Tucatinib Combo Explored in HER2-Positive Breast Cancer

Rashmi K. Murthy, MD, MBE

Central nervous system (CNS) metastases is a prevalent issue for patients with HER2-positive breast cancer, as approximately 50% of patients will experience them, according to Rashmi K. Murthy, MD, MBE. However, a novel agent has been in development to pass the blood-brain barrier and holds promise to potentially improve outcomes for this patient population.^1,2

An ongoing phase II trial, HER2CLIMB (NCT02614794), is randomizing patients with HER2-positive breast cancer with/without CNS metastases to tucatinib (ONT-380) plus capecitabine and trastuzumab (Herceptin) versus placebo plus capecitabine and trastuzumab. The primary endpoint of the study is progression-free survival (PFS) with secondary outcomes including overall survival and quality of life.

A pooled analysis of 2 phase Ib studies demonstrated a prolonged PFS when patients with or without brain metastases were treated with tucatinib. The median PFS was 8.2 months and 7.8 months in the respective studies. Nearly 20% of patients treated with tucatinib combinations demonstrated a prolonged PFS, defined as ≥16 months. Baseline brain metastases did not differentiate patients who achieved an extended PFS.³

OncLive: Can you give an overview of tucatinib and the HER2CLIMB trial?

In an interview with OncLive, Murthy, an assistant professor in the Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the role of tucatinib in CNS metastases for patients with HER2-positive breast cancer.Murthy: Tucatinib is a molecule that is exciting for the HER2 field. One of the challenges in the treatment of HER2-positive breast cancer is the frequent development of brain metastases, which can occur in up to 50% of patients. Tucatinib in combination has shown some early signs of activity in the CNS in addition to systemically.^2,3 It is an oral HER2-specific tyrosine kinase inhibitor that is well tolerated. Because it blocks only HER2, there are fewer off-target effects, such as rash and diarrhea, which are common with some of the other tyrosine kinase inhibitors.¹ It is currently being evaluated in a randomized clinical trial with capecitabine and trastuzumab.

How prevalent of an issue is CNS metastases in HER2-positive breast cancer?

What is your therapy of choice when treating CNS metastases?

The HER2CLIMB trial is currently enrolling patients who have metastatic HER2-positive breast cancer with prior exposure to taxane, trastuzumab, pertuzumab (Perjeta), and ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients can be enrolled with or without CNS metastases. This is a unique feature of the trial, as patients with brain metastases who have not had any of the standard local therapies may be enrolled; enrollment also allows for patients with progressive brain metastases and allows patients to stay on the study post-progression.Up to 50% of women with HER2-positive metastatic breast cancer experience CNS metastases. When they arise, they can compromise survival and impact quality of life for patients. There remains an unmet medical need for patients with HER2-positive metastatic breast cancer whose disease has metastasized to the brain. The current systemic therapies do not penetrate the blood-brain barrier well, so there is a need for anti-HER2 agents that successfully do cross over.The current approach to management involves a multidisciplinary team, including a medical oncologist, a CNS radiation oncologist, and in some cases, a neurosurgeon to decide upon the best local therapy.

In some cases, the patient could receive Gamma Knife or stereotactic radiotherapy to the lesions if there are few lesions, or whole-brain radiation therapy if there are multiple lesions.

What are some of the first things you take into consideration when treating a patient with HER2-positive disease?

Currently, there are no systemic drugs specifically developed to treat the CNS. The standard of care right now is to consider local therapy and then if there is no progression systemically, the patient is continued on the current systemic therapy, even after local treatment of CNS disease. If there is a systemic progression of disease in addition to the CNS progression, then that would warrant a change in systemic therapy.⁴ With a new patient with metastatic HER2-positive breast cancer, we need to consider their performance status, lab abnormalities, amount of visceral versus nonvisceral involvement, and cardiac function. Their cardiac history becomes especially important because we start thinking about the fact that they are going to need to be on lifelong HER2-targeted therapy.

The first-line treatment for HER2-positive metastatic breast cancer is well established by the CLEOPATRA study.⁵ It is a taxane chemotherapy in combination with trastuzumab and pertuzumab. Generally, we give this treatment for 6 cycles and then transition to maintenance treatment with trastuzumab and pertuzumab, assuming that they have either a good response or a stable disease and have no disease progression during the chemotherapy component.

Where do you see the future of the treatment landscape in the next 5 to 10 years?

Additionally, we consider whether patients are hormone receptor (HR) negative or HR positive. That has clinical implications, especially when you are transferring someone over to maintenance therapy. For those who are HR-positive in clinical practice, we also include an endocrine therapy agent as part of their maintenance regimen. First, there are a lot of interesting drugs being tested right now, especially in the metastatic setting. An area that could potentially change future management is immunotherapy. Recently, results from the PANACEA trial showed that patients who were treated with pembrolizumab (Keytruda) and trastuzumab achieved a disease control rate of 24% in PD-L1—positive patients.⁶ The idea of reprogramming the immune system to stimulate drugs to fight cancer is certainly an area of interest. Several agents are being studied in several settings and in combination with other agents. I am optimistic about the future of immune-oncology, especially in HER2-positive breast cancer.

The second area that could impact the landscape is CDK4/6 inhibition in HR-positive/HER2-positive disease. In the PATINA study, patients who have HR-positive/HER2-positive disease and are treated with the CLEOPATRA regimen (THP) with either having achieved a response or have stable disease and are transitioning over to the maintenance therapy will be randomized to trastuzumab/pertuzumab plus an endocrine therapy agent plus CDK4/6 inhibition versus placebo.

Other drugs, antibody-drug conjugates similar to T-DM1, are currently under investigation. DS-8201a is a novel antibody-drug conjugate comprised of a humanized anti-HER2 antibody attached via peptide linker to a novel topoisomerase I inhibitor is currently being studied in a 2-part phase I study, including a cohort of HER2+ breast cancer previously treated with TDM-1.⁷ These types of drugs are especially interesting from a toxicity perspective, since they utilize HER2 targeting to enter the cell but tend to spare the normal tissues from seeing the toxic effects.

As far as other challenges in HER2-positive breast cancer, we still struggle with how best to sequence all of the therapies that are now approved and whether we should use them in combination. That is an area where more research will be very impactful. Finally, we have some patients who do well with HER2-targeted therapy and can achieve complete responses. At this point, we continue anti-HER2 therapy indefinitely. There are unanswered questions about how long we need to continue the drugs and if we need to continue them until progression, especially in the setting of someone who has had a complete response to therapy.

References

1. Moulder SL, Borges VF, Baetz T, et al., Phase 1 Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+ Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-16-1496.
2. Hamilton, E, Borges V, Conlin A, et al., Efficacy of a Phase 1b Study of Tucatinib (ONT-380), an Oral HER2-Specific Inhibitor, in Combination with Capecitabine and Trastuzumab in HER2+ Metastatic Breast Cancer, Including Patients with Brain Metastases. Presented at the SABCS Annual Meeting 2016. December 9, 2016 (Poster P4-21-01).
3. Hamilton E, Murthy R, Ferrario C, et al. Prolonged progression-free survival (PFS) in advanced HER2+ metastatic breast cancer with or without brain metastases: A pooled analysis of tucatinib in phase Ib studies. Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec 5-9, 2017.
4. Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2—Positive Breast Cancer and Brain Metastases: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2100-2108. doi:10.1200/jco.2013.54.0955.
5. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med. 2015;372:724-734. doi: 10.1056/NEJMoa1413513.
6. Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.
7. Iwasa S, Shitara K, Takahashi S, et al. Updated results of phase 1 study of DS-8201a in subjects with HER2-expressing gastric cancer. J Clin Oncol. 2018;36 (suppl 4s; abstr 118).