When you speak about metastatic breast cancer, every patient can be seen as an unmet need because every patient will die at 1 point from that disease. Very few patients are cured. Even things that are not considered to be unmet needs feel like unmet needs at some point. Therefore, this combination with tucatinib can help address these unmet needs. Patients who have progressive brain metastases who have already been treated with radiation therapy cannot get radiation therapy again, but you can give them this triplet combination. When those patients progress again, we have another unmet need because if you cannot treat them, then their prognosis will be bad. But we have some new drugs coming out to treat 

 [human epidermal growth factor receptor 2]–positive breast cancer. The most exciting and most talked treatment is trastuzumab deruxtecan, or T-DXd. That is very impressive for an early clinical trial.

Unfortunately for this molecule, we are still waiting for the randomized study, so it is difficult to know exactly where we are going to put it. Most patients who received T-DXd [trastuzumab deruxtecan] have had very nice responses, and that is very unusual for patients with multiple pretreatments, so we are very happy to have T-DXd [trastuzumab deruxtecan] available to those patients because it will allow us to design treatment strategies that will help our patients and prolong their overall survival rates. It is difficult at the moment, because we have 2 treatments: the combination with tucatinib and this triplet combination with tucatinib on 1 hand, and on the other hand, T-DXd [trastuzumab deruxtecan], which came out around the same time. It is difficult to conduct a precise evaluation of which will be first or who will be second.

For the moment, we have to wait for a phase 3 trial with T-DXd [trastuzumab deruxtecan]. Most likely, in the months to come, there is going to be another other trial focusing on T-DXd [trastuzumab deruxtecan] vs T-DM1 [trastuzumab emtansine] in particular. In this trial, T-DXd [trastuzumab deruxtecan] was more effective than T-DM1 [trastuzumab emtansine] for the second line. Thus, the patient will receive T-DXd [trastuzumab deruxtecan] in second line, and tucatinib will be the third line after T-DXd [trastuzumab deruxtecan]. As for T-DM1 [trastuzumab emtansine], I do not know when we are going to use it. Maybe it will be used as a fourth line or in combination with tucatinib. There is another study, HER2CLIMB-02, that combined T-DM1 [trastuzumab emtansine] and tucatinib with randomization. The landscape is really going to change in the months and years to come for those patients. It will change for the better because those drugs are very efficient, so I hope that it will really improve the PFS [progression-free survival] rate, the quality of life, and the overall survival of our patients who have 

Because I am enthusiastic about this trial and all the new developments, I do think there are many unmet needs already. These unmet needs have been discussed in several meetings—even the virtual meetings—over the last year, and 1 unmet need is the prevention of brain metastases in patients with metastatic disease. It might be possible to add something to therapy—for example, tucatinib—and prevent the occurrence of brain metastases.

Some patients are unsuccessful when given local treatment for brain metastases, so radiotherapy and surgery are necessary. We may need some strategies to provide effective systemic therapy for these patients after the treatment failure of local therapy. Another point that came into my mind is that we need a better combination of endocrine therapy with HER2-targeted therapy, especially in the context of CDK4/6 inhibitors. They are not used as a standard of treatment for 

+ breast cancer. That is a field ready for development. That is going to be a place for endocrine treatment, together with HER2-targeted therapies.

Finally, it is important to prevent metastatic disease, so the ultimate goal is to optimize earlier treatment of breast cancer and to find strategies to cure more patients. In summary, given the status of the HER2CLIMB study and the approval in Europe, I am excited that we have a new drug, a new combination that prolongs overall survival, for not only patients with brain metastases but also our entire patient cohort. I am looking forward to the developments, and I am curious about what will come up.

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Considerations on the evolving landscape and ongoing unmet needs for patients with HER2+ breast cancer.

Unanswered Questions in HER2+ Breast Cancer

 [human epidermal growth factor receptor 2]–positive metastatic breast cancer. I am also excited about the data on trastuzumab deruxtecan. This was also approved by the European authorities, with a conditional approval based on the phase 2 data of the unrandomized DESTINY-Breast01 trial. This trial gave a remarkable response, but of course we lack randomized data. These trials are almost completed or completed already, so we are going look at that. We cannot use trastuzumab deruxtecan on a routine basis because it is not available in Germany unless there is a special situation. That might be different in other countries in Europe. We have to apply for it, and then we get an approval on an individual basis. We have also used this for several patients. In the HER2CLIMB study, we used trastuzumab deruxtecan, and I think it worked. All treatment sequence would be after T-DM1 [trastuzumab emtansine], tucatinib, and then trastuzumab deruxtecan.

Volkmar Mueller, MD, shares insight on the potential sequencing of available therapeutics for patients with metastatic HER2+ breast cancer.

Approaches to Sequencing for Metastatic HER2+ BC

The clinical implications of the approval of tucatinib are quite important, because, as you know, it is the first drug that was developed specifically—it was not developed for this originally, but in the clinical trial this was the case—to include patients with active brain metastases. This drug and trial is the only 1 to have done that. We have a strong rationale to use this combination for patients with active brain metastases. We did not have any randomized studies that had those kind of patients included, so the evidence is very strong; the trial presents strong evidence to use tucatinib for those patients because the data have shown that utilization of this triplet combination—with tucatinib, trastuzumab, and capecitabine—improves the overall survival rate for these patients.

Patients who have a progressive disease, especially patients with brain metastases that did not receive capecitabine before, will be candidates to use this triplet combination. We are very excited about that. Furthermore, even for patients with no brain metastases who have been progressing on T-DM1 [trastuzumab emtansine], this triplet combination can improve overall survival. It will be our first choice for those patients.

After the approval, tucatinib is going to be the standard treatment after trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine], and not only in Germany. We updated our German guidelines at the end of February 2021, and we prefer tucatinib, trastuzumab, and capecitabine as a treatment regimen after the failure of T-DM1 [trastuzumab emtansine].

The landscape is shifting. You might know that trastuzumab, pertuzumab, and T-DM1 [trastuzumab emtansine] are also used in the treatment of early diseases as neoadjuvant and postneoadjuvant treatments, so we are going to have a lot of patients who already had this treatment who might receive this combination with tucatinib in the first-line setting to treat metastatic disease.

Experts discuss the clinical implications of the approval of tucatinib in Europe, specifically for patients with active brain metastases. 

Clinical Implications of Tucatinib Approval in Europe 

My experience with tucatinib is driven by my participation in the HER2CLIMB trial. We had several patients in the trial. Many were from Germany, and I am unsure about what other countries patients came from. I have a feeling that it is good and manageable. After that, there came an expanded or early access program before the approval. We have also had several patients utilize open-label, non-placebo-controlled treatments on that combination, so it was effective from my limited experience.

One question we have is how do these data fit into data from the real world? One of my clinical and research interests is brain metastases because there is an unmet need in regard to treatment for that. It is an impairment and decreases patients’ quality of life and life expectancy. We have set up a registry for brain metastases in Germany, which includes more than 3600 patients. In our first publication 1½ years ago, with almost 2000 patients, we saw that the overall survival after the diagnosis of brain metastases was approximately 11 months. This is also in line—it may be a bit different but not completely different—with the French data. They have just found the overall survival of the entire patient crowd, not only those with the 

 [human epidermal growth factor receptor 2]–positive subtype, which was 8 months after the diagnosis of brain metastases.

The HER2CLIMB trial showed that overall survival, after the start of therapy for brain metastases, was 18 months. I do not know if you can compare it, but it does look a little better, given that the standard arm was only 12 months. There was an overall survival benefit with tucatinib for patients with active brain metastases at almost half. The hazard ratio was 1.5, so it really set the risk for dying to 50%.

I would like to discuss my experience and how it relates to the real-world data. For the moment, considering real-world data, we see this combination is quite small in France because we can use it only from 4 to 6 months. We do not have a lot of patients who were treated with this combination outside the clinical trial. I have some patients who have been treated with this combination after the clinical trial, but most of my patients were treated during the clinical trial. I do not see many differences. It is quite efficient for patients. We see some responses, as shown in the HER2CLIMB study. With regard to brain metastases, this combination is very nice.

We have had very good control of the treatment of our patients with brain metastases for a long time, as I told you before, with few toxicities. Our feeling is that it is really an improvement. This treatment is an improvement that will better treat our patients, especially those with brain metastases that have undergone multiple lines of treatment already. I do not have much experience regarding the real-world utilization of this molecule because it has been studied for such a short time, but the results are very much in line with what has been published in the HER2CLIMB study.

An examination of the real-world data supporting the use of tucatinib for patients with metastatic HER2+ breast cancer in Europe.

Real-World Experience With Tucatinib in Germany and France

Regarding the safety profile of tucatinib, I feel that it is very good. It is not complicated to use this molecule. Actually, it is easier to use tucatinib than other HER2 [human epidermal growth factor receptor 2] tyrosine kinase inhibitors, like lapatinib and neratinib. At this time, it is more toxic with 

; inhibition gives cutaneous toxicities and digestive toxicities like diarrhea. Tucatinib has some of those toxicities too, but they tend to be very mild.

I was an investigator on the HER2CLIMB study. Patients were randomized and given tucatinib, trastuzumab, and capecitabine or trastuzumab-capecitabine alone. I could not discern which patients were on the placebo or the experimental drug because there were not many differences in digestive toxicities, particularly diarrhea, which is the main toxicity that results from this combination. It was not much worse than the treatment we have with capecitabine alone. The management is quite simple. You have to give medication to prevent diarrhea if patients experience that; you can then adapt to the dosage of tucatinib. This toxicity occurred in only a few patients. In most patients, you could manage them very easily with some alimentary modifications. It is not a large problem to manage this agent.

 One important point to consider when considering every new compound is the safety profile. When adding an additional compound to a regimen, we expect some additional toxicity. In the context of the HER2CLIMB study, patients were at an increased risk of diarrhea and also elevated liver enzymes. However, I must say that I was impressed by the low rate of treatment discontinuation due to adverse events: 7% in the tucatinib arm and approximately 4% in the placebo arm. Going off my impression, patient management with the 3-drug arm is driven by the good management of capecitabine, which we have a lot of experience with. In my opinion, this is causing the diarrhea more often than tucatinib.

I do not feel that routine loperamide is required, so we do not use that. In the context of adverse effects, it is also important to know that there are a great deal of data concerning the quality-of-life data of patients in the trial. Actually, the first set of data was presented at ESMO [European Society for Medical Oncology Congress] 2020. These data indicated that the quality of life of patients was not impaired by adding tucatinib. Patients were able to maintain a good quality of life. Because patients had received treatment for a longer time, they had a longer period in which they experience good quality of life. However, because of the progression of disease, quality of life was also eventually worsening.

At the San Antonio Breast Cancer Symposium in December 2020, there were additional data sets available for patients with brain metastases. The quality of life for patients was also maintained for a longer time with an addition of tucatinib. There is a positive trial outcome but also a positive outcome in regard to quality of life.

Experts in breast oncology review the favorable safety profile of tucatinib for patients with metastatic HER2+ breast cancer.


Favorable Safety Profile of Tucatinib for Metastatic HER2+ BC

Today I am going to talk a little about the approval of tucatinib for the treatment of 

 [human epidermal growth factor receptor 2]–positive metastatic breast cancer. Actually, the European authorities approved tucatinib after 2 lines of previous therapy for 

+ metastatic breast cancer. The compound is also available in many countries, including Germany. The approval is based on the HER2CLIMB trial. HER2CLIMB was a trial that examined patients with metastatic 

+ breast cancer who had all received a previous line of treatment with trastuzumab, pertuzumab, as well as T-DM1 [trastuzumab emtansine]. This is the standard for first- and second-line therapy. Patients were randomized 2:1. Overall, 612 patients received either tucatinib or a placebo, each combined with trastuzumab and capecitabine.

The patients had a median 4 previous lines of therapy, and all patients were required to have a brain MRI [magnetic resonance imaging] at baseline. The primary end point was progression-free survival, and secondary end points included overall survival and progression-free survival in some patients with brain metastases. Actually, the trial also assessed the quality of life of the patients, and this is something I am going to talk about a little later. Regarding the efficacy of the results, the HER2CLIMB trial met all its primary end points. This is a little unusual. I do not think I have ever seen a trial—maybe there was, but I cannot remember—that met all the end points, both primary and secondary. The risk—that was the primary end point, progression-free survival—for progression fell by 46% in the trial.

The results of the trial showed that progression-free survival for 1 year was at 33% with tucatinib and only at 12% for the patients in the placebo group. The outcome for overall survival was positive. The risk of death reduced by 34%, and overall survival at 2 years was 45% likely with tucatinib and 27% likely with the placebo. For me, this is the most impressive result because this is a very positive outcome for patients overall. I also already mentioned that patients with brain metastases—patients received an MRI at baseline—were allowed to enter the trial, which was a little unusual. In many trials, patients with brain metastases were excluded. Patients with brain metastases were allowed and joined the study.

Entering the HER2CLIMB trial, 48% of the patients had brain metastases, and about half of them had treated and stable brain metastases. The other half of these patients with brain metastases had untreated or progressing brain metastases, or active brain metastases. For this group, the overall outcome was positive; overall survival was prolonged. The overall survival duration was 18.1 months with tucatinib and only 12 months with the placebo. The risk of death decreased by 42%. The intracranial response rate was about 47% for tucatinib and only 20% for the placebo. The additional data shown at ESMO [European Society for Medical Oncology Congress] 2020 and retrospective data analyses indicated that the occurrence of brain metastases in the overall patient crowd, or progression of brain metastases, was reduced by 50% when adding tucatinib to trastuzumab and capecitabine. Almost 40% of all patients with 

+ metastatic breast cancer developed brain metastases, so this is a clinically relevant result.

Volkmar Mueller, MD, reviews recent data from the HER2CLIMB trial and discusses the recent regulatory approval in Europe for patients with HER2+ breast cancer. 

Thomas Bachelot, MD, PhD, Centre Leon Berard

Articles

Unanswered Questions in HER2+ Breast Cancer

Approaches to Sequencing for Metastatic HER2+ BC

Clinical Implications of Tucatinib Approval in Europe

Real-World Experience With Tucatinib in Germany and France

Favorable Safety Profile of Tucatinib for Metastatic HER2+ BC

European Commission Approval of Tucatinib in HER2+ BC