Applying Updated Findings From SABCS 2023 to HER2+ Breast Cancer Practice

Carey K. Anders, MD

Professor of Medicine, Chief of Division of Medical Oncology, Duke Health,

Durham, NC

As part of an Around the Practice® discussion with CancerNetwork®, Carey K. Anders, MD, spoke about updated findings in the HER2-positive breast cancer space, which investigators presented at the 2023 San Antonio Breast Cancer Symposium (SABCS). She highlighted data related to agents such as pertuzumab (Perjeta) and tucatinib (Tukysa) and discussed how these results may impact the treatment paradigm in this population, including those with brain metastases.

Anders, a professor of medicine and chief of the Division of Medical Oncology at Duke Health in Durham, North Carolina, also reviewed ongoing research assessing tucatinib-based regimens across various treatment settings. Current studies aim to assess whether the brain-permeable agent may improve central nervous system (CNS) recurrence outcomes among patients with HER2-positive disease when administered in combination with standard treatment options.

Regarding those with brain metastases, Anders emphasized frequent communication with multidisciplinary partners such as nurses and radiation oncologists to help with managing symptoms and ensuring quality care. Overall, these novel therapeutic combinations may support “significant advances” in the treatment of patients with HER2-positive disease, although learning how to sequence these regimens represents an ongoing challenge.

Q/ What are the latest updates from the trials presented at the 2023 SABCS evaluating treatment approaches for HER2-positive breast cancer? What are the potential implications of these data on clinical practice?

Anders /I will start with some of the updates in the adjuvant and postadjuvant settings, including the phase 3 APHINITY trial [NCT01358877] subset analysis and the phase 3 KATHERINE trial [NCT01772472].^1,2 We’ve known for many years that the addition of pertuzumab to trastuzumab [Herceptin] in the adjuvant setting has afforded our patients improved outcomes. When we first learned about the addition of pertuzumab and the APHINITY subset analysis, we saw that there may be a difference [in outcomes] based on estrogen receptor signaling, effectively favoring pertuzumab among those whose tumors did not express estrogen.

As the data have matured, what was reassuring at the SABCS update was that the addition of pertuzumab helps our patients whose tumors do or don’t express the estrogen receptor. They also analyzed the amount of HER2 expression, and it appears that the addition of pertuzumab is beneficial regardless of estrogen receptor or HER2 expression. These [data were] very reassuring and continue to confirm our current practice.

We’ve also known for years that in the postneoadjuvant setting for our patients with HER2-positive disease, those who have residual disease at surgery benefit from completing their adjuvant treatment with ado-trastuzumab emtansine [T-DM1; Kadcyla] as opposed to trastuzumab. This was seen in the KATHERINE trial early on, with a disease-free survival [DFS] benefit favoring those who received T-DM1 in the adjuvant setting. Sibylle Loibl, MD, PhD, presented the final invasive DFS and overall survival [OS] analysis at SABCS. Data showed both an improvement in invasive DFS and a nearly 5% improvement in OS for our patients who have residual HER2-positive disease in the postneoadjuvant therapy setting with T-DM1 as opposed to standard trastuzumab…. In the KATHERINE trial, [it is important to know] that there was not a trastuzumab/pertuzumab arm because at the time the study was being conducted, that was not our standard of care.

Q/ What were the updates from the phase 3 HER2CLIMB-02 study (NCT03975647),³ and how might they impact
clinical practice?

Anders /For many years, we’ve been practicing with the brain-permeable HER2-selective tyrosine kinase inhibitor tucatinib in triplet form. Treatment would be with tucatinib, trastuzumab, and capecitabine [Xeloda]. In the original phase 2 HER2CLIMB study [NCT02614794], we saw that the addition of tucatinib to trastuzumab/capecitabine improved both
progression-free survival [PFS] and OS.⁴ This was also seen among patients with brain metastases, which can comprise approximately 40% to 45% of the patient population.

The design of HER2CLIMB-02 effectively added tucatinib to the antibody-drug conjugate T-DM1. At the time this study was being conducted, T-DM1 was our second-line standard of care, [which] has now been replaced with trastuzumab deruxtecan-nxki [T-DXd; Enhertu] based on the phase 3 DESTINY-Breast03 study [NCT03529110].⁵ This is an important distinction in terms of how we interpret these data and where we place T-DM1 into the treatment algorithm with tucatinib.

Effectively, what we saw is that the addition of tucatinib to TDM-1 was beneficial compared with T-DM1 alone. This did come with some toxicities, particularly liver dysfunction, [which is] something important to be paying attention to if we choose this doublet. The question that remains now is: What does the landscape or treatment algorithm look like? [Currently], our first-line therapy is taxane, trastuzumab, or pertuzumab. In most cases, we tend to go with T-DXd, but there are some cases where we might position tucatinib/trastuzumab/capecitabine in the second-line setting, particularly in the setting of active brain metastasis.

The question, then, is: Where would we position T-DM1 and tucatinib? It is important to note that patients in the HER2CLIMB-02 study had not received prior tucatinib. We’re still grappling with how to position this combination doublet therapy, but it may have a place for certain patients who may not tolerate T-DXd or have toxicity from T-DXd in the second-line setting, particularly pneumonitis. Additionally, [the doublet may be suitable for] patients who might not be able to tolerate capecitabine due to gastrointestinal [GI] toxicity.

Another important question that we must think about when designing studies or looking at real-world data is: Should we be continuing tucatinib in one line—perhaps with trastuzumab/capecitabine—and then continuing it into the next line with T-DM1? That’s a question we don’t know the answer to. Hopefully, we’ll see in the future whether continuing tucatinib beyond progression with an alternate backbone would be beneficial for our patients.

Q/ What was the design and rationale for the ongoing phase 3 HER2CLIMB-05 study (NCT05132582)⁶ evaluating the addition of tucatinib to trastuzumab and pertuzumab as maintenance therapy for HER2-positive metastatic breast cancer?

Anders /This study is effectively evaluating the addition of tucatinib to trastuzumab/pertuzumab as maintenance therapy for patients with HER2-positive breast cancer. Patients who’ve received their taxane portion are moving forward with trastuzumab/pertuzumab and the addition of tucatinib.

There are several things to think about here. What sort of toxicity profile might we see? We know that trastuzumab/pertuzumab comes with GI toxicity. We know that tucatinib might increase the diarrhea risk. It’ll be interesting to see what the toxicity profile looks like, particularly from a GI perspective. The other thing to consider here is the impact on intracranial and extracranial PFS. We know tucatinib is a brain-permeable compound; [CNS] recurrence is common among our patients with HER2-positive disease. One exciting possibility is that the addition of tucatinib would not only improve extracranial PFS but [also] potentially prevent, delay, or abrogate the potential for CNS recurrence when added to our backbone antibodies that historically don’t cross the blood-brain barrier to the same degree that a small molecule inhibitor would.

Q/ What were the design and rationale for the ongoing phase 2 BRIDGET study (NCT05323955)⁷ evaluating the addition of tucatinib to trastuzumab/pertuzumab or T-DM1 after local therapy in patients with isolated brain relapse or progression?

Anders /Like the HER2CLIMB-05 study, this is looking at the addition of tucatinib to HER2-directed antibody therapy with either trastuzumab/pertuzumab or TDM-1. Patients would enroll in the BRIDGET study at the time of CNS recurrence and local therapy to the brain. A patient might be doing well on their backbone trastuzumab/pertuzumab, have developed CNS relapse, have radiosurgery to intracranial lesions, and then would add tucatinib to trastuzumab/pertuzumab. Similarly, this would be the same if a patient was on single-agent T-DM1, which is fascinating now that we have the data for the HER2CLIMB-02 study showing the efficacy of T-DM1 and tucatinib.

The goal of this study was to delay the time to the next CNS progression. This would be considered a secondary prevention study. The patient has already experienced intracranial recurrence and disease progression, and now we’re trying to prevent or delay the time to the next CNS event. This [study] could have significant implications in future clinical practice because it would go against what we see in the American Society of Clinical Oncology guidelines for the management of HER2-positive brain metastasis.⁸ At present, after local therapy and in the absence of extracranial progression, patients are typically maintained on their current HER2-directed therapy. This study would add tucatinib to the current ongoing therapy if we see a delay in CNS progression. I am very excited to see these results.

Q/ What is your perspective on the future of HER2-positive breast cancer treatment, especially for those with brain metastases? Are you able to offer any clinical pearls for community oncologists treating patients with breast cancer?

Anders /It’s become very clear that we’re seeing significant advances in the care of our patients with metastatic HER2-positive breast cancer, both with and without brain metastasis. We now have antibody-drug conjugates and tyrosine kinase inhibitors; some are given on their own, but now we’re also starting to see combination strategies. One of our challenges as a community is how to best sequence these exciting therapies for individual patients. Many of the ongoing studies and real-world data will help us understand the activity of a certain molecule after prior therapies, particularly if those studies haven’t been done or if it is difficult to perform them in a prospective manner.

When it comes to our patients with brain metastases, one comment for our providers is just to lean heavily on our multidisciplinary partners. The care of our patients with brain metastases involves a multidisciplinary team, which involves our nurses, surgical colleagues, radiation therapy colleagues, and palliative care colleagues to help with symptom management and goals of care. I would highly encourage anyone who is taking care of patients with advanced HER2-positive disease and brain metastases to communicate frequently and often with their local therapy partners. Additionally, I look forward to what we have on the horizon for our patients with advanced HER2-positive breast cancer.

References

1. de Azambuja E, Agostinetto E, Samy F, et al. The benefit of adjuvant pertuzumab and trastuzumab according to estrogen receptor and HER2 expression: sub-analysis of the APHINITY trial. Presented at: 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-9, 2023; San Antonio, TX . PS09-04.
2. Loibl S, Mano M, Untch M, et al. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. Presented at: 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-9, 2023; San Antonio, TX.GS03-12.
3. Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at: 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-9, 2023; San Antonio, TX.GS01-10.
4. Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis.Ann Oncol. 2022;33(3):321-329. doi:10.1016/j.annonc.2021.12.005
5. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.Lancet.2023;401(10371):105-117. doi:10.1016/S0140-6736(22)02420-5
6. Hamilton E, Tsurutani J, Curigliano G, et al. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB05, Trial in Progress). Presented at: 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-9, 2023; San Antonio, TX . PO1-19-11.
7. Sammons S, Van Swearingen A, Noteware L, et al. Secondary Brain metastases prevention after Isolated intracranial progression on trastuzumab/pertuzumab or T-DM1 in pts with advanced human epidermal growth factor receptor 2+ breast cancer with addition of tucatinib (BRIDGET). Presented at: 2023 San Antonio Breast Cancer Symposium; San Antonio, TX; December 5-9, 2023. PO5-20-02.
8. Ramakrishna N, Anders CK, Lin NU, et al. Management of advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: ASCO guideline update. J Clin Oncol. 2022;40(23):2636-2655. doi:10.1200/JCO.22.00520