Response Rate and Safety of a Neoadjuvant Pertuzumab, Atezolizumab, Docetaxel, and Trastuzumab Regimen for Patients With ERBB2-Positive Stage II/III Breast Cancer: The Neo-PATH Phase 2 Nonrandomized Clinical Trial

Abstract

Importance: Addition of immune checkpoint inhibitors to anti-ERBB2 treatment has shown synergistic efficacy in preclinical studies and is thus worth investigating as a neoadjuvant treatment to maximize efficacy and to minimize toxic effects.

Objective: To determine if neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab therapy for ERBB2-positive early breast cancer warrants continuation to the next phase.

Design, setting, and participants: This nonrandomized, open label, multicenter, phase 2 trial was conducted by the Korean Cancer Study Group and enrolled patients across 6 institutions in Korea from May 2019 to May 2020. Eligible patients were diagnosed with ERBB2-positive breast cancer (primary tumor size >2 cm or pathologically confirmed lymph node-positive cancer, without distant metastases) with a clinical stage of II or III.

Interventions: Patients received 6 cycles of neoadjuvant pertuzumab (840 mg at first cycle, 420 mg during subsequent cycles), atezolizumab (1200 mg), docetaxel (75 mg/m2), and trastuzumab (600 mg via subcutaneous injection) every 3 weeks, followed by surgery. Patients with pathologic complete response (pCR) received 12 cycles of adjuvant atezolizumab, trastuzumab, and pertuzumab every 3 weeks after surgery. Patients without pCR were treated with 14 cycles of atezolizumab, 1200 mg, plus trastuzumab emtansine, 3.6 mg/kg, every 3 weeks.

Main outcomes and measures: The primary end point was pCR rate, which was defined as the absence of invasive cancer cells in the primary tumor and regional lymph nodes (ypT0/isN0). Secondary end points included clinical objective response rate, 3-year event-free survival rate according to pCR achievement, disease-free survival, overall survival, toxic effects, and quality-of-life outcomes.

Results: A total of 67 women (median [range] age, 52 [33-74] years) were enrolled. Hormone receptor expression was positive in 32 (48%) patients. Curative surgery was performed in 65 patients because 2 patients showed disease progression during neoadjuvant treatment and their tumors became unresectable. The overall pCR rate was 61% (41 of 67 patients). The pCR rate was higher in hormone receptor-negative disease vs hormone receptor-positive disease (27 of 35 [77%] patients vs 14 of 32 [44%] patients) and in programmed cell death 1-positive expression vs programmed cell death 1-negative expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Grade 3 and 4 neutropenia and febrile neutropenia occurred in 8 (12%) patients and 5 (8%) patients, respectively. Grade 3 and 4 immune-related adverse events occurred in only 4 patients (grade 3 skin rash, encephalitis, hepatitis, and fever). No treatment-related death occurred during the neoadjuvant phase.

Conclusions and relevance: In this nonrandomized clinical trial, treatment with the neoadjuvant atezolizumab, docetaxel, trastuzumab, and pertuzumab regimen in patients with stage II or III ERBB2-positive breast cancer appears to have had an acceptable pCR rate and modest toxic effects. Further investigation of this immunotherapy combination in ERBB2-positive early breast cancer is warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT03881878.

Figure 1.. CONSORT Diagram

Figure 2.. Pathologic Complete Response (pCR) Rate Overall and in Each Subgroup

Among the 67 patients included, 41 (61%) achieved pCR. The pCR rate was higher in patients with hormone receptor–negative (HR−) subtype vs hormone receptor–positive (HR+) subtype (27 of 35 [77%] patients vs 14 of 32 [44%] patients), estrogen receptor–positive (ER+)/progesterone receptor–negative (PR−) cancer vs ER+/progesterone receptor–positive (PR+) cancer (7 of 14 [50%] patients vs 7 of 18 [39%] patients), stages IIA and IIB vs stage III cancer (11 of 16 [69%] patients and 23 of 33 [70%] patients vs 7 of 18 [39%] patients), and positive programmed cell death 1 (PD-L1+) expression vs negative programmed cell death 1 (PD-L1−) expression (13 of 13 [100%] patients vs 28 of 53 [53%] patients). Error bars indicate 95% CIs.

Figure 3.. Objective Response

Clinical response (A) and the greatest changes from baseline in sum of the longest diameters of measurable tumors among the 67 included patients (B). pCR indicates pathologic complete response; PD-L1, programmed cell death 1.