Pertuzumab Plus High-Dose Trastuzumab in Patients With Progressive Brain Metastases and HER2-Positive Metastatic Breast Cancer: Primary Analysis of a Phase II Study

Abstract

Purpose: Effective therapies are needed for the treatment of patients with human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer (MBC) with brain metastases. A trastuzumab radioisotope has been shown to localize in brain metastases of patients with HER2-positive MBC, and intracranial xenograft models have demonstrated a dose-dependent response to trastuzumab.

Methods: In the phase II PATRICIA study (ClinicalTrials.gov identifier: NCT02536339), patients with HER2-positive MBC with CNS metastases and CNS progression despite prior radiotherapy received pertuzumab plus high-dose trastuzumab (6 mg/kg weekly) until CNS or systemic disease progression or unacceptable toxicity. The primary end point was confirmed objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases criteria. Secondary end points included duration of response, clinical benefit rate (complete response plus partial response plus stable disease ≥ 4 or ≥ 6 months) in the CNS, and safety.

Results: Thirty-nine patients were treated for a median (range) of 4.5 (0.3-37.3) months at clinical cutoff. Thirty-seven patients discontinued treatment, most commonly because of CNS progression (n = 27); two remained on treatment. CNS ORR was 11% (95% CI, 3 to 25), with four partial responses (median duration of response, 4.6 months). Clinical benefit rate at 4 months and 6 months was 68% and 51%, respectively. Two patients permanently discontinued study treatment because of adverse events (left ventricular dysfunction [treatment-related] and seizure, both grade 3). No grade 5 adverse events were reported. No new safety signals emerged with either agent.

Conclusion: Although the CNS ORR was modest, 68% of patients experienced clinical benefit, and two patients had ongoing stable intracranial and extracranial disease for > 2 years. High-dose trastuzumab for HER2-positive CNS metastases may warrant further study.

Conflict of interest statement

Nancy U. LinConsulting or Advisory Role: Seattle Genetics, Puma Biotechnology, Daiichi Sankyo, California Institute for Regenerative Medicine (CIRM), Denali TherapeuticsResearch Funding: Genentech, Pfizer, Seattle Genetics, Merck, NovartisPatents, Royalties, Other Intellectual Property: Royalties for chapter in Up-to-Date regarding management of breast cancer brain metastases, Royalties, Jones & Bartlett Mark PegramConsulting or Advisory Role: Genentech/Roche, Pfizer, Seattle Genetics, Puma, Novartis Solmaz SahebjamConsulting or Advisory Role: Merck, Boehringer IngelheimResearch Funding: Bristol Myers Squibb, Brooklyn ImmunoTherapeutics, MerckTravel, Accommodations, Expenses: Lilly Nuhad IbrahimConsulting or Advisory Role: Ipsen, ImmunomedicsResearch Funding: Nektar Therapeutics Anita FungEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Anna ChengEmployment: GenentechStock and Other Ownership Interests: Roche Alan NicholasEmployment: GenentechStock and Other Ownership Interests: Genentech Whitney KirschbrownEmployment: Genentech/RocheStock and Other Ownership Interests: Genentech/Roche Priya KumthekarConsulting or Advisory Role: Orbus Therapeutics, Janssen, ElevateBioResearch Funding: AngiochemNo other potential conflicts of interest were reported.

Figures

FIG 1.

CBR in the CNS at 4 months (n = 25) and 6 months (n = 19). CBR, clinical benefit rate; CR, complete response; PR, partial response; SD, stable disease.

FIG 2.

Duration of clinical benefit in the CNS at 4 monthsa (n = 25). aPatients with confirmed CR, PR, or SD ≥ 4 months. CR, complete response; PR, partial response; SD, stable disease.

FIG 3.

Largest percentage change in total sum of CNS target lesion diameters (n = 37). One patient without a postbaseline assessment was omitted from this analysis because of death within 30 days of last treatment, but was included in the efficacy-evaluable population. One patient was with an unconfirmed PR and was considered to have a confirmed best response of SD in the study. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A1.

Study design. Primary efficacy end point: ORR in the CNS. Secondary efficacy end points: DOR in the CNS, CBR in the CNS, PFS (CNS), PFS (CNS or non-CNS), PFS (non-CNS), and OS. Safety end point: Safety of pertuzumab and trastuzumab for the treatment of HER2-positive MBC with CNS progression postradiotherapy. aFollowing a protocol update in October 2018, patients were followed up for 12 months post-treatment. CBR, clinical benefit rate; DOR, duration of response; HER2, human epidermal growth factor receptor 2; IV, intravenous; MBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Q3W, once every 3 weeks; RANO-BM, Response Assessment in Neuro-Oncology Brain Metastases; SRS, stereotactic radiosurgery; WBRT, whole-brain radiotherapy.