The addition of durvalumab -(Imfinzi) to anthracycline/taxane-based chemotherapy had encouraging results as neoadjuvant therapy for early triple-negative breast cancer in the randomized phase II GeparNuevo study presented at the 2018 ASCO Annual Meeting.¹ The results were positive in a subgroup of patients who received durvalumab alone during a 2-week “window of opportunity” to prime the immune system prior to receiving chemotherapy. The study was conducted by the German Breast Group.

Durvalumab should be investigated further in patients with primary triple-negative breast cancer.

— Sibylle Loibl, MD, PhD

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Lead author Sibylle Loibl, MD, PhD, of the German Breast Group, Germany, said, “Durvalumab should be investigated further in patients with primary triple-negative breast cancer. Induction therapy seems beneficial, especially in patients who start with durvalumab before chemotherapy, those with stage IIA and higher disease, and patients younger than age 40. The addition of durvalumab was well -tolerated.”

The addition of durvalumab increased the pathologic complete response rate to 53%, compared with 44% for chemotherapy. Although this was not statistically significant, results were more promising in patients treated with durvalumab before receiving chemotherapy (ie, the “window” cohort). In the window cohort, the pathologic complete response rate was 61%, vs 41.4% with chemotherapy alone. 

Study Rationale

“Triple-negative breast cancer has high immunogenic potential. Several checkpoint inhibitors are being investigated in this disease. In preliminary studies, response rates were improved when checkpoint inhibitors were added, and tumor-infiltrating lymphocytes correlated highly with other immune genes, such as programmed cell death ligand 1. Several studies have shown that durvalumab is promising in non–small cell lung cancer (NSCLC). Our study looked at the addition of durvalumab in triple-negative breast cancer prior to surgery,” Dr. Loibl told listeners. 

Durvalumab is a checkpoint inhibitor approved for the treatment of locally advanced or metastatic urothelial carcinoma and for stage III NSCLC. It is investigational in triple-negative breast cancer.

Previously, I-SPY 2, a phase II study with an adaptive design, showed promising results for neoadjuvant therapy with pembrolizumab (Keytruda), another checkpoint inhibitor, plus chemotherapy in advanced triple-negative breast -cancer.²

Study Details 

GeparNuevo enrolled 174 patients with early triple-negative breast cancer and stratified them for tumor-infiltrating lymphocyte levels: low, 0% to 10%; medium, 11% to 59%; and high ≥ 60%. Patients were randomly assigned to receive durvalumab or placebo for 2 weeks, when a core biopsy was obtained. The experimental arm continued on nanoparticle albumin-bound (nab)--paclitaxel (Abraxane) plus durvalumab for 12 weeks, whereas the control arm received nab-paclitaxel alone. 

Patients were evaluated for clinical response and moved on to 8 weeks of 4 cycles of epirubicin plus cyclophosphamide plus durvalumab in the experimental arm and epirubicin plus cyclophosphamide alone in the control arm for 8 weeks. After completion of this phase, surgery was performed. 

At baseline, the median age was 49.5 years, and about two-thirds of patients had stage IIA or higher disease. Overall, 38% had low tumor-infiltrating lymphocyte levels, 48% had medium tumor-infiltrating lymphocyte levels, and 14% had high tumor-infiltrating lymphocyte levels. The number of treatment discontinuations and the reasons for discontinuation were evenly distributed between the two arms.

Efficacy

For the primary endpoint, pathologic complete response rates were 53.4% in the durvalumab arm vs 44.2% for chemotherapy alone (control arm), which was not statistically significant. In an analysis of predefined subgroups, the 117 patients who received “window” durvalumab did significantly better than the 57 patients who did not (P = .048).

For the “window” cohort, the rate of pathologic complete response was 61% vs 41.4%. For patients with stage IIa or higher disease, the pathologic complete response rate was 55.8% vs 38.6%, respectively, and for those under age 40, the pathologic complete response rate was 69.2% vs 42.9%, respectively.

The subgroup analysis of pathologic complete response also suggested that patients with any level of tumor-infiltrating lymphocyte expression benefited from durvalumab in this study, and those with the highest levels did the best. 

Safety

All patients received growth factor support during chemotherapy with epirubicin and cyclophosphamide. Grade 3/4 adverse hematologic events included anemia (2.2% in the durvalumab arm and 2.4% in controls), neutropenia (37.1% and 41.5%, respectively), and thrombocytopenia (1.1% and 2.4%, respectively). Febrile neutropenia was reported in 4.3% and 2.4%, respectively.

Noteworthy immune-related toxicities of any grade in the durvalumab arm were hypothyroidism (6.5% vs 2.4% in controls) and hyperthyroidism (7.6% vs 0%, respectively).

Dr. Loibl said that GeparNuevo and the I-SPY 2 trial both suggest a benefit for neoadjuvant therapy with a checkpoint inhibitor to prime the immune response. ■

DISCLOSURE: The study was funded by AstraZeneca and Celgene. Dr. Loibl is a consultant or advisor for Novartis, Pfizer, Roche, and Seattle Genetics and has received honoraria from Pfizer and Roche and institutional research funding from AbbVie, Amgen, AstraZeneca, Celgene, Novartis, Pfizer, Roche, Seattle Genetics, Teva, and Vifor Pharma.

REFERENCES

1. Loibl S, Untch M, Burchardi N, et al: Randomized phase II neoadjuvant study (GeparNuevo) to investigate the addition of durvalumab to a taxane-anthracycline containing chemotherapy in triple negative breast cancer. 2018 ASCO Annual Meeting. Abstract 104. Presented June 3, 2018.

2. Nanda R, Liu MC, Yau C, et al: Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer: Results from I-SPY 2. 2017 ASCO Annual Meeting. Abstract 506. Presented June 5, 2017.