Activity With Tucatinib Across the Blood-Brain Barrier Presents a Vital Option in HER2+ Breast Cancer

Tucatinib (Tukysa) was recently approved in the treatment landscape for advanced HER2-positive breast cancer, including in patients who have a history of brain metastasis or active brain metastasis. The drug is specifically indicated in combination with capecitabine and trastuzumab (Herceptin) as treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases who have received 1 or more prior anti-HER2-based regimens in the metastatic setting.

The role of tucatinib in this patient population fulfilled an unmet need for a drug that has the ability to cross the blood-brain barrier that could be added to standard capecitabine and trastuzumab This is, in fact, one of the mechanisms of tucatinib, and its capability was demonstrated in the phase 2 HER2CLIMB trial (NCT02614794), which met all of its efficacy end points, 1 of which was progression-free survival (PFS) among patients with brain metastases.

“There was no single standard of care with data showing substantial PFS benefit and certainly overall no overall survival benefit following pertuzumab and TD-M1,” Rashmi Murthy, MD, MBE told Targeted Oncology.

Now that tucatinib plus capecitabine and trastuzumab (Herceptin) is an approved regimen that has shown promise for safely and effectively treating HER2-positive breast cancer, others studies have been launched to investigate tucatinib in combination with TD-M1 or the approved tucatinib triplet to address unmet needs for patients with brain metastases or those who develop leptomeningeal disease.

In an interview with Targeted Oncology, Murthy, assistant professor, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center discussed the final results from the HER2CLIMB study and the future of tucatinib as it makes its way to the community setting as treatment of advanced HER2-positive breast cancer.

TARGETED ONCOLOGY: Can you discuss the prevalence of HER2 overexpression in breast cancers and the activity seen with available treatments before the approval of tucatinib? What about patients with brain metastases?

Murthy: HER2 overexpression occurs in about 20% to 25% of breast cancers and prior to the approval of the newer agents that we’ve recently heard about, there was no single standard of care in the third-line setting, after exposure to trastuzumab, pertuzumab (Perjeta), and TD-M1 (Kadcyla). There were several NCCN-approved chemotherapy regimens like capecitabine in combination with trastuzumab or even other HER2 tyrosine kinase inhibitors (TKIs) such as lapatinib (Tykerb) in combination with trastuzumab or capecitabine.

But again, there was no single standard of care with data showing substantial PFS benefit and certainly overall no overall survival (OS) benefit following pertuzumab and TD-M1.

As far as brain metastasis, these can occur and up to 50% of patients with her two positive breast cancer surface presents a big problem. The standard of care treatment when brain metastases are found to occur has been limited to a local therapy such as resecting that the tumor or offering radiation treatments, which would either be local radiation gamma knife or whole-brain radiation. We've had limited systemic treatment options to date. Although, in 2019, the NCCN guidelines did endorse the use of capecitabine and neratinib as a systemic therapy option for patients with HER2-positive breast cancer and brain metastases based on the TBRC-22 trial.

Beyond that, there has been a great need to develop more drugs that cross the blood-brain barrier effectively.

TARGETED ONCOLOGY: What was the rationale for the HER2CLIMB study?

Murthy: We noticed that there was no single standard of care treatment that was established in the third-line setting prior to the recent approval. There is definitely a need for more drugs in the space.

Tucatinib has 2 features that make it a strong partner or backbone for capecitabine and trastuzumab. One is its HER2 selectivity. It is very selective for HER2, as opposed to being selective for EGFR inhibition. This feature allows for efficacy, while at the same time limiting, toxicities that are often related to EGFR inhibition, such as diarrhea and rash. The second feature of tucatinib is the fact that it is able to cross the blood-brain barrier because, as I noted, brain metastases are a problem for patients with HER2-positive disease.

Both of these features made tucatinib an ideal partner to be added to the standard background of capecitabine and trastuzumab as tested in the HER2-CLIMB study.

TARGETED ONCOLOGY: What are the results observed with tucatinib/trastuzumab/capecitabine in this trial are unique compared with other small molecule TKIs?

Murthy: As we get into the results is really important to highlight 2 features of the patient population enrolled in the trial. One is that these patients were heavily pretreated. They all had exposure to trastuzumab, pertuzumab, and TD-M1. The other unique feature of the trial is that it included patients with both a history of brain metastases and those with active brain metastases. In fact, out of over 600 patients, approximately 50% of the trial population had a history of brain metastases, and about 40% had a newer progressive brain disease. This highlights the fact that this is a high-risk population.

Moving onto the results, the trial met all 4 of its end points, including PFS, OS, PFS in the brain, metastasis patient population, and objective response rate. We saw in the trial that when tucatinib was added to trastuzumab and capecitabine, this resulted in an improvement in

PFS, both in the overall patient population as well as in the brain metastasis patient population. Further, there is an unprecedented improvement in OS of 4.5 months in this heavily pretreated and high-risk patient population.

The benefit from tucatinib was noted across all the clinically relevant subgroups, and also we saw a near doubling in the confirmed objective response rate with the addition of tucatinib.

One of the most striking results from the study was that among patients with brain metastases, who received tucatinib, a quarter of them remained on the study at the 1-year mark, whereas, none of the patients with brain metastases who were randomized to placebo did not remain.

I think this is a really big step forward. We need to continue to develop drugs that have the ability to cross the blood-brain barrier without complications.

TARGETED ONCOLOGY: Based on this study how safe is this combination in patients with HER2-positive breast cancer?

Murthy: I think the study results confirm that the combination is very safe and well-tolerated. The most common adverse events that noted were diarrhea, hand/foot syndrome, nausea, vomiting, and fatigue. These were all mostly low grade. There was also an elevation in liver transaminase levels noted with the addition of tucatinib, but these also were largely low grade, transient, and reversible with either treatment hold or discontinuation of the drug. There was no signal for any kind of long-term damage.

Treatment discontinuation due to adverse events was very low in both arms of the trial, and most patients discontinued due to disease progression.

TARGETED ONCOLOGY: Now that the drug is approved, what advice can you give to community oncologist who use this combination for their patients?

Murthy: Based on its tolerability profile, the unprecedented overall survival benefit that we saw in this high-risk patient population, and the activity of tucatinib across the blood-brain barrier, this is an important treatment option to offer patients with advanced HER2-positive breast cancer. This included both those who do not have brain metastases and those who do.

As I mentioned before, it has been a safe and tolerable regimen. Any toxicities were easily managed. One of the key adverse events is low-grade diarrhea, which can be well-managed with antidiarrheals.

TARGETED ONCOLOGY: What is next for tucatinib in the breast cancer space?

Murthy: There is other research with tucatinib combinations. One exciting trial is the HER2CLIMB-02 study which is another randomized study testing the addition of tucatinib to TD-M1. This trial is currently in enrolling and it also allows locations with a history of or active presence of brain metastases.

Another difficult problem that we run into with this patient population in the development of the leptomeningeal disease. This, unfortunately, is associated with the poor prognosis we have limited treatment options for this. We do have a trial ongoing through the Translational Breast Cancer Research Consortium to evaluate the combination of tucatinib, capecitabine, and trastuzumab specifically for patients with leptomeningeal disease.