At an Across the Observe® program hosted by CancerNetwork®, a panel of specialists mentioned the implications of mind metastasis amongst sufferers with HER2-positive breast most cancers, in addition to optimum therapy methods in superior settings. The dialogue was led by Joyce O’Shaughnessy, MD, the Celebrating Ladies Chair in Breast Most cancers Analysis at Baylor College Medical Heart and director of the Breast Most cancers Analysis Program at Texas Oncology, US Oncology in Dallas.

Panelists included Virginia Kaklamani, MD, a professor of drugs at The College of Texas Well being Science Heart at San Antonio (UT Well being San Antonio) and chief of the Breast Most cancers Program at UT Well being San Antonio MD Anderson Most cancers Heart; Andrew J. Brenner, MD, PhD, a medical oncologist and neuro oncologist at Texas Oncology–Austin Mind Tumor Heart; and Heather McArthur, MD, MPH, affiliate professor, Komen Distinguished Chair in Scientific Breast Most cancers Analysis, and scientific director of the Breast Most cancers Program at Harold C. Simmons Complete Most cancers Heart at UT Southwestern Medical Heart in Dallas, Texas.

Second-Line Remedy Methods

O’SHAUGHNESSY: How do you usually deal with sufferers within the second-line setting?

KAKLAMANI: Till not too long ago, the usual of care could be giving ado-trastuzumab emtansine [T-DM1; Kadcyla] based mostly on the section 3 EMILIA trial [NCT00829166].1 Now we’ve new knowledge. We have now one other antibody-drug conjugate, fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], based mostly on the section 3 Future-BREAST03 trial [NCT03529110], which might most likely be my first possibility right here.2 An alternative choice is the section 2 HER2CLIMB [NCT02614794] routine: tucatinib [Tukysa], trastuzumab, and capecitabine.3

O’SHAUGHNESSY: When sufferers are asymptomatic, you at all times [wonder whether there’s any role for endocrine therapy]. Normally if sufferers are on upkeep trastuzumab and pertuzumab [Perjeta], that’s the place I’d use an endocrine agent as a result of it’d lengthen progression-free survival. It appears it’s the sufferers with estrogen receptor [ER]–optimistic illness who ultimately expertise development. Some sufferers keep on trastuzumab and pertuzumab for all times—[most often] these with ER-negative illness somewhat than ER optimistic.

MCARTHUR: Within the section 3 CLEOPATRA trial [NCT00567190], hormone remedy was permitted as upkeep remedy, but it surely wasn’t mandated.4 As such, there was a variety of variability round follow.

Nonetheless, I agree. I’ve begun incorporating hormone remedy for sufferers with hormone receptor [HR]–optimistic illness who’ve response and whom I keep on HER2-directed remedy.

BRENNER: When it comes to tolerability and [ease of] tailoring to particular person sufferers, trastuzumab appears to be effectively tolerated. Most sufferers will comply with that [regimen] very effectively. The response charges look nice.

With capecitabine, you do have to fret typically about diarrhea, and sufferers won’t have the ability to tolerate the HER2CLIMB routine within the second-line setting. As such, you may favor trastuzumab deruxtecan in that setting.

Mind Metastases: Scientific Practices

MCARTHUR: When is one of the best time to display screen for mind metastases?

O’SHAUGHNESSY: That is an attention-grabbing query. We don’t see many recurrences lately in our follow amongst sufferers handled with docetaxel, carboplatin, trastuzumab, and pertuzumab, adopted by optimum endocrine remedy. The historical past of first-line HER2-positive metastatic illness is such that greater than half of instances are de novo metastatic lately.

These sufferers can do nice. These are the sufferers who can keep on [treatment] for a really very long time. We do see recurrences, like within the ER-negative, HER2-positive setting. Typically it’s a consequence of this hybrid most cancers of HER2-positive and basal-like [disease], which isn’t as delicate to HER2-based remedy.

What’s your normal first-line therapy in these sufferers?

MCARTHUR: I’ve had the uncommon affected person on upkeep trastuzumab plus pertuzumab for years—typically even a long time—who must take a break from remedy for journey or private causes.

Given the dangers [surrounding] HR-negative, HER2-positive illness, I’ve been reluctant to introduce “drug holidays” in that inhabitants. I’d, in that setting, proceed with trastuzumab/pertuzumab, reintroduce a taxane if I used to be involved about development, [and then] transfer on to second-line remedy if there’s an ample interval since final publicity. That is the artfulness of drugs.

BRENNER: It relies upon additionally on a affected person’s illness burden. I typically see sufferers who begin off with minimal illness burden who do very effectively [on treatment] for an extended time frame, who can take a break from trastuzumab/pertuzumab and proceed on an aromatase inhibitor. Once more, it’s important to base [the decision] on the person affected person, and that’s the artwork of drugs.

O’SHAUGHNESSY: What are the choices for second-line remedy in these sufferers?

KAKLAMANI: I don’t [perform brain imaging] until a affected person has symptomatic illness. If a affected person does develop symptomatic illness, we’ve choices to deal with them and enhance their signs. Lots of my colleagues will carry out mind imaging at first or second development, which is completely superb, however I differentiate between lively and inactive mind metastases. HER2CLIMB was the one randomized section 3 trial to incorporate sufferers with lively mind metastases. In that case, I’d favor tucatinib, however for these with out mind metastases or with handled mind metastases, T-DXd is my go-to agent.

O’SHAUGHNESSY: When and the way ought to clinicians carry out surveillance imaging?

BRENNER: The suggestions concerning surveillance imaging for mind metastases have modified barely; it’s now not discouraged, [but it’s not] beneficial both. The information are indeterminate.

[However,] there are some knowledge suggesting what modifications with early detection. There was one research from round 10 years in the past wherein investigators screened sufferers with HER2-positive illness from the start.5 They handled a few of these sufferers with asymptomatic mind metastases that have been by the way discovered at staging and in contrast them with different sufferers who have been solely handled on the time they grew to become symptomatic. There was no distinction by way of survival consequence, however there have been variations by way of development, which you’d anticipate.

Now that there are knowledge on a tucatinib-based mixture from HER2CLIMB and on T-DXd from the section 2 TUXEDO-1 trial [NCT04752059], it’s important to surprise [whether] it’s time to revisit these research.6 As of proper now, nonetheless, the information [are] not convincing that we will change outcomes by performing early imaging to detect asymptomatic mind metastases.

O’SHAUGHNESSY: What’s your strategy in your follow?

BRENNER: There are a number of necessary factors to think about when speaking about mind imaging.

Firstly, 50% of the HER2 metastatic inhabitants will develop mind metastases. That’s a big quantity. Furthermore, the time to improvement of mind metastases is comparatively quick; it’s about 12 months from the analysis of metastatic illness. About 60% of those sufferers will develop mind metastases previous to their second-line routine. So it tends to occur early.

I’m at all times vigilant when on the lookout for neurologic signs. Typically it might be one thing so simple as a affected person not feeling cognitively effectively or having an elevated stage of fatigue. Typically it might be one thing extra particular—some neurologic signs that clearly point out mind metastases. Clinicians ought to have a really low threshold for concern. That’s the easiest way to go.

MCARTHUR: It is a little bit of a shifting goal. As has been talked about, we don’t have a lot knowledge to tell after we needs to be on the lookout for mind metastases and whether or not early surveillance impacts the course of the illness. In a current replace from the section 3 KATHERINE trial [NCT01772472], there was a stunning variety of sufferers who introduced with mind metastasis who had residual illness, which most likely heightened my consciousness.7 [Nowadays we have] therapy choices which might be efficient in sufferers with mind metastases, which has traditionally been an space of unmet want, however once more, there aren’t any knowledge.

I can’t say I’m performing mind imaging up entrance at metastatic analysis, however I’m watching [for brain metastases] earlier on than I’ve traditionally. Whereas earlier than I’ve seemed solely when sufferers had signs, now I’d look when transitioning to second-line remedy.

KAKLAMANI: If I carry out imaging, it’ll be an MRI, however I don’t usually carry out it until a affected person has a symptomatic manifestation. [Of course], you may’t ignore little signs as a result of they may find yourself being necessary. You don’t desire a affected person going into the hospital with a seizure. If you happen to’re in a position to seize that symptom earlier than it manifests itself with a seizure, that may be vital.

O’SHAUGHNESSY: What’s the function of the neuro-oncologist within the therapy of HER2-positive sufferers?

BRENNER: It varies from follow to follow, however there are a pair totally different pivotal roles. One is to assist with symptom administration for sufferers experiencing premetastasis. You’re typically coping with seizures, edema, and even the implications of prior therapies, reminiscent of stereotactic radiosurgery [SRS]. It’s typically tough to discriminate between development and pseudoprogression from prior therapy. We have now some methods we may help with that [as neuro-oncologists, such as] perfusion imaging, which we could also be slightly extra accustomed to than the overall medical oncologist.

Moreover, neuro-oncologists may help decide easy methods to deal with a affected person with native remedy. [For example, they can help with] neurosurgery for a craniotomy to take away a symptomatic solitary massive lesion, adopted by SRS, switching to whole-brain radiation with hippocampal avoidance [while] guaranteeing that sufferers are on memantine to protect cognitive operate.

So [neuro-oncologists help] with each decision-making and administration of morbidity. Given that fifty% of sufferers with HER2-positive metastatic breast most cancers may have mind metastases, administration of morbidity is necessary.

O’SHAUGHNESSY: What are your practices concerning third-line therapy?

MCARTHUR: I take into consideration the situation of metastasis. I take into consideration the burden of illness. I take into consideration intervals, about prior publicity to remedy. Within the first-line setting, I’d reintroduce a taxane if there was a ample interval. I take into consideration timelines since final publicity, and mind metastasis is a vital consideration.

I additionally take into consideration affected person choice as a result of now we’ve choices, and affected person enter is vital. I’m struggling a bit with T-DM1. The place do I fold it into the therapy? Is it a third-line therapy? Is it fourth line or past? These have gotten very nuanced discussions.

O’SHAUGHNESSY: How can clinicians management systemic illness and likewise attempt to stop the scientific manifestation of mind metastases?

BRENNER: Typically talking, if a affected person has untreated mind metastases and progresses intracranially however has good extracranial management, I don’t swap to a systemic routine. We deal with domestically first to handle the mind metastases and [then] proceed the systemic routine. That’s essential: If in case you have native therapy choices, you don’t abandon remedy.

As soon as a affected person doesn’t have native therapy choices accessible anymore and if they’ve recurrence on the website of prior therapy, they’re not a candidate for both craniotomy or radiation. At that time, I look towards which [treatments] have one of the best central nervous system [CNS] exercise, and tucatinib has one of the best [supporting] proof, with 50% of sufferers in HER2CLIMB having an intracranial response. These sufferers are likely to do very effectively on the tucatinib routine.

Different therapy choices embody T-DXd, supported by knowledge from TUXEDO-1, which is a really small research, but it surely confirmed a excessive stage of exercise. There are different soon-to-be-published research displaying the CNS exercise of T-DXd. We even have salvage regimens reminiscent of lapatinib [Tykerb], however that turns into a questionable possibility after tucatinib.

O’SHAUGHNESSY: Can any brokers forestall the event of mind metastases?

KAKLAMANI: Margetuximab-cmkb [Margenza] is the latest drug to be accepted within the HER2 house.8 We don’t have the CNS knowledge, however we all know it’s an lively agent and we will mix it with a number of chemotherapeutic choices to learn the proper affected person.

In any other case, concerning neratinib [Nerlynx], I draw from the section 3 ExteNET trial [NCT00878709], wherein neratinib prevented the event of mind metastasis in an early-stage setting.9 We all know that neratinib is lively. Will it work after tucatinib? We don’t know. We don’t know if tucatinib will work after T-DXd both.

All these trials are evolving so shortly that we’ve a variety of questions with out solutions, however we’ve at all times executed this in oncology. In some unspecified time in the future, we’ve to work with the information we’ve.

O’SHAUGHNESSY: Within the third line, I are likely to deal with everybody with tucatinib, capecitabine, and trastuzumab. That is due to the proof [supporting them] but additionally due to the subset evaluation of sufferers who hadn’t but had mind metastases, in whom [this regimen] decreased the incidence of those metastases.10 We don’t know if it prevents these metastases, but it surely reduces the danger.

Hopefully the section 3 CompassHER2 RD trial [NCT04457596] will lastly present some impression on mind metastases. Provided that greater than 60% of sufferers will develop these metastases, it’s greatest to delay them for so long as doable.

BRENNER: A lot of the accessible knowledge on T-DM1 [shows that it] prevents development of CNS metastasis in sufferers with secure illness or responses in secure illness, [but it doesn’t prevent] mind metastasis [altogether]. It’s good to differentiate [between] secure vs lively mind metastasis. I’m much less snug utilizing T-DM1 for sufferers with lively mind metastases as a result of we don’t have strong knowledge.

KAKLAMANI: The one necessary factor is for sufferers to be compliant. We’ve talked about the advantages of oral brokers, but when a affected person doesn’t take them—or doesn’t take them accurately—they received’t work.

We have now nurses and pharmacists name sufferers to make sure they obtain the drug and that they’re compliant with their appointments as a result of [otherwise] they could not come each 3 weeks for chemotherapy. Assuming all that is in place, the HER2CLIMB routine is my go-to [in the third line].

These antibody-drug conjugates which might be massive molecules one way or the other do deal with mind metastases. Particularly should you’ve handled one in every of these metastases, the blood-brain barrier all of us love to debate most likely doesn’t exist anymore, proper?

BRENNER: Sure, it is a very lively space of analysis. There’s the blood-brain barrier and what we name the blood-tumor barrier, which is normally denuded of the buildings [that] assist stop issues from crossing by means of, reminiscent of astrocytes and parasites. There are some research of radiolabeled antibodies displaying that the focus inside mind metastases is far larger than in regular mind [tissue]. So that they do get throughout.

The query is: to what extent do they get throughout? It’s clearly not going to be the identical as in different elements of the physique the place the bigger molecules can go by means of. It’s disrupted. The quantity that will get throughout is totally different than the remainder of the physique, and [this amount] is probably not ample to end in exercise.

O’SHAUGHNESSY: How typically ought to clinicians carry out mind MRIs as soon as a affected person has developed a mind metastasis?

BRENNER: For a affected person who’s clinically asymptomatic after therapy, the rules advocate each 2 to three months. That’s what I do in my follow. I carry out one each 2 months. I favor the shorter interval as a result of it offers me slightly extra time to be proactive. Typically you may monitor lesions to acquire extra scientific knowledge.

O’SHAUGHNESSY: Let’s think about a affected person who receives T-DXd and a mind MRI each couple months and [that] she develops a few mind metastases however stays systematically secure on her routine. How would you handle this?

MCARTHUR: For this reason multidisciplinary collaboration is so vital. Usually, it is dependent upon what’s doable domestically, whether or not that be extra SRS, whole-brain radiation, or neurosurgery. Afterward, I’d proceed the systemic remedy, assuming the non-CNS illness is managed. Native methods are necessary for controlling lively mind metastasis.

O’SHAUGHNESSY: As a neuro-oncologist, is that this what you’d advocate?

BRENNER: Sure, that’s what the information presently [show]. For sufferers with endocranial development, you give an area remedy first, and also you proceed with the systemic agent; you maximize its use.

If the affected person has new lesions which might be recurrent in an already-treated space, it turns into extra difficult. It’s good to take into account what your salvage regimens are. [You need to consider] if the affected person is a candidate for whole-brain radiation with hippocampal avoidance, for instance, in the event that they’ve already acquired SRS.

There’s additionally this idea of mind metastasis velocity. One factor we have to determine is: Do you have to give SRS to a affected person if they’ve 1 or 2 mind metastases? What was the timeline since their prior mind metastasis?

A few of the research analyzing salvage remedy recommend that if a affected person has greater than 4 mind metastases per 12 months, you most likely want to maneuver from a stereotactic strategy to a whole-brain therapy or at the very least take into account whole-brain with hippocampal avoidance for these sufferers with a better mind metastasis velocity.

O’SHAUGHNESSY: Many tips are round counting on native remedy for the mind and staying the course on a profitable systemic remedy. If any person retains creating these metastases or in the event that they develop a number of or massive [metastases], isn’t it time to consider a therapy which may do a greater job for the mind?

BRENNER: How HER2CLIMB was carried out, and the way I conduct my follow, is thus: Sufferers with an lively mind metastasis needed to be clinically secure, and there should be time for systemic remedy to work. [When treating] sufferers with very massive tumors inflicting a variety of mass results or sufferers who’ve illness in a really eloquent space, you won’t have time to attend for a systemic routine.

As such, you additionally want to think about, as was executed within the research, whether or not the signs derive from the metastasis when selecting [between] an lively, systematic CNS routine and native remedy.

Halting Remedy, Switching Therapies

O’SHAUGHNESSY: When and the way do you make the choice to halt a therapy?

MCARTHUR: These are luxurious challenges as a result of we’ve choices now. We haven’t but talked about toxicity monitoring [regarding] T-DXd and interstitial lung illness [ILD] and the way it coincides with monitoring for mind metastasis. I’d take into account switching [treatments if a patient had] recurrent mind metastasis.

O’SHAUGHNESSY: If a therapy is starting to indicate crimson flags, [such as with] life-limiting websites of metastasis, then we’ve to [respond].

BRENNER: That’s an excellent level. For sufferers who develop mind metastases from HER2-positive illness, 70% will die from CNS development. It’s necessary to proceed treating them systemically should you really feel their native choices are working out.

KAKLAMANI: You get the intestine feeling [on when to switch treatments]. Each time you do a scan, you’re beginning to see the mind illness taking up a lifetime of its personal. No matter how a lot we love our systemic brokers, in some unspecified time in the future, we understand that they’re not controlling this illness. Although I [may] attempt to proceed it for so long as doable, I do know deep down that I’m not [treating the disease in] the mind. I’d have the ability to use SRS, however in some unspecified time in the future, should you use sufficient SRS, it’s like doing whole-brain radiotherapy.

O’SHAUGHNESSY: May you keep away from SRS and simply deal with with the tucatinib triplet?

BRENNER: If a affected person isn’t terribly symptomatic, has lively mind metastases, and also you’re frightened about administering extra localtherapy, you may. I’ve and can do that. I’ll swap sufferers to a CNS-active routine just like the tucatinib triplet, and I’ve seen nice outcomes.

The query turns into: When do you drop the capecitabine? [At a certain point you achieve] good management intracranially, and if the affected person has been on capecitabine for some time, they [tend to experience] hand-foot syndrome [or] some stage of diarrhea.

O’SHAUGHNESSY: How do you handle the toxicity?

BRENNER: I drop the capecitabine as soon as they begin to develop these toxicities, and I hold them on tucatinib and trastuzumab. Typically I [can achieve] wonderful ongoing management with that [approach].

MCARTHUR: I’ve to be sincere. I’ve been administering the capecitabine spine in a 1-week-on, 1-week-off vogue based mostly on the dose-dense modeling by Larry Norton, MD, and colleagues.11 I discover it’s significantly better tolerated than a 2-weeks-on, 1-week-off [schedule].

KAKLAMANI: I’ll deliver sufferers again shortly to make sure they’re taking the routine accurately and that their hostile occasions [AEs] are manageable. I usually proceed administering capecitabine till I start to see fatigue. Importantly, fatigue just isn’t essentially simply from the drug.

Particularly with HER2-positive illness, sufferers [can] stay for greater than 5 years with metastatic illness. It is a marathon, not a dash. They’re going to obtain a variety of chemotherapy of their lifetime, so we’ve to tempo ourselves. The minute I see that they’re working out of persistence, I halt it.

If I do have to present capecitabine and the affected person has had a variety of toxicity, I swap to the 1-week-on, 1-week-off strategy. There [are] some knowledge from the gastrointestinal world suggesting it might be as efficacious [as the alternative], which is nice, however I’ll begin with the unique 2-weeks-on, 1-week-off routine.

O’SHAUGHNESSY: I at all times begin with full-dose tucatinib to make sure I get one of the best outcomes for the mind, and I begin slightly decrease on the capecitabine. I don’t begin on the HER2CLIMB dosage of 1000 mg per meter twice a day [because] you don’t wish to have an excessive amount of directly. [However], I push [the dosage] up as a lot as I can.

It sounds just like the consensus is to modulate the capecitabine dosage and schedule and to attempt to hold the tucatinib dosage as excessive as doable. I haven’t had many issues doing this. The diarrheal toxicities from tucatinib don’t appear insupportable. It appears that evidently the capecitabine and tucatinib mixture is extra of the problem.

Future Views

O’SHAUGHNESSY: How do you hope this subject develops within the subsequent 5 to 10 years?

MCARTHUR: Probably the most thrilling house is shifting methods from the metastatic setting into the curative-intent setting. I like to see [research into] escalation methods for sufferers at larger danger of recurrence to optimize their likelihood of curability [and research into] de-escalation methods for sufferers who might expertise good outcomes with much less remedy.

BRENNER: I wish to see extra CNS trials. I used to be excited to see HER2CLIMB as a result of they included sufferers with lively mind metastases, and it’s a disgrace we don’t embody extra sufferers with lively mind metastases in section 3 trials. There are methods to do it safely. There are ongoing research like section 3 DESTINY-B12 [NCT04739761] [that] are nearly like section 4 trials [in terms of] mind metastasis. We’ll see what occurs there.

KAKLAMANI: We all know that T-DXd has a ten% to fifteen% incidence of ILD, which may be deadly. We all know that it may possibly induce nausea and vomiting. We all know tucatinib can induce diarrhea. It’s necessary that we maximize our therapies and reduce AEs for these sufferers on the similar time. These are sufferers who’re prone to stay for a very long time, and we wish to enhance their high quality of life when treating them with lively remedy. There are additionally new brokers rising that can hopefully present much more choices for these sufferers.