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Optimizing First-line Maintenance for HER2+ MBC: Equipping the Multidisciplinary Team With the Latest Evidence and Guidance on Novel Regimens

Let us get into the actual data in this new study that we have for HER2+ metastatic breast cancer.

Patient Case: Selecting 1L Maintenance Therapy in ER+/HER2+ MBC

Let us put this into a context and a clinical case. Imagine that we are in clinic and we are seeing a patient that is 62 years old, presenting with disease recurrence. It is metastatic breast cancer that is HER2+ and ER+ disease.

This patient was previously treated for an earlier stage HER2+/ER+ cancer. Has a biopsy of the liver that confirms the disease recurrence. It is ER+, HER2+, PIK3CA wild-type. Patient has a preserved general health status. Good echocardiogram. She was treated with a standard CLEOPATRA regimen with six cycles of THP, achieves a very good, sustained partial response. Her primary goal is to delay disease progression as long as possible.

Based on the latest evidence, what would be the optimal approach for this patient?

Guideline Recommendations for HER2+ MBC: First-line Therapy

Here we have the guidelines for the management of HER2+ metastatic breast cancer. As I said, for many years, since 2012, we had the CLEOPATRA regimen, so we are all familiar with the benefits of the dual HER2 blockade. More recently, we had the results of DB-09 leading to the approval of T-DXd with pertuzumab in the first-line setting.

We have the results here on the right side of the PATINA trial that basically focuses on the subset of patients with HER2+ and ER+ disease with the addition of palbociclib. This is included in the NCCN as a recommendation, and we have the standard second-line regimens here for HER2+ disease.

CLEOPATRA: Trastuzumab + Docetaxel ± Pertuzumab in Untreated HER2+ MBC

Briefly, as I said, since 2012, we had the THP regimen from CLEOPATRA. This is a study that the primary endpoint was progression-free survival, and evaluated the dual HER2 blockade at that point.

CLEOPATRA: Survival With Pertuzumab, Trastuzumab, and Docetaxel as 1L Therapy in HER2+ MBC

On the left, here we have the overall survival results, and on the right, the PFS. I want to bring your attention to the right curves here, where the addition of pertuzumab in the CLEOPATRA regimen gave us about six months in terms of median PFS. The control was to half with P/H/D 18.7 months.

What is interesting of the CLEOPATRA is that we have this very long-term outcome now, and we all see patients in clinic that are doing incredibly well, even with this regimen, with the addition of novel agents.

I want to bring your attention here to the PFS curves on the right between 40 and 60 months. What we see here on these curves is that they start to plateau, and we have between 15% to 20% of patients on the CLEOPATRA regimen who were free of disease progression for many years since the diagnosis. I believe that we all have seen these patients in clinic, where it seems that they go into a very long-term disease remission, but it is interesting to see that by about 50 months, that is where we start to see this curve is achieving a plateau. This is going to be important for us when evaluating these additional studies that have been presented.

2026 1L SoC and Maintenance Pathways

Basically, this idea of CLEOPATRA that we do this THP and you stop the taxane and maintain patients on Herceptin-pertuzumab was not designed as such. There was no concept that for this disease, an induction therapy would be really needed. The idea here was that clinicians had to discontinue taxane because of toxicity. What we call today as an induction therapy, it is artificial in itself as a term because it is just a regimen where we give some chemotherapy, and we know that patients do well once we discontinue chemotherapy.

The ADC-based approach from DB-09 as a study design, patients were randomized to continue on THP or T-DXd with pertuzumab until disease progression or toxicity. It comes with a different concept in terms of the intensity of medications given to these patients in the first-line setting. Those are things that are very important for us as clinicians and when discussing with patients.

We know that those are pathways that are in guidelines now. We all have discussions in terms of how we are going to select more intense regimens for these patients early on versus the CLEOPATRA. There is always discussions about the CNS history, disease burden, patient symptoms, but it is very important for us to put this into our real clinical context.

DESTINY-Breast09: T-DXd ± Pertuzumab vs THP as 1L Treatment for HER2+ MBC

Here we have the DESTINY-Breast09 study design. I believe that most of us have seen this being published and presented.

What was reported so far is what we have here in this red block for the comparison of the THP with T-DXd plus pertuzumab. The arm that contains just T-DXd has not yet been reported. This study was reported with a relatively short median follow-up given the superiority of T-DXd with pertuzumab, but it is important for us to pay attention in a couple of things in terms of toxicity and in terms of use of hormonal therapies and how this was managed from a clinical standpoint.

DESTINY-Breast09: Baseline Characteristics

Here we have the patient characteristics of this study. More than half of the patients had HER2+ and ER+ disease. A small percentage of patients had history of brain metastases at the time of diagnosis. It is a study where we have about 20% of patients enrolled in Western Europe and North America.

This is important for us, not for today's discussion, but once we have additional follow-up of this DB-09 and additional studies, we, as clinicians, should always pay attention to where studies were conducted because the access to medications in subsequent lines of therapy is very diverse. Many countries outside of Western Europe and the US, the access to second-line, even in HER2, is not really available, so this is important when interpreting long-term follow-up.

DESTINY-Breast09: Previous Therapy for Breast Cancer

Here we have the prior therapies that we are giving for these patients in DB-09. We do not need to spend a lot of time here.

DESTINY-Breast09: PFS by BICR (Primary Endpoint)

The top-line results that we are presenting showing the superiority of T-DXd with pertuzumab versus THP in the first-line setting. There is no doubt we all know that T-DXd is a very efficacious agent for HER2+ disease. This is consistent results across subgroups, and as I mentioned before, still a relatively short median follow-up for this clinical trial, but no doubt that this is a positive study.

DESTINY-Breast09: Secondary Efficacy Endpoints

There is a lot of attention to the overall response that we get with this regimen in the first-line setting. A lot of us as clinicians and the reaction of our breast oncology community is that this is an agent that is very effective.

We have very good response rates, but I want to bring your attention here to the confirmed overall response rate for the direct comparison of T-DXd versus the THP. We have 85 versus 78.6. This is a population that has a very good response to the classic THP, the induction regimen. Here we do see a numerical slightly higher response rate with T-DXd, but in reality, we are talking about close to 80% of overall response with both regimens, which is consistent with what we had in the CLEOPATRA regimen.

In other words, once we have a patient presenting to clinic with metastatic HER2+ disease, the patient is symptomatic. We, as clinicians, we want medications that give us a good response rate. It is clear that we get a very good response rate with both regimens.

DESTINY-Breast09: Most Frequent TEAEs and AESIs

T-DXd is a medication that has serious adverse events, and we have been using it for a while now in different indications. There is a lot of attention to the pneumonitis, including grade 5 adverse events. It is a medication that has a lot of nausea and sometimes neutropenia, the fatigue, the alopecia. We did a small clinical trial here at the Farber to see if the cold cap would work in preventing hair loss with Enhertu. Unfortunately, the cold cap did not seem to work well.

All those things are important when we are having discussions with patients because with THP, we are able to prevent hair loss with the cold cap very well, so all those things should be taken into consideration in terms of where we are going to place these drugs in our clinical practice.

Unmet Needs Remain Despite the Historical THP to HP Maintenance Paradigm

Of course, there are many unmet needs in terms of the CLEOPATRA regimen. We are talking about metastatic disease. I would say that I see brain metastasis as one of the major problems that we have in HER2+ disease. We are doing a lot better with a number of novel medications. Unfortunately, the incidence of brain metastases for this population tends to be very high. As we move along into subsequent lines of therapy, this can be as high as 50%.

Whenever there are discussions about DB-09, CLEOPATRA, HER2CLIMB, and PATINA, we will hear more and more about this notion that there is some attrition, meaning that some patients may eventually, unfortunately, die in the first-line setting, so as to justify more intensive regimens early on. I would say that the attrition is not real if we pay attention to where this data is coming from and what type of medications patients had as access in subsequent lines.

In other words, if you are using a CLEOPATRA regimen for a patient and you have access to Enhertu for a patient who is not benefiting or for a patient who has this very small subset that progress early on, on THP, basically, this notion of attrition is not real based on what has been documented.

There is a lot of discussion for us to discuss these first-line regimens and how we want to intensify and what we are trying to achieve in the long run for patients diagnosed with HER2+ disease.

PATINA: Palbociclib + Anti-HER2 + Endocrine Therapy in Previously Treated HR+/HER2+ MBC

Here we have the PATINA trial. This is a study that I had the privilege to conduct through Alliance. Alliance was the study sponsor, and with support from Pfizer, we were able to do this independently with an academic consortium including countries here, Western Europe and Australia. Basically, it is a study that focuses on HER2+ and the ER+ disease. The study begins at the time where patients have had a few cycles, six to eight cycles of the classic THP, and has no evidence of disease progression prior to randomization.

Basically, study evaluates the addition of palbociclib to this maintenance regimen. The primary endpoint here is PFS by investigator.

PATINA: Baseline Characteristics

Here we have the patient characteristics. The median number of cycles that patients got of THP was about six. Basically, I want to bring your attention here to the right side table, where we have this best response to induction therapy. It is very interesting. Six cycles of THP. We have an overall response rate of 70%.

This is a subset of patients who really do very well in terms of what can be achieved with a few cycles of chemotherapy for those patients. The majority of patients in this study were treated with AI. Fulvestrant was also an option.

PATINA: PFS and Interim OS

Here we have the results that were recently published showing that the progression-free survival went from 29 to 44.3 months with the addition of palbociclib. This is like a big improvement for the first-line setting. We are talking about 44 months for patients who had been on six cycles of THP. This is like the median PFS of PATINA. It is much greater than four years.

If you remember what I told in the beginning of the presentation when we were looking to the CLEOPATRA curves, here in PATINA, when we are getting to year four at 48 months, then we start to see the curve is achieving the same plateau as we had for CLEOPATRA.

When we look into where we are in terms of the percentage of patients free of disease progression, it is very high. It is like greater than 40% of patients are free of disease progression at this point. The median follow-up of PATINA is over 50 months. The study was taking forever to read out because it is event-driven. The reason is patients were not having events towards the end of the day of the curves for both the investigation and the control arm.

Even when we focus here just on patients getting HP and hormonal therapy without palbociclib, it is remarkable to see how well patients are doing, and even much better than what we had in the CLEOPATRA regimen where hormonal therapy was not allowed.

Here PATINA gives us a clear message that palbociclib adds benefit, and also a clear message that what we have been doing in clinical practice since CLEOPATRA, with the addition of hormonal therapy is very important.

PATINA: Safety

Whenever we added agents, we pay attention to toxicities. What we have for PATINA is similar with what we know with palbociclib in the ER+ setting. Apart from diarrhea, we did see a higher-than-expected incidence of diarrhea. We are still trying to dissect this better. Based on the information that I have, most of the grade 3 diarrhea happened for patients who already had some diarrhea at baseline, and this was very close to the prior chemotherapy.

I do not think that diarrhea is a major problem, but of course, here is the data, and there was a higher incidence of diarrhea.

Neutropenia is the most common adverse event. It did not seem to be different than what we know in the ER+ setting.

PATINA: Discontinuations, Interruptions, and Reductions

Here we have the reasons for treatment discontinuation and interruption. It is basically the neutropenia. We basically followed the same guidelines that we use in the ER+ setting for dose reduction and interruption. In retrospect, I wished we could have been even more flexible for the protocol-mandated dose discontinuation, but we did follow the same guidelines that we have for the ER+ setting. We did not run into trouble with infections, neutropenia, any of that with palbociclib.

Endocrine Therapy Selection in HR+/HER2+ First-line Maintenance

The choice of endocrine therapy on PATINA was open to investigator with these two options: AI or fulvestrant. Most patients got an AI, given that it is hard to get patients in the fulvestrant schedule and particularly in the first-line setting.

Basically, as clinicians, we choose if a patient was on, let us say, on letrozole before and at the time of disease progression, it is not unreasonable to use a PATINA regimen with exemestane, for instance. For the rare patients who have disease progression while on an adjuvant AI, it is also not out of question to consider fulvestrant for some patients. Here there is a lot of flexibility.

On PATINA, if a patient had to discontinue hormonal therapy for toxicities or for whatever reasons, clinicians could still continue with palbociclib and HP. This is important because the idea here was that palbociclib is not just reversing the endocrine resistance that exists in this subset of breast cancer, but it has also been shown to be very effective in potentiating the effects of the anti-HER2 therapy. That is why there was flexibility in terms of how we would manage the hormonal therapy.

HER2CLIMB-05: Tucatinib vs Placebo Added to HP as 1L Maintenance for HER2+ MBC

Let us move to HER2CLIMB-05, which is the most recent study that was presented and followed the design that we had for PATINA using this maintenance approach after THP, patients were randomized to get tucatinib versus not. Here we have a triple HER2 blockade. HP, tucatinib, basically adding a TKI to HP in the maintenance setting for all HER2+, ER+ versus not. Basically, investigator-assessed PFS is the primary endpoint.

HER2CLIMB-05: Baseline Characteristics

Briefly here, again, half of the patients ER+ disease. Hormonal therapy was not used as much. Just half of the patients with ER+ disease got hormonal therapy. Median number of induction cycles was about the same. Again, the response rate to the induction therapy was also remarkable as demonstrated in CLEOPATRA, PATINA, and so on.

HER2CLIMB-05: Investigator-Assessed PFS (Primary Endpoint)

Here we have the top-line results showing the benefit with the addition of tucatinib to HP, reaching close to 25 months versus 16 months. Really a positive study demonstrating that there is benefit here with the triple HER2 blockade.

HER2CLIMB-05: OS and CNS-PFS

The overall survival results are still immature, but it is interesting that numerically we are seeing benefits here. Here, given what we know for tucatinib as being an agent that has efficacy for patients with brain metastases, there is a strong emphasis into looking to the CNS-PFS for the overall population, which did not seem to be different.

Also, here on the top table on the right, where we have the CNS-PFS in patients who had a history of brain metastases at baseline. Not a large number of patients, but larger than PATINA. We did see that in this subset of patients, the addition of tucatinib seems to have a benefit.

We all know that for patients who have CNS metastases in the HER2+ setting, it is more likely that additional lesions in the brain are going to show up. This is what is demonstrated here. Even with the small numbers, we see that the median PFS for this population tends to be smaller. There seems to have a benefit once we add tucatinib there.

HER2CLIMB-05: Safety Summary

In terms of the toxicity, tucatinib is also an agent that we have been using in different lines. I believe that most of us have some experience with tucatinib. The adverse events that we pay more attention here are basically diarrhea and liver toxicity. I would say that liver toxicity is the most important. We do not see that much of diarrhea with tucatinib. This table is going to be shared with you. We can review it in more details.

HER2CLIMB-05: Hepatic and Diarrhea Treatment-Emergent Adverse Events.

Let us look here into the liver toxicity in terms of the grade 3 adverse events. It is not so uncommon that we have a high grade transaminitis with tucatinib. This tends to happen more often in the initial cycles. Here, days to grade 3 onset is about 40 days on average for this grade 3 transaminitis. Usually tends to be benign, but we need to remember to monitor that and to stop the medication if this happens until it resolves.

In general, I personally feel that it is an agent that does add some toxicity. It is an oral agent and relatively well tolerated.

Personalizing 1L Maintenance: A Practical Decision Framework

There is a lot of space here for us to talk forever about how we put all this into context, how we can come up with a perfect first-line treatment for HER2+ disease. I feel that it is interesting that we have more options, and there are a lot of things that are important. The CLEOPATRA regimen is still the standard. There is a space for us to consider T-DXd with pertuzumab in the first-line setting for a subset of patients.

No one knows exactly which are those patients and for how long we are going to continue T-DXd and pertuzumab like a DB-09 style because the study was basically designed and conducted to them to continue with this regimen until disease progression.

There is a lot of clinicians and debates saying, "Well, maybe we just give a few cycles of six to eight cycles of Enhertu with pertuzumab, stop, and go into a maintenance regimen." That is not the way the study was conducted. If we want to interpret the results of this study and adapt it into our clinical practices, we should improve follow-up what was done.

The other point that is important for this discussion of Enhertu early on versus in later lines is that it is a medication that is very effective in subsequent lines, very effective when patients are presenting with more aggressive disease. It is effective as an agent for patients who have brain metastases. The placement of Enhertu in the first-line treatment of HER2+ disease, it does require some thoughtful clinical judgement. I do not think that an approval or guideline recommendations means that everyone should be treated with this agent in the first-line setting.

Of course, now with PATINA, we do pay more attention to the ER than we did before. Patients do very well on a maintenance therapy with oral agents without hair loss for many years. This is important for patients where we have a disease with a very long natural history. The presence or a history of baseline brain metastasis does play a role. We did see, for these patients, a benefit with tucatinib.

There are interesting aspects that we should pay attention. There are even clinical trials. There is more clinical trial that we are doing here to see if we should be doing baseline brain MRI for all patients with HER2+ disease, because of the guidelines, we know that what is recommended is to do if patients have symptoms suggestive of CNS metastasis. It is an area that is evolving, and I am glad patients are doing better, but we do pay attention to that.

When we talk about novel agents, there is always the toxicities and all those things that are really important.

Let’s Revisit a Few Questions.

Let us make a transition here. Go to a few questions so it gives us some time to breathe, and then we can continue for a little bit longer, but I promise that not too long.

Posttest 1

When counselling a patient with HER2+ metastatic breast cancer after induction therapy, which explanation best describes the purpose of the first-line maintenance therapy? I am not going to read the answers because that is the same that we had before.

Speaker: This poll is open. Please vote. Give everybody a few more seconds to submit the response. Here are your results.

Dr. Metzger: Outstanding. Everyone got it very well. That is totally correct.

Posttest 2

Now, let us see what is the agent that has demonstrated benefit in the maintenance setting.

Speaker: This poll is open. Just a few more seconds for incoming answers. Looks like everybody's had their coffee this morning. Here are your results.

Dr. Metzger: Outstanding. It is very clear that we have the results from the PATINA trial that demonstrated the benefits with palbociclib.

Posttest 3

Here, that is the question about the HER2CLIMB and what is the benefit with tucatinib.

Speaker: This poll is open. Here are your results. There you go.

Posttest 3: Rationale

Dr. Metzger: HER2CLIMB gives us 24 months with the addition of tucatinib.

Multidisciplinary Strategies for Supportive Care and AE Management

Now I want to switch gears and talk a little bit about what we have in terms of supportive care and AE management. We are going to go relatively quick over these slides. Not too many details, given those are agents that we have been using different settings. It is more for us to review and remind ourselves of some very important aspects.

NCCN Guidelines and Emesis Risk for Anticancer Therapies

Let us start with Enhertu. Enhertu is really highly emetogenic. The idea here is that we need to max out on management of nausea. Here we have the guidelines. We use all the medications possible to control nausea and vomiting. I have to say that in my clinical setting, I am relatively flexible with using some olanzapine for a couple of days to help. It is an agent that has a lot of nausea, but with all the medications we are able to control well.

DESTINY-Breast09: Most Frequent TEAEs and AESIs

Here we have the table of the most common adverse events on DB-09. The pneumonitis is not trivial in terms of how we monitor, and it is not so uncommon. We can see here that any pneumonitis happening in 12% of patients. More than 10% had some pneumonitis. It does require a lot of attention from our side.

The 5 “S” Rules: Detecting and Managing T-DXd–Related ILD

Here we have the classic 5S rules for detecting and management Enhertu-related interstitial lung disease. We need to basically be more careful in terms of the history of any pulmonary symptoms at baseline. This baseline scan is important because once we have a high-resolution CAT scan at the baseline, it allows us for a good comparison because interstitial disease is hard. Sometimes if we do not have a baseline, we do not know if that was there before, was some infection. When it gets to the winter months, it is a nightmare for us to follow that. But it really helps us.

In this scenario of pneumonitis, we basically need to interrupt the treatment. We need to treat pneumonitis with high-dose steroids. For patients who really have a high-grade toxicity, it is an agent where it can be life-threatening, so we really need to stop the idea of rechallenge. It is just for patients who had lower-grade toxicity.

This in itself is important because we are talking about a patient population that has this very long disease control. Toxicities here, we really need to pay attention because it has not only impact on quality of life, but also long-term outcomes for those patients.

Managing Palbociclib-Induced Neutropenia

In terms of palbociclib, as I mentioned, the neutropenia, fatigue, some stomatitis is the same that we have for ER+ disease. It is important to discuss with patients that in this study, there was a higher incidence of diarrhea. I would just encourage all of us to try to keep an eye on that, but basically I do not think that is any major problem. We should manage the dose reductions and the treatment holds in the same way that we do for your positive disease.

Here we have the standard recommendations that exist for your positive disease. If you go into the actual PATINA protocol, which is now available as a supplement in The New England publication, you can see that we are even more flexible with the evaluation of the CBC on the initial cycles.

Given that patients were coming every 21 days for their HP, in the initial cycles, we checked not on day 15; we checked on the beginning of the third week. Because we know how safe palbociclib is. Even for patients who end up with neutropenia, it is a neutropenia that is not associated with a higher incidence of infections because it is just the production machinery of the white cells that gets very slow as opposed to the neutropenia with chemotherapy or there is real risks of infection.

Basically, I find that relatively easy. Once we go over a couple of cycles of palbociclib, we get a very good hands-on management of neutropenia. In that case that we had at the beginning, if you remember, the clinician had checked the CBC on day 15 of cycle five. It is not really recommended. This is an agent that has this benign neutropenia. If we end up checking too much, we almost get in trouble finding neutropenia that is not clinically meaningful, similar to what we have for ER+ disease, not a major issue.

Key Principles for Managing Palbociclib-Induced Neutropenia

The dose reductions, dose holds, G-CSF growth factor is not recommended. We always talk to patients about how this is managed. Given palbociclib is given on a monthly cycle and the HP every three weeks, basically when we are designing PATINA, we said, "Well, this is going to be hard because patients are on different cycles," but in reality, patients get it very well. Once we go through this dose adjustments in the initial cycles, patients just manage their palbociclib by themselves and start and stop a cycle without much trouble.

CBC checks after these initial months were required just every three months on PATINA. No risks of neutropenia. It is a safe drug, as we know, for ER+ disease, and it is reassuring that when combined with HP, it did not seem to be different.

Patient Case Continued: Neutropenia on Palbociclib-Containing Maintenance

Here is the case that I just mentioned. If we end up checking a lot of CBCs, we get into trouble because we may find neutropenia that will lead to dose reductions, and so we do not need to go over this in more details.

Multidisciplinary Pearls: What Nurses and Pharmacists Can Operationalize Early in Treatment

Here we have a summary of what nurses and pharmacists should know about this choice of therapies that we have. For all patients, we should always confirm diagnosis, the label, the usual recommendations in terms of management of side effects. For T-DXd, this education in terms of respiratory symptoms is important, particularly for us in the fall-winter months because it becomes quite intense.

The antiemetic regimen has to be the best. We need to monitor patients with CBC and close monitoring as we do with Enhertu throughout the whole regimen. There is no flexibility. Those are like more intense regimens that feel like classic chemotherapy.

The palbociclib, as I said, some early checks early on, and then we should be really flexible in terms of this CBC monitoring because it is really safe. I really like that because the whole idea of maintenance regimens is that patients are getting their HP sometimes on a weekend or whatever time they want to get this quick injection if it is Phesgo, and then they take their oral agents and they are as much as possible back to their normal lives and feeling well without cancer-related symptoms and really doing well for years.

The tucatinib is an agent that does require some additional education in terms of this LFT monitoring early on, specifically in this initial two months. Tends to be safe in terms of liver toxicity moving forward, but there is a need to check it more often. As I said, I do not think that diarrhea is a major problem with tucatinib. I do not think that it becomes a major problem, but we always talk to patients about potential things to prevent and giving them some medications and keep an eye on a patient-by-patient basis.

Monitoring Checklist Across 1L Maintenance Strategies

The cardiac monitoring is the same across these regimens. We still do the echocardiograms that sometimes we have to do more than what we would like to do because they seem to be safe. Let me see what else here. This is what we just talked about.

Key Takeaways for Community Practice

What are the key takeaways here? I would say that the treatment has changed. We have T-DXd plus pertuzumab as an option in the first-line setting. It is no doubt that is a positive study. My only pause here is that I do not feel that this is a regimen that should be used for all patients. I struggle myself in trying to find patients who I feel that would benefit from this in the first-line setting, as opposed to the classic CLEOPATRA regimen.

I feel that Enhertu is one of the most effective agents that we have seen in breast oncology recently, and I really like to have it as an option when patients really need effective agents. I have treated patients with leptomeningeal disease with Enhertu and I have seen responses that are incredible, really remarkable. I do not feel that there is a real benefit in intensifying treatment early on for all patients.

We need to do better when even doing guidelines because we should not just be saying what is being done in the first-line setting, but also in the subsequent lines. Because what we do if we treat someone with Enhertu plus pertuzumab in the first-line setting, what is our second-line setting? Are we going to get back to CLEOPATRA? Are we going to use the tucatinib? This is important for us because we are going to be the ones making the decisions.

The CLEOPATRA regimen is still a good regimen. It is impressive that we have many patients that do well and go into remission. I wished we were better in trying to identify who these patients are. That is always the challenging.

The data from PATINA, in my opinion, it is important because of the reasons I said. It is an oral agent. We are talking about four years of disease control with a well-tolerated regimen. It does come with some toxicity. It is not free of toxicities, of course, but given what we know from palbociclib, it is remarkable that this agent did what we thought it could do, basically potentiate the benefits not just by maximizing how hormonal therapy works in HER2+ disease, but also potentiating the effects of the anti-HER2 agents. We had this dual hypothesis there that may explain why the outcomes are so good.

The tucatinib in the maintenance setting also added benefit. We can see here the actual numbers, but we are talking about a big percentage in terms of relative risk reduction. It is interesting that for patients who had a history of brain metastases in HER2+/ER-, I think tucatinib is promising there because it seems to expand the duration of disease control in a better way than the control arm.

We did not have time to show here. This was presented, and it is going to be an upcoming publication from PATINA. Palbociclib on the PATINA regimen did seem to prevent CNS recurrences from happening. It is different than what we saw on HER2CLIMB-05, where it did seem to have a benefit for patients who had a history of CNS metastasis.

In PATINA, we did see a lower incidence of CNS disease relapse for patients who did not have a history of CNS metastases at baseline. It is an area that we need to do more research because if palbociclib is preventing the CNS recurrences from happening, it is huge for these patients. Supportive care is critical. We need to be extremely careful with the pneumonitis.

Posttest 4

Let us get back to my list of the favorite questions that we have here. I will give you some time to answer how we should manage the toxicity with palbociclib in terms of neutropenia.

Speaker: This last posttest is open. Please vote. Just a few more seconds for incoming answers on this question. Here are your results.

Posttest 4: Rationale

Dr. Metzger: Excellent. Everyone got the correct answer one more time. That makes me happy. If a patient were on a lower dose, like the lowest dose at this point, where we would not have a further dose reduction, if patients were treated in the PATINA study, we would have to interrupt the drug. I would say that if this happens in clinical practice, it is a CBC that should not be done on that day 15. It is probably benign. I would just give some time and restart the patient at the same lower dose, and not worry much in terms of the neutropenia because that is benign. That is what we had to do.

Poll 4

Based on this lecture, do you plan to make any changes in your clinical practice?

1. Yes;
2. No; or
3. Uncertain.

Speaker: The poll is open. Here are your results.

Dr. Metzger: Excellent. 60% is a lot.

Poll 5

Speaker: This final question, again, this is the QR code. If you have any comments that you would like to make in regards to how you might change what you do in your practice. Please scan that QR code or submit your question or comment in the Q&A section. Again, Dr. Metzger, because of the time here, I will go ahead and collect this information in the background.

Dr. Metzger: Okay.

Speaker: You can move on to the next slide.

Thank You for Attending!

Dr. Metzger: Thank you, everyone, for attending this morning. As I said, I wish this was live or in-person so we could do this in a more interactive manner. We have the information for the CME credits. These slides are going to be available. That this QR code will get you all of that. Thank you again for attending this morning.

Q&A

Speaker: Thank you so much, Dr. Metzger, for your presentation. There are a few questions that have come into the Q&A. If there are any further, you are welcome to enter those. As Dr. Metzger pointed out, there are two QR codes on the screen. There are also links in the chat panel. One will lead to the downloadable slide deck from today's presentation, and the other is for the program evaluation link to claim your credit for attending today. You will need to log in to or sign up for a DCE account, and we would encourage you to claim your credit within 30 days, as credit for today's program will expire after this time frame.

Dr. Metzger, are you able to see those questions in Q&A? I will be happy to read those to you if you are not able to see those.

Dr. Metzger: I cannot see them. If you can read them.

Erika Hamilton: That is all right. I will do that. The first is, when is the appropriate time to refer a patient to a clinical trial?

Dr. Metzger: That is an excellent question. Usually, before a subsequent line of therapy is recommended or considered, because that is the time where we are able to check on potential clinical trials.

Speaker: Thank you. The next is, should a biopsy be repeated on metastatic lesions to confirm if the HER2 status has changed from the primary tumor?

Dr. Metzger: Whenever possible, we like to have a biopsy to confirm the disease recurrence, but it gets nuanced in terms of the interpretation of the HER2 status based on the site of biopsy. Sometimes, particularly with bone lesions, we need to be careful because there are preanalytical features that may interfere with the results. The main purpose of the biopsy is really to confirm the disease recurrence. We also pay attention to the receptors with these caveats. If a patient has HER2+ disease early on, it is more likely to be HER2+ at the time of disease relapse

Speaker: Okay, great. There is one final question, it looks like. It says, do you refer patients to patient support groups?

Dr. Metzger: We do. Here at the Farber, we have a very interesting program created by a colleague of mine that most of you may know, Nancy Lin, that is called EMBRACE. It is a program for patients who have metastatic breast cancer. EMBRACE provides a lot of support to patients dealing with metastatic breast cancer in terms of educational resources, directing them to support groups when appropriate.

What I love of EMBRACE is the fact that when we see patients together or patients come for a second opinion, EMBRACE helps us in the coordination of care. Whenever we need to check on a potential clinical trial or reschedule a visit, do a screening test for a given clinical trial, the EMBRACE coordinators who come to clinic with us, they help us get this all organized in a very nice way. That is not just good for patients, but for us as clinicians as well.