then later on abemaciclib, or abemaciclib immediately thereafter. But a subset appears to benefit, and I’ve seen that in my practice.

Gabe, how do you approach the choices we have after CDK4/6?

This is a relatively data-free zone, so it’s a rapidly evolving area. My first choice—I’m fortunate enough to live in a situation where I have several clinical trials to choose from at all times, so that’s my go-to. It’s also a complex discussion with the patient because this is 1 area where I might choose endocrine therapy alone. I might choose everolimus and exemestane or some other endocrine backbone. Of course, in the PI3 kinase mutant group, I will also discuss alpelisib. Different patients will make different choices in this situation. The standard algorithm would be mutant alpelisib, non-mutant everolimus, then subsequent treatment. But it’s more complicated than that. Many patients fall out because of comorbid conditions, many patients fall out because the benefit you offer them isn’t attractive enough for them. It’s a complex but important discussion with the patient because these drugs are clearly associated with greater toxicity, and the patient needs to understand that. He needs to understand that there will be more work required on her or his part and on my part to make this work safely and well.

That’s a good groundwork with pluses and minuses. It’s going to be a little more effort on our part, but it’s a good option. It’s not chemotherapy. I’ll tell you my experience with everolimus as I’m progressing on CDK. For the bone-only patients and those with ER-dependent sites of disease, I get benefit. The bone-only patients will go on and get 6, 9 months, sometimes a year out of everolimus. If they’d benefit more than 6 months, then I can come in with single-agent tamoxifen. They escaped through the estrogen receptor. But I’ve found conversely that, if patients are progressing in their liver on CDK4/6, I’ve not had benefit with everolimus. I wonder if the EVERMET was skewed toward not showing benefit because there were some liver patients in there. This is just my experience. If I pick the bone-only patients, or the pleural disease, the pulmonary disease, or the lymph node disease, I get good results with everolimus if they don’t have a 

 mutation. We’re figuring it out until we get more data.

Variables that impact how breast oncologists should sequence therapies when managing patients with HR+/HER2- metastatic breast cancer.

Sequencing Therapy in HR+/HER2- MBC

I’d love to hear from everybody what your personal experience has been with alpelisib. We also want to touch on toxicity so we can weave together a little bit of your personal experience efficacy-wise—which patients, where you’ve seen things not work and work, toxicity. Gabe, you could start? What have you seen so far?

 Clearly, the PI3 kinase inhibitors and alpelisib in particular have more adverse events associated with them than the CDK4/6 inhibitors or endocrine therapy alone. Virtually all patients have some adverse events, and about three-quarters of them have hyperglycemia, which is arguably the most common adverse event. Unfortunately, this requires attention because you need to monitor this carefully from the beginning. You need to be proactive in controlling hyperglycemia. Many of us oncologists have fallen a little away from our endocrine days, but we need to recover those skills.

The second is diarrhea. Diarrhea is fairly common, including some grade 3 diarrhea. The same way we deal with diarrhea with abemaciclib and ribociclib, we need to deal with this proactively. Rash is another important adverse effect associated with alpelisib. It can be maculopapular. It can be acne form. Some of it is grade 3 or 4. It can be pruritic. It can be painful. It has to be addressed, both symptomatically and to reduce the severity of it. Otherwise, your patients will quit. Then there are the usual adverse effects of fatigue, asthenia, loss of appetite, and some weight loss.

This drug is in a different category from the CDK4/6 inhibitors. It’s closer to everolimus, which also has its own safety issues, although I find that alpelisib is somewhat more toxic than everolimus. It’s a good drug, but it’s a drug that you need to use with a very aggressive supportive care plan, an education plan, for your patient. If you do that, most of them will take the drug and many will benefit from it. In the SOLAR-1 trial, 25% of patients discontinued prematurely alpelisib. That’s an important figure to keep in mind.

Now that we know what the adverse effects are and the probability of adverse effects and how to deal with them—and there are very clear guidelines as to how to deal with them—we can make alpelisib a tolerable drug, an effective drug. As you said at the beginning, the drug that you don’t take can’t help you.

Thanks, Gabe. Thanks for setting the stage for us. How about you, Sarah? What’s your experience been? Any caveats on the toxicity management?

I’ve become more familiar and more comfortable with using alpelisib in the clinic. We’re lucky enough to have an excellent clinical pharmacist who helps us manage the toxicity. A week prior to starting any patient on alpelisib, we start everyone on 500 mg of metformin XR regardless of their hemoglobin A1C. We can peel that off if they don’t have issues with their hyperglycemia, but we have a fairly hardy population in North Carolina. We’ve had success doing that, so we start everyone on metformin XR a week before.

That’s being looked at in clinical trials. We also have 2 trials here [at Duke University School of Medicine] in patients on alpelisib with hyperglycemia resistant to metformin, looking at glucagon inhibitor and a GLP1 analog. There’s a lot going on in that space. We also start patients on Zyrtec [cetirizine] 7 days prior to starting alpelisib. I start them on Zyrtec twice a day; most of my colleagues start them on Zyrtec daily. Seven days prior to starting, we’re starting metformin and Zyrtec on all patients. We’re monitoring them based on guidelines with clinical pharmacy and nursing. I’ve had success that way. It is a good drug if you can manage the toxicity.

I do just want to put 1 caveat [out there]. One of my biggest success stories as an oncologist is that I had a patient in visceral crisis with dual PI3 kinase mutations, with leukemia-like blood counts, and she’s now a year and a half into alpelisib-fulvestrant NED [no evidence of disease].

Packed marrow, lobular breast cancer, dual PI3 kinase mutations. I gave her chemotherapy for a little while, but she was having terrible toxicity. She turned it around with alpelisib and fulvestrant because of those. Data have shown that, preclinically, it looks like dual PI3 kinase mutations are explicitly sensitive to the drug.

Thanks. I love those stories because it’s a terrifying situation to be in for the patient and for us. How about you, Neil? What’s your experience been?

 I echo a lot of what’s been said. This is a drug that to patients is worth the effort that you put in. It does take some effort on the patient’s part. But as we’ve heard, it’s a very efficacious drug. One thing to remember is that the hyperglycemia is an on-target effect of PI3 kinase inhibition. This is expected, and this essentially is telling us that it’s working.

What we’ve seen in preclinical models paradoxically is that hyperglycemia and resultant hyperinsulinemia can provide a positive feedback loop that then reduces the antitumor efficacy of PI3 kinase inhibition. Some of these ongoing trials Sarah mentioned. We have a trial testing a ketogenic diet vs a low-carbohydrate diet vs an SGLT2 inhibitor. These are going to be important as we think about hyperglycemia management strategies. I’m optimistic that there are all these ongoing trials, so that in the near future we won’t have 1 optimal hyperglycemia management strategy. We’ll have multiple hyperglycemia strategies that the patient can choose from. The future of the use of this drug is optimistic.

With regard to the rash, it’s the same thing. This is something we can prophylax for. We also have a clinical trial testing and antieosinophilic agent. This underscoresthe point that the drug is ultimately a good drug and certainly a good enough drug. There’s a lot of interest and effort being put into managing these adverse effects—some of them on target—so that ultimately we can wield this powerful tool in the clinic in a way that’s also palatable to patients.

Breast oncologists share pearls regarding best practices treating patients with HR+/HER2- metastatic breast cancer with PI3K inhibitor therapy and mitigating treatment-related adverse events.

Managing Patients With HR+ MBC on PI3K Therapy

Up to half of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab (Herceptin)-based therapy will develop breast cancer brain metastases (BCBMs).

 Women with early-stage HER2- positive breast cancer treated in the adjuvant setting with trastuzumab-based therapies and/or ado-trastuzumab emtansine (T-DM1; Kadcyla) are at risk of developing BCBMs, which are often the only site of recurrence.

Isolated intracranial recurrence remains a clinical problem in the early stage and advanced setting and is likely due to poor central nervous system (CNS) penetrability of the best available HER2-targeted agents used in HER2-positive early-stage MBC (trastuzumab, pertuzumab [Perjeta], and T-DM1). First-line treatment of HER2-positive MBC includes taxane-based chemotherapy added to trastuzumab (T) and pertuzumab (P) for at least 6 cycles followed by TP alone (with the addition of endocrine therapy for patients with hormone receptor—positive disease).

In the third-line setting and beyond, we have several options with clear evidence of intracranial efficacy in the treatment of HER2-positive BCBMs (

). Our arsenal of highly effective, targeted agents including tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates for the treatment of HER2-positive MBC in the third line and beyond has expanded by more than 50% in the past year.

The combinations of neratinib (Nerlynx)/ capecitabine, tucatinib (Tukysa)/trastuzumab/ capecitabine, and fam-trastuzumab deruxtecan-nxki (Enhertu) have all shown impressive results in the past year for patients with HER2-positive BCBMs. Given these breakthroughs that have broadened the arsenal of treatment options for our patients, oncologists are now left with uncertainty about how to best sequence therapies for patients with HER2-positive BCBMs that will optimize both intracranial and extracranial progression-free survival (PFS), and OS, especially in the third-line setting and beyond. Choice of and sequencing of therapy between neratinib/ capecitabine; tucatinib/trastuzumab/capecitabine; and trastuzumab-deruxtecan generally depends on stable versus progressive nature of brain metastases, prior systemic treatments, state of extracranial disease status, and diverse toxicity profiles.

What to Do With First Intracranial Recurrence? 

Initial treatment for BCBMs in patients with HER2-positive breast cancer traditionally includes local therapies, such as neurosurgical resection and/or radiation therapy (stereotactic radiosurgery vs whole brain radiation). Resection is considered with a single, space-occupying brain metastasis when systemic disease is otherwise stable in patients with a good performance status. Stereotactic radiosurgery is the preferred radiation modality for a limited number of brain metastases. Current national guidelines recommend local therapy to the existing brain metastases and to continue on current HER2-targeted systemic therapy if extracranial disease is stable or absent.

For example, patients receiving first-line TP would receive upfront local therapy and then continue on TP if extracranial disease is stable or absent. Upon second and third intracranial recurrence, the treatment course is highly patient-specific, and there is no single consensus on local therapy or systemic treatment recommendations. Multidisciplinary evaluation is recommended.

Neratinib is an oral, irreversible, TKI with activity against HER1, HER2, and HER4. Neratinib has shown intracranial efficacy and blood—brain barrier penetration in preclinical models.

 The Translational Breast Cancer Research Consortium 022 trial (TBCRC 22; NCT01494662) is a phase 2, open label clinical trial of neratinib 240 mg once daily plus capecitabine 750 mg/mg

 A strength of this study is that patients have to have measurable and progressive HER2-positive BCBMs after local therapy.

Forty-nine patients enrolled in cohorts 3A/ lapatinib-naÏve (n = 37) and 3B/prior lapatinib (Tykerb) (n = 12; cohort closed for slow accrual). The CNS ORR was 49% in cohort 3A (95% CI, 32%-66%) and 33% in cohort 3B (95% CI, 10%-65%). Median PFS was 5.5 and 3.1 months in cohorts 3A and 3B, respectively. Of note, single-agent neratinib was studied with minimal efficacy.

The PFS was 8.8 months versus 6.6 months favoring N+C. Six- and 12-month PFS rates were 90.2% versus 87.5% and 72.5% versus 66.7% for N+C versus L+C, respectively (HR, 0.88; 95% CI, 0.72-1.07; 

 = .2086). OS was similar between arms. Clinical benefit rate (44.5% vs 35.6%; 

 = .0328) and duration of response (HR, 0.50; 95% CI 0.33-0.74; 

 = .0004) favored N+C. Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; 

 = .043) was delayed with N+C versus L+C. Importantly, there was a higher rate of grade 3 diarrhea with N+C versus L+C (24.4% vs 12.5%). Based on results of the phase 2 CONTROL study (NCT02400476), rates of grade 3 diarrhea can be more effectively managed with prophylactic loperamide and the addition of colestipol to improve gastrointestinal toxicity.

 The FDA approved neratinib for HER2-postitive MBC on February 26, 2020, for patients who have received at least 2 lines of anti-HER2—based regimens in the metastatic setting.

The accumulation of data suggests that neratinib and capecitabine together have intracranial efficacy in both stable and progressive brain metastases in patients who have received at least 2 prior HER2-directed regimens. Intracranial response is superior in a lapatinib-naÏve population but is still respectable in a lapatinib-treated population. Diarrheal prophylaxis is paramount for tolerability of this combination.

Tucatinib is an oral, potent, HER2-specific reversible TKI, demonstrating preclinical intracranial activity when used with standard doses of capecitabine and trastuzumab.

 In 2 phase 1b dose-escalation trials, tucatinib in combination with either trastuzumab/capecitabine, trastuzumab alone, or T-DM1 showed encouraging intracranial disease activity and control in patients with untreated, progressive, or stable HER2-positive metastases.

Furthermore, practice-changing results were recently reported for the phase 2, randomized, multicenter, international, HER2CLIMB trial (NCT02614794) in patients with HER2-positive MBC that were treated with the addition of tucatinib to trastuzumab and capecitabine versus trastuzumab, capecitabine, and placebo. All patients in this trial had received previous TP and T-DM1; therefore, the regimen was beyond second line. Patients with stable untreated, treated progressive, and stable treated brain metastases were well-represented, a novel inclusion criterion for a phase 2 clinical trial in MBC.

The addition of tucatinib improved both PFS and OS in the intention-to-treat population and the population with BCBMs. For the patients with brain metastases (47% of participants), the addition of tucatinib resulted in a 52% reduction in disease progression or risk of death (HR, 0.48; 95% CI, 0.34-0.69; 

 Among the 511 patients with measurable disease, the percentage who had a confirmed objective response was 40.6% (95% CI, 35.3%-46.0%) in the tucatinib-combination group and 22.8% (95% CI, 16.7%-29.8%) in the placebo-combination group (

The FDA approved tucatinib in combination with trastuzumab and capecitabine on April 17, 2020, for the treatment of patients with HER2-positive MBC, including patients with brain metastases who have received 1 or more prior anti-HER2 based regimens in the metastatic setting.

Tucatinib in combination with trastuzumab and capecitabine is an excellent option for women with HER2-positive BCBM after progression of pertuzumab, trastuzumab, and T-DM1. Sequencing of tucatinib prior to or in combination with T-DM1 is an area of active research. Our preference would be to enroll patients in the ongoing, phase 3 clinical trial of T-DM1 with or without tucatinib that allows patients with brain metastases (NCT03975647).

Trastuzumab deruxtecan is an antibodydrug conjugate including an anti-HER2 monoclonal antibody, a cleavable tetrapeptide-based linker, and a healthy payload of cytotoxic topoisomerase I inhibitor. It has a higher drug-to-antibody ratio than T-DM1 (approximately 8 vs 3-4, respectively).

DESTINY-Breast01 (NCT03248492) was a 2-part, open-label, single-group, multicenter study of trastuzumab deruxtecan in adults with pathologically documented HER2- positive, unresectable MBC who had received previous treatment with T-DM1. In total, 184 heavily pretreated patients (median 6 previous treatments) received trastuzumab deruxtecan 5.4 mg/kg. In the intention-totreat analysis, a response to therapy was reported in 112 patients (60.9%; 95% CI, 53.4%-68.0%). The median response duration was 14.8 months (95% CI, 13.8-16.9), and the median duration of PFS was 16.4 months (95% CI, 12.7-not reached).

This is an unprecedented finding in such a heavily pretreated population. Patients on this study could have stable brain metastases; untreated or symptomatic brain metastases was an exclusion criterion. In total, 24 patients with stable brain metastases were included and, among those, the median PFS was 18.1 months (95% CI, 6.7-18.1). Intracranial efficacy was not tracked formally. Pneumonitis is a serious adverse event observed with trastuzumab deruxtecan.

Further studies are needed to understand intracranial efficacy of this compound and optimal usage in patients with untreated or progressive brain metastases despite prior local therapy. Trastuzumab deruxtecan is an excellent option for patients with stable/treated brain metastases and no history of pneumonitis.

At the current time, the recommended first- and second-line treatment of patients with HER2-positive MBC and brain metastases remains the same as those without brain metastases: (1) taxane/ trastuzumab/pertuzumab (2) T-DM1. Pertuzumab added to trastuzumab and a taxane prolonged survival in patients who eventually went on to develop BCBM. T-DM1 improved overall survival in patients with baseline stable/treated brain metastases over capecitabine/lapatinib in the second-line setting in a subgroup analysis. Tucatinib added to trastuzumab and capecitabine was recently approved after 1 prior line of HER2-targeted therapy; however, all patients in the pivotal trial had received both prior TP and T-DM1.

Studies are ongoing and in the planning phases to determine the impact of moving tucatinib, in combination with HER2-targeted agents, earlier in the traditional treatment sequence, particularly for those with BCBM. We would encourage participation in these important clinical trials to gain evidencebased guidance.

Upon first intracranial progression, CNS-directed, local therapy is typically recommended for the majority of patients. Systemic therapy following local therapy has been shown to improve survival and is recommended pending the patient’s performance status.

 Treatment choice largely depends on the status of extracranial disease. If the patient is stable or if there is no evidence of disease, continuing current therapy at first intracranial progression is preferred. If extracranial disease is progressive, advancing to the next line of therapy is recommended. Upon further intracranial progressions, recommendations are patient-specific and tailored by prior CNS and systemic treatments, patient performance status, and adverse event profiles. It is increasingly appealing to introduce highly effective, CNS-penetrant drugs such as tucatinib into the earlier settings in patients whose intracranial disease is the primary disease site. A phase 3 clinical trial of tucatinib added to T-DM1 is ongoing and is enrolling patients with untreated, stable, or progressive brain metastases (NCT03975647).

We now have several good options beyond the second-line setting for patients with HER2- positive BCBM (

Factors paramount in determining which agent to select and when include both extracranial disease status and the status of intracranial disease—stable and treated, treated and progressive, or asymptomatic and untreated. For patients with stable brain metastases after local therapy who are progressing extracranially, tucatinib/trastuzumab/capecitabine or trastuzumab deruxtecan are both reasonable choices. For patients with rapid, visceral progression in need of a robust response, the overall response rate of trastuzumab (61%) is superior to HER2-directed TKIs, with corresponding duration of response approaching a year and half. Trastuzumab deruxtecan has yet to be formally studied in patients with treated, but progressive, or previously untreated brain metastases and intracranial response remains unknown.

Finally, tucatinib/trastuzumab/capecitabine and neratinib/capecitabine have both illustrated efficacy in treated, but progressive or untreated brain metastases; however, these regimens have not been compared head to head. It is important to note that activity of neratinib/ capecitabine after lapatinib is more limited.

Collectively, there are more options than ever in the space of HER2-positive BCBM, a significant advance for our hundreds and thousands of patients facing this challenging disease. Our goal now is to determine the optimal combination and sequence of therapies to extend survival in a meaningful way. Continued development of rationally designed clinical trials, and integrating systemic and local therapies, will lead the way forward.

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NALA (NCT01808573) was a phase 3 international, randomized clinical trial of neratinib plus capecitabine (N+C) versus the reversible dual TKI lapatinib plus capecitabine (L+C) in patients with HER2-positive MBC who had received at least 2 prior HER2-directed regimens.

 Six hundred twenty-one patients were randomized in a 1:1 fashion.

The addition of pertuzumab to taxane/ trastuzumab has increased time to BCBM development in the first line and has improved overall survival (OS) in patients who progress and develop BCBMs. This was demonstrated in the phase 3 CLEOPATRA trial (NCT00567190), which tested the regimen in MBC.

 Patients with baseline BCBMs were not included in the study population. T-DM1 is the current standard- of-care second-line treatment for patients with HER2-positive MBC due to its superiority over capecitabine/lapatinib demonstrated in the EMILIA clinical trial (NCT00829166). Patients with stable and treated baseline brain metastases were included in this clinical trial. Among patients with BCBM at baseline, there was a significant improvement in OS observed in the T-DM1 arm compared with the capecitabine/lapatinib arm (HR, 0.38; 

 At this time, for most patients, first- and second-line treatments for HER2-positive MBC are the same regardless of the presence or absence of brain metastases.

Articles

Collectively, there are more options than ever in the space of HER2-positive breast cancer brain metastases, a significant advance for our hundreds and thousands of patients facing this challenging disease.

Sarah L. Sammons, MD

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