Phase 1-2 Trial of Pembrolizumab and Either Doxorubicin or an Aromatase Inhibitor for Triple-Negative or HR-Positive Metastatic Breast Cancer

Conference Correspondent  - SABCS

Metastatic triple-negative (TN) and hormone receptor (HR)-positive breast cancer are incurable with current therapies. Preliminary data suggest modest activity with the PD-1 inhibitor pembrolizumab in metastatic breast cancer.1 The addition of doxorubicin may increase the expression of neoantigens enhancing PD-1 activity, whereas the effect of an aromatase inhibitor (AI) may be enhanced by the PD-1 inhibitor in HR-positive disease.

In this phase 1-2 trial of pembrolizumab plus either doxorubicin or an AI in TN or HR-positive metastatic breast cancer, the primary end point was overall response, with secondary end points including clinical benefit, safety, and progression-free survival.2 Cohort 1 included patients without prior exposure to an anthracycline. Patients received escalating doses of doxorubicin at 50 and 60 mg/m2 to define the recommended phase 2 dose for a maximum of 6 cycles, as well as pembrolizumab at 200 mg every 3 weeks for up to 2 years. Cohort 2 included 20 HR-positive patients with treatment consisting of pembrolizumab 200 mg every 3 weeks, and any AI to which a patient had not been exposed previously (exemestane was preferred). PD-L1 expression was assessed by central laboratory‒conducted immunohistochemistry.

Cohort 1 (TN metastatic breast cancer) accrued 3 patients without dose-limiting toxicities with doxorubicin 50 mg/m2, with no grade 3 adverse events, resulting in 1 partial response (PR), 1 unconfirmed PR, and 1 patient without progression for 7 cycles. Cohort 2 (HR-positive metastatic breast cancer) completed accrual of the planned 20 patients. There was 1 unconfirmed PR (still receiving therapy after 3 cycles), 1 stable disease (progressed after 12 cycles), and 3 other patients who were still receiving therapy after 1 to 2 cycles. One patient discontinued therapy due to grade 3 liver enzyme (liver function test [LFT]) abnormalities in cycle 1, and 14 patients progressed within 4 cycles. Grade 3 toxicities included 1 LFT abnormality, 1 grade 3 rash, and 1 grade 3 lymphocytopenia. Grade 2 toxicities were fatigue (N = 5), rash (N = 3), and 1 each of cough, headache, hot flashes, hypertension, insomnia, arthralgia, and ankle edema.

The authors concluded that the combination of doxorubicin or an AI with pembrolizumab is feasible, and correlative analysis is underway to explore opportunities for patient selection. Early proliferation of peripheral blood T-cell subsets may be a potential on-treatment biomarker to identify the metastatic breast cancer subset that will benefit from the addition of pembrolizumab, and a full analysis of correlative studies is underway in the TN cohort to better guide effective and efficient cancer immunotherapy.

References
1. Nanda R, et al. J Clin Oncol. 2016;34:2460-2467.
2. Somlo G, et al. SABCS 2017. Abstract P1-08-04.

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Last modified: April 27, 2020