Episode Notes

It has been our policy from the  start not to shy away from the most difficult subjects.

This season is no different. Brain metastases are unfortunately an all too common and devastating complication of HER2 positive breast cancer. Local radiation therapy has long been the mainstay of treatment, but recent years have seen growing interest in systemic treatments as well. We would like to end this season on a positive note. Our guest Dr. Nancy Lin will review the latest advances in the systemic treatment of CNS metastases.

The treatment of patients with HER2-positive metastatic breast cancer can now be tailored based on the presence of active central nervous system (CNS) disease, due to substantial advances made in the past few years into small molecule inhibitors and macromolecule biologics, according to a presentation by Mark Pegram, MD, at the 39th Annual Miami Breast Cancer Conference.

“Macromolecule biologics, such as monoclonal antibodies or antibody-drug conjugates [ADCs], can penetrate the blood–brain barrier, resulting in objective responses,” Pegram, an associate dean for Clinical Research Quality, Stanford University School of Medicine, said during his lecture. “Tucatinib [Tukysa]-based therapy improves overall survival [OS] for patients with HER2-positive breast cancer with brain metastases, while maintaining overall health-related quality of life, with some potential benefit also seen in leptomeningeal metastasis.”

Systemic Therapies for Brain Metastases

The blood-brain barrier has long been a key obstacle to developing effective systemic therapies to treat CNS disease; however, newer agents have shown signs of overcoming this challenge. Studies with 89zirconium-trastuzumab (89Zr-trastuzumab) have shown the ability of monoclonal antibodies to cross the blood-brain barrier. In these studies, a high-dose version of trastuzumab (Herceptin) was tested in combination with pertuzumab (Perjeta) for patients with HER2-positive metastatic breast cancer with progressive brain metastases, with promising results demonstrated in the phase 2 PATRICIA study (NCT02536339). Here, the CNS objective rate (ORR) was 11% (95% CI, 3%-25%) and the median duration of response was 4.6 months; the 4- and 6-month clinical benefit rates were 68% and 51%, respectively.

The HER2-targeted ADC ado-trastuzumab emtansine (T-DM1; Kadcyla) has also shown efficacy in patients with brain metastases and HER2-positive metastatic breast cancer. ORRs in this retrospective study were similar between those with brain metastases (35.1%) and for those without (38.3%), demonstrating the efficacy of ADCs in this space. Additionally, the disease control rates were 53.3% and 66.6%, respectively. The median OS was 14.0 months (95% CI, 12.2-15.8) in the patients with brain metastases compared with 32.0 months (95% CI, 24.4-39.6) in those without (P< .0001).

The ability of ADCs to cross the blood-brain barrier to elicit intracranial responses was further demonstrated with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in the phase 3 DESTINY-Breast03 study (NCT03529110), with intriguing efficacy noted in patients with brain metastases that was superior for T-DXd over T-DM1.6 In data from this pivotal study, the intracranial response rate was 63.9% with T-DXd compared with 33.3% for T-DM1. Moreover, T-DXd remained superior to T-DM1 across several efficacy end points in addition to response for patients with brain metastases.

In addition to biologics, the small molecule inhibitor tucatinib, in combination with trastuzumab and capecitabine, has also demonstrated efficacy for patients with brain metastases in the HER2CLIMB study (NCT02614794). In this study, the confirmed intracranial ORR with tucatinib was 47.3% compared with 20.0% with placebo, trastuzumab, and capecitabine.7 In updated results, this also translated to a marked improvement in progression-free survival and OS.8

Based on the HER2CLIMB results, the FDA approved tucatinib in April 2020 for use in combination with trastuzumab and capecitabine, for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer, including those with brain metastases, who have received 1 or more prior anti–HER2-based regimens in the metastatic setting.

This tucatinib regimen was also explored as a potential treatment for patients with HER2-positive breast cancer and leptomeningeal metastasis, in the phase 2 TBCRC049 study. In data from this study, 35% of patients remained alive at a median follow-up of 18 months. The median OS was 10 months (95% CI, 4.1-not reached) and the median time to CNS progression was 6.9 months (95% CI, 2.3-13.8).

“Following taxane, trastuzumab, and pertuzumab therapy, T-DXd is now the preferred regimen for those without CNS disease. For those with active CNS disease, clearly tucatinib, trastuzumab, and capecitabine is a strong consideration, because there's level 1 evidence of OS benefit with statistical confidence,” Pegram said. “For those with stable CNS disease, it is probably more of a toss-up.”

With the number of agents now available with proven efficacy in brain metastases, Pegram noted that screening guidelines should be updated to look for CNS involvement more frequently. “Screening guidelines recommend screening for CNS metastases only in symptomatic patients, but this may not adequately capture all patients with brain metastases,” he concluded.

Subjects and Terms Included in This Episode

Novel Therapies Mentioned in the Episode

Clinical Trials Mentioned in this Episode

• Phase 2 PATRICIA study (NCT02536339)

• Phase 3 DESTINY-Breast03 study (NCT03529110)

• Phase 2 HER2CLIMB study (NCT02614794)

• Phase 3 HER2CLIMB-02 study (NCT03975647)

• Phase 2 Non-randomized Study to Assess the Safety and Efficacy of the Combination of Tucatinib and Trastuzumab and Capecitabine for Treatment of Leptomeningeal Metastases in HER2 Positive Breast Cancer (NCT03501979)

• Phase 2 Screening MRI of the brain in patients with metastatic breast cancer managed with first through fourth line chemotherapy or inflammatory breast cancer managed with definitive intent: A prospective study (NCT04030507)

• Phase 2 A Single Arm, Open Label Phase 2 Study of Tucatinib in Combination with Trastuzumab Deruxtecan in Subjects with Previously Treated Unresectable Locally-Advanced or Metastatic HER2+ Breast Cancer (NCT04539938)

• Phase 3 THE COMPASSHER2 TRIALS (COMPREHENSIVE USE OF PATHOLOGIC RESPONSE ASSESSMENT TO OPTIMIZE THERAPY IN HER2-POSITIVE BREAST CANCER): COMPASSHER2 RESIDUAL DISEASE (RD), A DOUBLE-BLINDED, PHASE III RANDOMIZED TRIAL OF T-DM1 AND PLACEBO COMPARED WITH T-DM1 AND TUCATINIB
  

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