: It continues to be a really exciting time in the HER2 [human epidermal growth factor receptor 2] world. A number of agents are under investigation, including novel antibody-drug conjugates, immune-based therapies, and CDK4/6 inhibitors. I think the outcomes are going to continue to improve for women, and hopefully, we’ll be curing more women and treating fewer with metastatic disease. However, in the short-term setting, I think we’re going to be seeing some changes based on the results from clinical trials that have completed enrollment, looking at whether we can move T-DXd [trastuzumab deruxtecan] into the second-line setting, and whether we will be adding tucatinib to T-DM1 [trastuzumab emtansine]. Studies are looking at the use of tucatinib in early stage disease, as well as T-DXd in early stage disease. So, I think the landscape and our guidelines regarding how to sequence and use these agents is going to rapidly change in the next 2 to 3 years. It’s a very exciting time.

Videos

Sara A. Hurvitz, MD, reviews therapy options for patients with HER2-positive metastatic breast cancer and comments on emerging therapeutic strategies.

Future Directions in HER2-Positive Metastatic Breast Cancer

When deciding how to sequence therapies, we don’t have clear guidance based on evidence. From a practical standpoint, if I have a patient in my clinic whose disease has progressed after T-DM1, or trastuzumab emtansine-based therapy, I will usually discuss tucatinib, capecitabine, trastuzumab, and the alternative, T-DXd [trastuzumab deruxtecan] with the patient. I explain that tucatinib is FDA approved based on a large, randomized placebo-controlled trial. Level 1 evidence supports the use of this regimen because it has been shown to improve overall survival and progression-free survival, even in patients with brain mets [metastases] and in those with visceral metastases. On the other hand, T-DXd also has very promising phase 2 data supporting it’s high level of efficacy in heavily pretreated disease. The downside to T-DXd, of course, is the risk of interstitial lung disease. So, I won’t put a patient with a history of pulmonary fibrosis or serious lung disease at baseline on T-DXd. I would pursue tucatinib instead. For a patient who has active or previously treated CNS [central nervous system] metastases, I would likely go for tucatinib as the preferred regimen first, then switch to T-DXd at the time of progression. It’s shared decision-making between myself and the patient when we decide how to sequence the therapy based on the data. I think both tucatinib-based and T-DXd–based therapy are very appropriate third-line agents. But the use of patient factors, wishes relating to adverse effects, and ability to comply with oral medications all weigh into the decision-making.

Sara A. Hurvitz, MD, comments on her preferences for treating patients with HER2-positive metastatic breast cancer and shares her strategy for sequencing therapies.

Treatment Sequencing for HER2-Positive Metastatic Breast Cancer

: Longer-term safety data were also presented at ASCO [the American Society of Clinical Oncology annual meeting] for the HER2CLIMB trial. The safety data were reassuring; there were no new safety events or signals that were picked up. It’s still a fairly low percentage of patients who discontinued tucatinib or trastuzumab for adverse event [AE]-related issues. For example, with tucatinib, about 6% of patients discontinued treatment due to an AE; for trastuzumab, only about 4%; and for capecitabine, about 12% of patients discontinued due to an AE. That was similar between the 2 treatment arms. The most common adverse events that were noted remained stable when compared to the original reporting of this clinical trial, with about 13% of patients in the tucatinib arm having a grade 3/4 diarrhea, which is about 4.5% greater than what was seen in the placebo arm. The hand-foot syndrome rates were about 5% greater in the tucatinib arm, focusing on grade 3/4 rates. However, other AEs seemed to be fairly similar when you compare the 2 treatment arms with the exception of AST [aspartate aminotransferase] and ALT [alanine aminotransferase] elevation, which occurs roughly 4.5% more in the tucatinib arm compared to the placebo at a rate of grade 3 or 4. Overall they are encouraging and consistent safety data.

When I’m initiating a patient on tucatinib, capecitabine, and trastuzumab, it’s important to spend a good amount of time on patient education regarding adverse effects that may be encountered. Specifically, it’s important to talk about diarrhea and make sure the patient has antidiarrheals on hand. It’s not necessary to start antidiarrheals immediately, unlike with other TKIs [tyrosine kinase inhibitors], where a patient has to use loperamide from day 1, for example, with neratinib. I haven’t needed to do that in my practice when initiating tucatinib with capecitabine, and trastuzumab. However, some patients will develop serious diarrhea, so I will do phone calls. My nurse practitioner or I will reach out to the patient on a weekly basis for the first month to make sure that they’re not running into trouble, and provide education on dietary things that can be done to improve diarrhea. Similarly, with hand-foot syndrome, we have patients moisturize their hands well and avoid things like gardening without gloves or doing the dishes without gloves, very practical things that can help, and also have them call us if they get into trouble. Of course, patients should be monitored for their liver enzymes and visit the clinic at least every 3 to 4 weeks to have laboratory tests and an examination done.

Recommendations for mitigating and managing common treatment-related adverse events associated with tucatinib, trastuzumab, and capecitabine based on safety data from HER2CLIMB.

Adverse Events in HER2-Positive Metastatic Breast Cancer Treatment

In the HER2CLIMB study, the protocol specified that another analysis of overall survival would be done approximately 2 years after the last patient was randomized. These updated survival data were presented at ASCO [the American Society of Clinical Oncology annual meeting] this year. Interestingly, the overall survival differences, in spite of the fact that patients crossed over from the placebo arm to the tucatinib arm, continued to favor patients who were originally assigned to the tucatinib arm. The hazard ratio was 0.73, which is statistically significant. The median overall survival for patients in the tucatinib arm was 24.7 months, compared to 19.2 months in the placebo arm. So there was about a 5.5-month benefit with the use of tucatinib in this particular clinical trial. A nice separation of the curves is easily seen on the Kaplan-Meier analysis. Prespecified subgroups, an exploratory analysis, was also presented, and interestingly, the survival improvements appeared to be seen with tucatinib regardless of patient age, race, hormone receptor status, and in patients who have baseline brain metastases, you’re seeing a significant improvement in overall survival, with a trend toward one in patients without brain metastases. There wasn’t a subgroup that wouldn’t tend to benefit from the use of tucatinib.

A lot has been made about choosing agents that are particularly active if a patient has visceral metastasis and the need for getting a dramatic response. I think it’s important that the investigators did an exploratory analysis looking at outcomes for patients based on whether they have visceral metastasis. Over 450 patients had visceral metastases on this clinical trial. The hazard ratio was 0.70 for them, which was statistically significant at 0.004. The median overall survival was about 21.6 months for those treated with tucatinib vs 16.9 months for those not. For those without visceral metastases, again, a smaller number of patients, the trend was toward the favor of tucatinib, with a hazard ratio 0.80. This wasn’t statistically significant. This wouldn’t discourage me from using tucatinib in patients without visceral metastases. However, it gives me reassurance that using tucatinib in patients with visceral metastasis is a safe thing to do.

Combination therapy with tucatinib, trastuzumab, and capecitabine shows efficacy in all patient populations studied.

Updated Results from HER2CLIMB and Tucatinib Use in Patient Subgroups

: HER2CLIMB was a large, randomized, placebo-controlled clinical trial evaluating trastuzumab combined with capecitabine, in combination with either tucatinib, the HER2-selective tyrosine kinase Inhibitor, or placebo. In this study, patients with heavily pretreated HER2-positive metastatic breast cancer were assigned to 1 of these treatment arms and followed for efficacy. The important key feature of this clinical trial, in terms of the eligibility criteria, is that patients who had a history of brain metastases—either stable, previously treated brain mets [metastases], or newly diagnosed brain metastases, or progressing brain metastases after treatment for the brain metastases—were allowed on the clinical trial. Oftentimes in studies for metastatic breast cancer, those patients would be excluded. Knowing that tucatinib can cross the blood-brain barrier, investigators designed this study to include these patients. Close to 50% of patients enrolled in this study did have a history of brain metastasis. In this study, the median progression-free survival in the intent-to-treat population was significantly prolonged. Also, the progression-free survival in the subset of patients with brain metastases was prolonged. Moreover, the overall survival in the intent-to-treat population was significantly prolonged, with a hazard ratio of 0.66, which is highly statistically significant. The overall survival was also prolonged in patients who had brain metastases. The percentage of patients who had an intracranial objective response in their brain metastases was about 50%, which was about double that seen in the control arm.

These very exciting data led to the FDA approval of this agent. When the data came out sayingthe overall survival improved significantly in the tucatinib-treated patients, a decision was made to unblind patients and allow those receiving the placebo to cross over to the tucatinib arm. Unblinding and crossover can affect long-term overall survival analysis because if patients move to the arm that is associated with better survival, this can certainly impact the readout of the intent-to-treat analysis for overall survival later. However, it’s an ethical thing to do when you know that a particular agent is so active that it’s improving survival. I applaud the sponsor of the study for deciding to do that.

Efficacy of tucatinib in combination with trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer, including patients with brain metastases or visceral disease.

Tucatinib for HER2-Positive Metastatic Breast Cancer

: The treatment of HER2 [human epidermal growth factor receptor 2]-positive metastatic breast cancer has vastly improved in the past several decades. In the past, the outcomes associated with this type of breast cancer were quite poor, and this subtype was associated with one of the worst prognoses. But now we know from recently collected data about the outcomes of patients newly diagnosed with metastatic breast cancer that patients with HER2+ metastatic breast cancer may have the longest median overall survival. This is likely due to the fact that we have so many targeted therapies available. At last count, we had 8 HER2-targeted therapies for metastatic disease, thus providing multiple options for patients whose disease progresses after first-line therapy. Right now, in the second-line setting, we use trastuzumab emtansine, or T-DM1, the antibody-drug conjugate, in the second-line approach. But that may change in the near future as new studies are published that compare T-DM1 to other types of therapies. So, we may see that second-line position change in the coming years.

In the third-line setting and beyond, we still have a multitude of options available for patients.

One exciting option that has been recently approved in the last few years is trastuzumab deruxtecan, or T-DXd, another antibody-drug conjugate that has been studied in a single-arm phase 2 clinical trial. T-DXd demonstrated remarkable efficacy, with an objective response rate greater than 60%, and a median progression-free survival around 20 months, in very heavily pretreated disease. This included patients with a heavy disease burden, including visceral disease. The other agent that’s very exciting is tucatinib, in combination with capecitabine and trastuzumab. This agent is a HER2-selective tyrosine kinase inhibitor. It’s a pill formulation given with a capecitabine, a pill chemotherapy, in combination with trastuzumab. In a phase 3 clinical trial, it showed remarkable efficacy, not only for patients with visceral mets [metastases] and nonvisceral metastases, but for patients with brain metastases. So, we have these 2 options available. Many would say that these would be the top 2 options we would consider in the third-line setting, and maybe selecting between those 2 based on whether a patient needs a quick objective response, or whether the patient has brain metastases. Ultimately, most patients will go on to receive the agent they don’t receive in the third-line setting. They’ll receive the other agent in the fourth-line setting. It is an exciting time to have all of these agents available.

An overview of treatment options for HER2-positive metastatic breast cancer and practical guidance on selecting therapy.

Sara A. Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center

Articles

Future Directions in HER2-Positive Metastatic Breast Cancer

Treatment Sequencing for HER2-Positive Metastatic Breast Cancer

Adverse Events in HER2-Positive Metastatic Breast Cancer Treatment

Updated Results from HER2CLIMB and Tucatinib Use in Patient Subgroups

Tucatinib for HER2-Positive Metastatic Breast Cancer

Treatment Options in HER2-Positive Metastatic Breast Cancer