Neoadjuvant Durvalumab Regimen Shows Promise in TNBC

Lajos Pusztai, MD, DPhil

A durvalumab (Imfinzi)-based neoadjuvant regimen induced a pathologic complete response (pCR) rate of 44% in patients with triple-negative breast cancer (TNBC), according to results of a phase I/II study presented in a poster at the 2019 San Antonio Breast Cancer Symposium.

The 44% (95% Cl, 30%-57%) pCR comprised 24 of the 55 patients treated at the recommended phase II dose of 10 mg/kg of durvalumab. In the study, durvalumab was administered concomitantly with sequential nab-paclitaxel (Abraxane) and the AC regimen of doxorubicin and cyclophosphamide.

Fifty-seven of the 59 patients treated overall completed surgery, with 46% (n = 26) achieving a pCR. This included 2 pCRs among patients who received durvalumab at a lower dose of 3 mg/kg.

Among PD-L1—positive patients, the pCR rate was 59% (n = 17/29; 95% Cl, 0.39-0.76) and the pCR rate was 32% (n = 6/19; 95% CI, 0.12-0.56) in PD-L1–negative patients. The difference was not statistically significant (P = .26).

“The 95% confidence interval (30%-57%) includes the 53% pCR rate reported with a similar regimen in the GeparNuevo trial [NCT02685059],” lead study author Lajos Pusztai, MD, DPhil, director of Breast Cancer Translational Research, Yale University, and coinvestigators wrote in their poster conclusion.

“An identical chemotherapy regimen resulted in a pCR rate of only 29% in TNBC in the SWOG S0800 trial (NCT00856492), consistent with an improvement in pCR rate with inclusion of durvalumab, as was seen in GeparNuevo,” added Pusztai et al.

The phase II portion of the study included 59 patients with stage I to III TNBC who had no prior therapy. Exclusion criteria included no active autoimmune disease or history of autoimmune disease within 2 years, no primary immunodeficiency or allogenic organ transplant, and no active hepatitis 8 or C or HIV infection or history of tuberculosis.

The median patient age was 50 years and all patients were aged <70 years. About two-thirds of patients were white. Patients’ tumor sizes were either T1 (35%), T2 (51%), or T3 (14%), and clinical node status was either cN0 (52%), cN1 (42%), cN2 (2%), or cN3 (4%).

PD-L1 expression was assessed using the VENTANA SP263 assay, and PD-L1—positive status was defined as ≥1% staining on immune and tumor cells. Among the 50 patients with available PD-L1 status, 52% (n = 31) were PD-L1–positive and 32% (n = 19) were PD-L1–negative.

Patients received durvalumab at either 3 mg/kg (n = 4) or the recommended phase II dose of 10 mg/kg (n = 55). Durvalumab was administered every 2 weeks concurrently with sequential nab-paclitaxel (100 mg/m² weekly for 12 cycles), followed by the AC regimen of doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) every 2 weeks for 4 cycles. Following the neoadjuvant treatment, patients received surgery and the investigators obtained a residual disease sample and research blood draw.

Regarding safety, the authors wrote, “Concomitant administration of durvalumab at 10 mg/kg every two weeks with sequential weekly nab-paclitaxel and dose dense AC neoadjuvant chemotherapy showed no unexpected toxicities.”

The most common grade 1/2 adverse events (AEs) were fatigue (n = 55), nausea (n = 45), hypothyroidism (n = 32), maculopapular rash (n = 27), diarrhea (n = 23), and peripheral sensory neuropathy (n = 20).

Grade 3 AEs included hypothyroidism (n = 3), decreased neutrophil count (n = 3), decreased lymphocyte count (n = 3), white blood cell decrease (n = 2), hyperglycemia (n = 2), fatigue (n = 1), maculopapular rash (n = 1), oral mucositis (n = 1), and hypokalemia (n = 1). Grade 4 AEs included 2 cases of decreased white blood cells, and 1 case each of decreased neutrophil count and hyperglycemia.

Specifically highlighting immune-related AEs, the most common was grade 1/2 hypothyroidism. Grade ≥3 immune-related AEs included hypothyroidism (n = 3), hyperglycemia (n = 3), colitis (n = 1), and Guillain-Barre syndrome (N = 1).

Pusztai L, Reisenbichler E, Bai Y, et al. Durvalumab (MEDI4736) concurrent with nab-paclitaxel and dose dense doxorubicin cyclophosphamide (ddAC) as neoadjuvant therapy for triple negative breast cancer (TNBC). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract PD1-01.

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