Thank you all for the great discussion. I have 1 last question for everyone. What’s an important question you have in the field of 

 [human epidermal growth factor receptor 2]–positive metastatic breast cancer? Dr Criscitiello, you can start.

 An important and interesting question for the near future would be to understand optimal sequencing of treatments, not only for the drugs that we have available and those that will be available soon, but also those for which we have less evidence. Another important issue will be to understand, in light of new drugs, potential effects on brain maps. We may remodulate the way we use local treatments for patients with brain metastases and 

 We have drugs in the metastatic setting that may dramatically affect the outcome. This is quite important. Many of these agents in the early breast cancer setting will increase dramatically to the number of patients that could be cured. The question is how to differentiate a treatment in a special population of patients, like the brain metastases population. They have metastatic disease. Why not the triple-positive system? Treatment of any ER [estrogen receptors]–positive 

+ in the future will be different from patients who are ER- and 

+. The future will differentiate niche patients with 

+ disease, but the treatment algorithm that we have today will be different.

 I’ll echo what my colleagues have said. I also considered where else there might be gaps. It would be wonderful to find an opportunity to de-escalate some of our poly-drug, poly-chemotherapy, and targeted-therapy regimens in the early stage setting, to refine who needs to escalate therapy based on failure of [inaudible]. Is there a simpler approach with some of these amazing new drugs as a monotherapy, with an antibody-drug conjugate in a de-escalation strategy. Brain metastases remain an area of unmet need. The third area would be, how do these agents combine with checkpoint inhibitors? We know PD-L1, after triple-negative breast cancer, is highly expressed in 

+ breast cancer. Could there be an opportunity to see how these drugs partner with checkpoint inhibition?

It’s difficult from the last 1, the combination with anchor therapy. That’s aligned with de-escalation toxicity, which is something that could be explored. I’d love to see more trials that have a focus on that. Thank you for this great discussion. It was inspiring. I hope those who watch it give us feedback and tune in again.

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Unmet needs regarding the selection and sequencing of therapies for patients with HER2-positive metastatic breast cancer.

Addressing Treatment Gaps in HER2+ MBC

 I’d like to know about the availability of drugs in your country. What’s available? Reimbursement is not the same in every country, so please comment on that briefly.

 In Italy, we don’t have a reimbursement for tucatinib or trastuzumab deruxtecan, but we have expanded access. We can access both trastuzumab deruxtecan and tucatinib.

 Regarding the sequencing issue, trastuzumab deruxtecan will likely become the new standard of care for second-line treatment. I’d prefer tucatinib as third line, but there will be differences across countries if regulatory agencies adopt different positions. In some countries, tucatinib will remain available after 2 prior lines of anti–HER2 [human epidermal growth factor receptor 2] agents; in others, after prior T-DM1 [trastuzumab emtansine]. We have to consider access to drugs across the world, especially in low-income countries. These are matters that should be considered when discussing sequencing. It will affect the choice of treatment sequencing on what patients will receive as part of the adjuvant treatments because these drugs are moving earlier in the course of the disease.

 If we’re sequencing these agents with monoclonal antibody or antibody-drug conjugate, as a mechanism of resistance you begin to see the extra-cellular domain of HER2 downregulated? Could there be a rationale for sequencing your tyrosine kinase inhibitor between these agents to mix up the strategy with which we’re targeting the cancer cell? That would be interesting to see, and we need help sequencing these agents and data to guide us.

That’s an important point. One reason I prefer third-line treatment with tucatinib for sequencing is because most patients also receive a fourth-line treatment.

A global perspective on managing patients with HER2-positive metastatic breast cancer through multiple lines of therapy based on treatment advances.

Optimizing Therapy in HER2+ MBC Across the Globe

Returning to brain mets [metastases], we saw retrospective data of patients who did not have brain metastases at initial diagnosis and entry into the trial. It appears that the more active combination of tucatinib, trastuzumab, and capecitabine can prevent the occurrence of brain metastases. That’s something we have not addressed yet. Half of the patients who have HER2-positive metastatic disease will develop brain metastases, so we urgently need strategies to prevent this. We need to focus not only on treated patients who have been locally pretreated, but also prevention. That’s one of the other wishes we have, we believe this combination might help prevent the occurrence of new brain metastases. What are your thoughts?

 That’s a generating hypothesis for moving tucatinib, as the TKI [tyrosine kinase inhibitor] that crosses the blood-brain barrier, early into the treatment algorithm. I’d love to see those studies, Dr Criscitiello mentioned a combination with T-DM1 [trastuzumab emtansine]. You can envision in the highest-risk population in early stage disease who failed pathCR [pathologic complete response], if you had evidence that the combination with tucatinib could prevent the development of brain metastases, that would be an answer to a huge unmet need. The data you’re referring to are hypothesis generating, to look in that space and hopefully change the natural history of HER2+ metastatic disease.

 We have performed a big part of the process with these new drugs, but there is still an unmet need in treating patients with brain metastases. The longer these patients live, the higher chance they will develop brain metastases at some point. One problem is the progression of brain metastases in patients who have already received radiation therapy and cannot do it again. Some patients undergo multiple local treatments, but eventually they are no longer feasible. Traditionally, systemic drugs are not that effective on brain metastases. We shouldn’t forget the physical and cognitive deterioration in response to radiation therapy. With effective drugs on the brain, we could be less aggressive in local treatments. Another problem is the presence of leptomeningeal metastasis, which is related to end of life in these patients. It’s important to understand if and how we can prevent brain metastases.

There were several reports, one mentioned at ESMO [European Society for Medical Oncology annual meeting], about T-DXd [trastuzumab deruxtecan] and active brain metastases. There’s also a small subset of the DESTINY-Breast01 trial that was reported at ASCO [American Society of Clinical Oncology] this year, 2021. Dr Criscitiello can you comment on that?

 At ASCO this year was a subgroup analysis of the DESTINY-Breast01 trial. Patients with a history of brain metastases were presented. The study enrolled 24 patients with baseline brain metastases that were treated as symptomatic and did not require therapy to control symptoms. In the subanalysis, the outcomes of efficacy were comparable to those in the total patient population; 14 of 24 patients had the baseline diameters of brain metastases. Among these patients, 7 of 14 had a response in the brain. It’s important to remember that of these 14 patients, 12 had received prior radiation therapy before enrollment in the study. Trastuzumab deruxtecan works in patients with brain metastases as we have seen from the TUXEDO trial mentioned earlier. But we are talking at the moment about a few patients. In the subanalysis of the DESTINY-Breast01 trial, we’re talking about patients with stable brain metastasis; patients with active brain metastases were ineligible for this study. Most of these patients received prior radiation therapy. It’s important to differentiate between active progressing brain metastases and stable brain metastases. Also, in the best sequencing of tucatinib versus trastuzumab deruxtecan in patients with brain metastases, tucatinib is the only data in this setting in which we have, from a phase 3 randomized controlled trial, proof of efficacy on acting brain metastases. So in patients with active brain metastases, I would choose tucatinib first. For patients with stable brain metastases, our data suggest a superior trastuzumab deruxtecan over tucatinib. While there are no direct comparisons, this may change in the future based on the results of the ongoing trials.

 Yes, that was beautifully said and comprehensive. It’s difficult to make cross-trial comparisons when recognizing patient populations in the DESTINY-Breast01 trial and how that differs from the HER2CLIMB population. It’s encouraging to see the beginnings of a signal of CNS [central nervous system] penetration and activity from an antibody-drug conjugate [ADC], where we felt traditionally that kind of construct was too big or bulky to cross the blood-brain barrier. There’s evidence that that’s not the case, and perhaps the permeability and the cleavable linkers in the engineering of these new ADCs may allow for CNS penetration. They are exciting and encouraging data in both respects, to have tucatinib and [trastuzumab] deruxtecan as an option.

There are a lot more data coming. We mentioned that earlier use of tucatinib and T-DXd might offer insight if we are able to prevent [brain metastases]. The DESTINY-B12 trial will allow the recruitment of patients with active brain metastases but also those without brain metastases; it will have 2 cohorts. It will give us insight into whether we are capable of preventing brain metastases, but also about the efficacy of T-DXd, trastuzumab deruxtecan, in those patients with active brain metastases. We already have some evidence on how we can use these drugs in different patient cohorts. Moving forward there will be many new trials, exciting meetings, and new data for this big unmet need of brain metastases, but also for all the other patients.

Recent advances in the characterization and treatment of patients with HER2-positive metastatic breast cancer and brain metastases.

Updates in the Management of HER2+ MBC With Brain Metastases

Moving on to the new drugs, there are fantastic and exciting developments we can discuss. One aspect we can discuss are new studies and combined therapies, tucatinib. There are several ongoing studies. Dr Criscitiello can you comment on that?

Yes, there are…several ongoing trials with combinations of tucatinib and trastuzumab deruxtecan. One is the HER2CLIMB-02 trial, which is a phase 3 study in which patients with metastatic 

 [human epidermal growth factor receptor 2]–positive breast cancer, who have had prior treatment with taxane and trastuzumab [INAUDIBLE], are randomized to receive either T-DM1 [trastuzumab emtansine] plus placebo or T-DM1 [trastuzumab emtansine] in combination with tucatinib. In this study, baseline brain MRI is required, and patients with stable, progressing, or untreated brain metastases may be eligible. The primary end point of the study is progression-free survival. Overall survival and objective response rate are key secondary end points of the study.

Another ongoing trial is HER2CLIMB-04, which looks at a combination of tucatinib and trastuzumab deruxtecan. This is a single-arm, open-label, phase 2 trial that evaluates the efficacy and safety of those combinations with 

+ metastatic breast cancer with at least 2 prior anti-HER2 regimens in the metastatic setting. There’s a similar study, the DESTINY-Breast07 trial, which is a phase 1b/2 trial with multiple arms; 1 of those arms is assessing the safety of tucatinib plus trastuzumab deruxtecan. In the HER2CLIMB-04 trial, patients with the brain metastases, including the active brain metastases, may be included. The primary end point is confirmed objective response rate when looking at their assessment. The secondary end points are progression-free survival, duration of response, disease control rate, overall survival, and safety.

You mentioned brain metastases, which is an important point. The longer we have survival, there’s an increasing rate of brain metastases. For the HER2CLIMB trial, nearly 50% of the patients had brain metastases. You mentioned that patients with active brain metastases are eligible. In your clinical practice, do you differentiate between patients with active and progressing brain metastases and stable brain metastases? Does that have any implications for treatment in your clinical practice?

These situations are clinically diverse. Stable brain metastases are those previously treated with no evidence of progression. Active progressing brain metastases are those previously treated with progression of existing, new, or untreated lesions at baseline. Stable brain metastases are not a problem because they don’t affect the choice of treatment. Whereas progressing brain metastases in patients who have already received radiation therapy, cannot undergo further radiation therapy. Here, it’s 3 years.

That’s the most clinical implicant aspect. We need special trials. In the context of trastuzumab deruxtecan there are some ongoing trials.

An overview of novel combination regimens being investigated for the treatment of HER2+ metastatic breast cancer.

Novel Combination Approaches for HER2+ MBC

Coming back to ILD [interstitial lung disease]. There’s a potential adverse effect of the drug that must be watched, but can we manage? What’s your approach and your experience with that?

Trastuzumab deruxtecan is extremely effective, so I’m not afraid to use it with a potential ILD. When we think of trastuzumab deruxtecan and ILD, we’re influenced by the DESTINY-Breast01 trial data, where there was 2.2% of grade 5 ILD. Whereas in the DESTINY-Breast03 trial, there are no grade 5 and 4 ILD and just 0.8% of grade 3 ILD. This suggests that toxicity decreases with experience in managing it right. We must be aware of the potential adverse events so we can recognize it promptly and start early management in case of toxicity. I’ve seen 2 women with ILD occurring during trastuzumab deruxtecan treatment. We monitor for ILD in clinical trials, so most of ILD has been detected in symptomatic patients with regular CT scans performed every 3 cycles. Most of the ILD events occur within the first 12 months of treatment, and there’s decrease after that period…. In the first year, patients should perform regular CT scans…and bring the…identification and effective management of ILD treatment. We must remember how to manage the toxicity in terms of treatment. Patients with ILD should stop therapy. In the case of grade 2 or more ILD, treatment must be withheld; in the case of grade 1 ILD, treatment may be resumed upon resolution. Steroids may also be used to manage ILD.

Not all patients must come off treatment. If they develop a mild, low-grade ILD, we will learn to manage it. We must be careful, but the patient…will contribute to that. Thank you for your thoughts.

Recommendations for managing patients with HER2+ metastatic breast cancer who develop interstitial lung disease, an adverse event of trastuzumab deruxtecan.

T-DXd for HER2+ MBC and Interstitial Lung Disease

 Dr Müller, because we have the data from the HER2CLIMB trial, what’s the new treatment algorithm for HER2 [human epidermal growth factor receptor 2]–metastatic breast cancer?

Returning to these regimens, quality of life despite survival is important. I want to address your experience and your feelings on the adverse effects of these regimens. Dr Traina, can you explain the different adverse effects of these regimens, your management, and your experience?

You raise an excellent point. Getting the disease under control helps our patients feel their best, but they’re on therapy for a long time, and we want to ensure that the toxicities are manageable and not impacting their health-related quality of life. Trastuzumab and pertuzumab as a combination is well tolerated. We often see pertuzumab with a GI [gastrointestinal] toxicity; that is, diarrhea or nausea that the backbone chemotherapy or taxane [paclitaxel] can contribute to. In general the trastuzumab-pertuzumab combination, incrementally, is well tolerated, but the chemotherapy adverse effects are what we’re managing with that triplet. With capecitabine and TKI [tyrosine kinase inhibitors] combinations, there’s a pill burden to manage and toxicity related to that. There is also the GI toxicity around managing diarrhea and nausea, which is more significant than with the pertuzumab. Concern around hand-foot syndrome, rash, GI toxicity, LFT [liver function test] abnormalities, and the financial burden of an oral regimen has a different structure in the United States in terms of reimbursement for patients. They may have a higher out-of-pocket cost for a full oral regimen compared with an intravenous regimen.

Moving on to newer drugs—trastuzumab deruxtecan, for example—this ADC [antibody-drug conjugate] has asthenia and fatigue associated with it. A significant adverse event that we’re aware of is interstitial lung disease or pneumonitis. In the DESTINY-Breast01 trial, that occurred about 15% to 16% of the time of all grades, but there were grade 5 fatal events related to pneumonitis, about 2% to 3%. That is significant and gives us pause. In subsequent protocols, there were strict guidelines around managing, observing, and monitoring pneumonitis. In my practice, we’re monitoring with high-resolution CT scans that we use to evaluate for response to therapy. There’s a low threshold to whole drug, even with ground-glass opacities. If anyone is symptomatic, we are not only holding drug but intervening with corticosteroid and involving our pulmonologist to support these patients. It’s a different adverse event that we need to be aware of and intervene accordingly. We discussed TDM-1 [trastuzumab emtansine], which is well tolerated, but there are often LFT abnormalities, monitoring for thrombocytopenia, and dose adjustments around thrombocytopenia.

 I completely agree. We experience the same adverse effects that you’ve described. Additionally, there’s ILD [interstitial lung disease], which is potentially a fatal complication. It’s important to increase awareness, and oncologists must recognize it clearly to start appropriate treatment with steroids to avoid a fatal outcome. In the DESTINY-Breast03 trial, we achieved this end point because there were no patients who died from ILD. In the real world we should be careful. We must recognize the symptoms to start an appropriate treatment as soon as possible.

 These drugs can potentially cause adverse events, but it’s important to be familiar with potential events to recognize and manage them. In this scenario it’s important to educate both patients and physicians. The toxicity may be reduced with our experience in using the drugs. The more we use the drug, the more we become confident and experts in managing them, even with the potential of adverse events.

There’s a learning curve from study to study, and supporting that curve has to be steep.

Recommendations for monitoring for and managing adverse events associated with newer therapies being sequenced into HER2+ metastatic breast cancer treatment algorithms.

Managing TRAEs Associated With Novel HER2+ MBC Therapies

Three weeks ago, we had data from the DESTINY-Breast03 trial during the ESMO [European Society for Medical Oncology] meeting. I would like hear your comments on how those data are changing practice. Dr Criscitiello, can you please explain the DESTINY-Breast03 trial?

Yes, as a reminder the DESTINY-Breast01 trial led to the introduction of trastuzumab deruxtecan into the treatment paradigm for patients with metastatic HER2-positive breast cancer. That was a phase 2 study of trastuzumab deruxtecan in heavily pretreated patients who had HER2+ metastatic breast cancer, with an impressive 6 median prior lines of treatment. We have presently seen updated results of that trial, increased duration of survival in follow-up, with confirmed benefit. At the San Antonio Breast Cancer Symposium 2020, we saw the update in median progression-free survival, which was 19.4 months, and at ESMO this year we saw the updated results for the overall survival [OS], with a median OS of 28.4 months. This is very impressive.

The DESTINY-Breast03 trial is even more impressive. That is a randomized phase 3 study comparing efficacy and safety of trastuzumab deruxtecan versus T-DM1 [trastuzumab emtansine] in patients with HER2+ metastatic breast cancer who were previously treated with trastuzumab and a taxane. In this study, the patients were randomized in a 1:1 ratio. The primary end point was progression-free survival by blinded independent central review, while the secondary end points were overall survival, objective response rate, the duration of response, progression-free survival…and safety.

The study randomized 524 patients, and the results presented at the latest ESMO meeting showed an impressive, compelling hazard ratio in progression-free survival of 0.28. That’s amazing, we have never seen…in a clinical trial in breast cancer. With regard to the overall survival, at the interim analysis we saw an encouraging hazard ratio of 0.56, with a 

 value of 0.007, although it did not cross…for significance. Another important finding is the 12-month overall survival rate, which is 94% with trastuzumab deruxtecan versus 86% with T-DM1. In terms of objective response rate, it was 80% with trastuzumab deruxtecan and 34% with T-DM1. It’s important and quite impressive that with trastuzumab deruxtecan, only 1.1% of patients had progressive disease as best response. This is a truly amazing drug.

Practice-changing data from the DESTINY-Breast03 trial evaluating trastuzumab deruxtecan as second-line therapy in HER2-positive metastatic breast cancer presented at ESMO 2021.

Updated Data From DESTINY-Breast03 in HER2+ MBC

, “The Changing Landscape of HER2+ Metastatic Breast Cancer.” I’m Volkmar Müller from the University Medical Center Hamburg-Eppendorf, in Germany. Joining me today through virtual discussion are my colleagues who have great expertise in the field.

 I’m Carmen Criscitiello, medical oncologist at the European Institute of Oncology and assistant professor at the University of Milan, Italy.

 My name is Giuseppe Curigliano, I work at the European Institute of Oncology and University of Milan.

 I’m Tiffany Traina. I’m a breast medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

 Thank you for being here. Today we will review treatment approaches for HER2-positive metastatic disease. We will be discussing new data from recent congresses and how these results might impact our clinical practice in the future. It’s a great opportunity to have a multinational board, as we can discuss broad perspectives. In the first segment we will cover the current treatment landscape for HER2+ metastatic disease from different perspectives. Are there differences between various regions of the world in the incidence and other factors of HER2+ metastatic disease?

 Breast cancer is the most diagnosed cancer worldwide. We have more than 2 million new cases yearly, and it accounts for roughly 12% of new total cancer cases; it’s the leading cause of cancer among women. HER2+ breast cancer accounts for 15% to 20% of all breast cancers, and the incidence rates are highest in America, Australia, and Europe, and lowest in Asia. Twelve percent of all breast cancer cases are HR+ [hormone receptor-positive], HER2+, while 5% are HR-negative, HER2+, the lowest rates for all races and ethnicities. Up to 50% of patients with HER2+ breast cancer will develop brain metastases throughout the course of the disease, and approximately 50% of patients with HER2+ breast cancer and brain metastases die from intracranial disease progression. This is an important topic for HER2+ metastatic breast cancer, and the incidence of brain metastases appears to be higher in patients with HR-, HER2+ tumors compared to patients with HR+, HER2+ tumors.

 I completely agree of course on the epidemiology described. It’s quite clear that in the United States and the Western world we have a higher incidence with respect to Asia. In terms of biology, it’s more common to have HER2+ breast cancer in younger, premenopausal and postmenopausal women than in the elderly population because there are studies addressing patients over 75, usually there is a lower incidence of HER2 positivity.

 One thing that we’ve observed over the past several years is, the introduction of highly active drugs has reduced the number of patients we’re seeing in the first-line metastatic setting, as the influence of those highly active therapies is curing women who are diagnosed with early stage HER2+ breast cancer.

 Yes, that may be true especially for countries that have available adjuvant setting treatment, which is also influencing metastatic disease.

Breast oncologists from across the globe react to incidence rates of HER2-positive metastatic breast cancer as they relate to rates of progression to brain metastases and treatment advances.

Carmen Criscitiello, MD, PhD

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