Addition of Tucatinib to Breast Cancer Maintenance Therapy Aims to Fill Unmet Need for Patients With Brain Metastases

The first-line standard-of-care treatment for patients with metastatic HER2-positive breast cancer, consisting of a taxane and trastuzumab (Herceptin) plus pertuzumab (Perjeta) followed by maintenance therapy, has proven to be an efficacious option for patients, however, combating resistance mechanisms and treating brain metastases in this patient population remain areas of unmet need.

“One of the greatest challenges [in caring] for patients with metastatic HER2-positive breast cancer is the prevention and treatment of brain metastases because up to 50% of our patients will develop brain metastases,” Kay T. Yeung, MD, PhD, said in an interview with OncLive^®.

With a primary end point of progression-free survival (PFS), the phase 3 HER2CLIMB-05 trial (NCT05132582) is examining the efficacy of the addition of tucatinib (Tukysa) to trastuzumab and pertuzumab as maintenance therapy for patients with advanced HER2-positive breast cancer who have received 4 to 8 cycles of induction therapy with trastuzumab, pertuzumab, and a taxane.¹ The trial is enrolling patients with asymptomatic brain metastases that are untreated and do not need immediate treatment, those with asymptomatic metastases that were previously treated, and those without brain metastases.

“In other settings tucatinib has been shown to delay resistance to trastuzumab-based therapy,” Halle C.F. Moore, MD, an associate professor in the Department of Medicine at Case Western Reserve University School of Medicine and member of the Population and Cancer Prevention Program at Case Comprehensive Cancer Center in Cleveland, Ohio, noted in an interview with OncLive.

“The tyrosine kinase inhibitor [TKI] tucatinib does represent a different mechanism of action in terms of targeting the HER2 pathway,” Yeung, an associate professor of medicine at UC San Diego Health in California, added. “We are hoping that tucatinib can not only address the unmet need in brain metastases, but also potentially extend that duration of response without incurring too much impact on quality of life [QOL].”

Tucatinib, which inhibits phosphorylation of HER2/3 resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation,² has shown promise for patients with brain metastases as the small molecule inhibitor of HER2 can cross the blood-brain barrier.³ Additionally, the agent is highly selective for HER2, with a greater than 1000-fold specificity for HER2 compared with EGFR.

Previously, data from the pivotal phase 2 HER2CLIMB (NCT02614794) study showed that, regardless of whether patients with HER2-positive breast cancer had active or stable brain metastases, treatment with tucatinib in addition to trastuzumab and capecitabine resulted in a 61.4% reduction in the risk of central nervous system (CNS)-PFS vs placebo plus trastuzumab and capecitabine (HR, 0.39; 95% CI, 0.27-0.56; P < .001).³

“When patients develop brain metastases their QOL suffers,” Nicholas P. McAndrew, MD, MSCE, an assistant professor in the Division of Hematology/Oncology at UCLA David Geffen School of Medicine in Los Angeles and Santa Monica, California, said in an interview with OncLive. “If this drug combination does reduce the rate, or at least significantly delay the likelihood, of developing brain metastases, that would be an important unmet need.”

Targeting Brain Metastases Early On

Findings from HER2CLIMB led to the April 2020 FDA approval of tucatinib in combination with trastuzumab and capecitabine for those with or without brain metastases and unresectable or metastatic HER2-positive disease, providing an efficacious option for those with brain metastases but only in the second line or beyond.⁴

“The goal is to see whether we can bring tucatinib into an earlier line, in this maintenance line, before brain metastases even develop or before brain metastases progress,” Yeung said.

In HER2CLIMB, 48% of patients had brain metastases, which closely aligns with the rate of brain metastases in the real-world population of patients with HER2-positive metastatic breast cancer. An analysis of patients with brain metastases (n = 291) demonstrated that adding tucatinib to trastuzumab and capecitabine reduced the risk of intracranial progression and death; patients in the tucatinib arm (n = 198) achieved a median CNS-PFS of 9.9 months (95% CI, 8-13.9) compared with 4.2 months (95% CI, 3.6-5.7) for those who received placebo plus trastuzumab and capecitabine (n = 93).⁵

“The original HER2CLIMB study is enlightening in the sense that we see that patients with active brain metastases, or even treated stable brain metastases, can experience an overall survival [OS] benefit,” Yeung noted. Additionally, patients in the tucatinib arm experienced a 68% reduction in the risk of progression in the brain or death vs the placebo arm (HR, 0.32; 95% CI, 0.22-0.48; P < .0001). The estimated 1-year OS rate was 70.1% (95% CI, 62.1%-76.7%) vs 46.7% (95% CI, 33.9%- 58.4%), respectively.⁵

Aiming to Increase Efficacy For All

“HER2CLIMB-05 is interesting because it offers a nonchemotherapy triplet combination, and hopefully will also delay the time to progression which would then delay the time to needing additional chemotherapy,” Moore explained.

In patients evaluable for the OS analysis in HER2CLIMB, the median OS for those treated with tucatinib plus trastuzumab and capecitabine (n = 410) was 21.9 months (95% CI, 18.3-31.0) vs 17.4 months (95% CI, 13.6-19.9) for those who received placebo plus trastuzumab and capecitabine (n = 202; HR, 0.66; 95% CI, 0.50- 0.87; P = .0048). The median PFS was 7.8 months (95% CI, 7.5-9.6) for patients in the investigational arm (n = 320) compared with 5.6 months (95% CI, 4.2-7.1) for patients in the control arm (n = 160; HR, 0.54; 95% CI, 0.42-0.71; P < .00001).²

“[With] HER2CLIMB-05 [we’re] trying to see if we can improve upon the maintenance phase of the first-line treatment of metastatic HER2-positive breast cancer,” McAndrew explained. “The current SOC is to give approximately 6 cycles of a taxane combined with trastuzumab and pertuzumab.

Then, if the patient’s still responding well and tolerating the regimen, we typically drop the taxane and continue with trastuzumab and pertuzumab. Patients do very well with this first-line regimen; however, progression is still essentially universal in this population, unfortunately.”

Keeping a Close Eye on Tolerability

Treatment with HER2-targeted TKIs may result in high incidences of adverse effects (AEs) such as diarrhea and skin toxicity due to the off-target effects the drugs have on the EGFR receptor. However, tucatinib is highly selective for the HER2 receptors and has demonstrated minimal inhibition of other HER2 receptors, including EGFR.⁶

“In the past HER2CLIMB study a lot of the AEs can potentially be [attributed to] capecitabine,” Yeung said. “With tucatinib and trastuzumab I would look at [data from the phase 2] MOUNTAINEER study [NCT03043313] in terms of the safety profile.”

Although it was conducted in patients with gastrointestinal cancer rather than breast cancer, findings from MOUNTAINEER, which examined tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wildtype unresectable or metastatic colorectal cancer, demonstrated a favorable safety profile. When investigators evaluated treatment-emergent AEs in the safety population treated with the combination (n = 86), no deaths were attributed to AEs and 5 patients discontinued treatment due to AEs.⁷

Further, 22.1% of patients experienced serious AEs and 38.4% experienced grade 3 or higher AEs encompassing hypertension (7.0%), diarrhea (3.5%), and fatigue (2.3%) among others.⁷

McAndrew added that “as a class of drugs, TKIs, especially HER2-targeted TKIs, can cause diarrhea. Pertuzumab can cause diarrhea [as well]—it causes it by a different mechanism of action––and we’re interested to see to what degree differences in diarrhea between the 2 groups [are observed].”

McAndrew also explained that liver function test abnormalities can be seen with tucatinib. Yeung noted that “there is a chance for liver injury, which typically is elevation of liver enzymes; sometimes when it’s bad, it can cause hyperbilirubinemia, but fortunately that is not common, and it could be monitored and tracked. Also, with any medications, tucatinib is not an exception, there can be allergic reactions which I have seen [with the drug].”

An analysis of the HER2CLIMB trial data showed that health-related QOL (HRQOL) was preserved for patients treated with tucatinib in combination with trastuzumab and capecitabine. For those with brain metastases, HRQOL was maintained for longer in patients who received tucatinib than in those who did not.⁶

“We know that the combination of trastuzumab and pertuzumab can increase the risk for cardiac toxicity, and that does not appear to be further increased with the addition of tucatinib,” Moore explained.

Enrollment Criteria

The randomized, double-blind HER2CLIMB-05 study will enroll patients with locally advanced or metastatic HER2-positive breast cancer that is unresectable who have received 4 to 8 cycles of prestudy induction therapy with trastuzumab, pertuzumab, and taxane as first-line therapy; patients must not have experienced disease progression following the completion of induction therapy. Additionally, both patients with hormone receptor–positive and those with hormone receptor– negative disease will be enrolled and status must be known.¹

The primary end point is PFS by investigator assessment per RECIST 1.1 criteria. Secondary end points include OS, time to deterioration of HRQOL, CNS-PFS, and AEs, among others.

Patients will receive tucatinib 300 mg orally twice daily or placebo orally twice daily in addition to intravenous (IV) trastuzumab 6 mg/kg or 600 mg via subcutaneous injection every 21 days and IV pertuzumab 420 mg every 21 days. A combination trastuzumab/pertuzumab product may also be administered in place of the individual agents and is comprised of pertuzumab 600 mg, trastuzumab 600 mg, and 20,000 units hyaluronidase given via subcutaneous injection every 21 days.¹

Patients must be able to undergo a contrast-enhanced brain MRI to be enrolled in the study. Those who received prior HER2-targeting or EGFRtargeting TKI therapy will not be included. CNS exclusion based on screening of brain MRIs and clinical assessments will occur for those with symptomatic brain metastasis after CNS-directed local therapy; progression of brain metastases since starting first-line trastuzumab, pertuzumab, and taxane treatment; untreated brain lesions in anatomic sites that may pose risk; and known or suspected leptomeningeal disease.

“We will have to see whether tucatinib is helpful in the first-line setting,” Yeung said. “My hope is that we will see some positive signal. At the end of the day, it’s how we can understand the approaches of managing and limiting the occurrences of brain metastases in patients with HER2-positive breast cancer [that is key]. We should pay close attention to any agents that can pass the blood-brain barrier and see if we can bring them into studies.”