A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013

Abstract

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).

Fig. 1. CONSORT diagram.

Flow of patients randomly assigned in NCI 10013.

Fig. 2. Pathological complete response according to study arm.

Arm A (orange bar) represents patients randomly assigned to chemotherapy alone, Arm B (blue bar) represents patients assigned to atezolizumab plus chemotherapy. Error bars represent the 95% confidence interval of pCR rate.

Fig. 3. Representative H&E sections demonstrating TIL percentage in breast cancer specimens.

a Low TIL (5%). b high TIL (80%). Scale bar, 100 μm.

Fig. 4. TIL analyses.

Boxplots of logarithm transformed TIL (%) by pCR status (a) and treatment arm (b), where the box stands for the interquartile range, the bar inside a box represents the median, and the whiskers represent the whiskers represent 5^th and 95^th percentiles.

Fig. 5. Pathological complete response by PD-L1 status.

a PD-L1 status assessed by VENTANA PD-L1 (SP142) assay in patients treated with chemotherapy alone and chemotherapy plus atezolizumab. Orange areas represent Arm A chemotherapy only. Blue areas represent Arm B chemotherapy plus atezolizumab. b PD-L1 status assessed by multiplex immunofluorescence in patients treated with chemotherapy alone and chemotherapy plus atezolizumab. PD-L1-positive status represents the percent positive cells on inflammatory cells (PD-L1-positive cytokeratin-negative or CD8-positive cells), divided by the total number of cytokeratin-negative and CD8 positive cells. Orange areas represent Arm A chemotherapy only. Blue areas represent Arm B chemotherapy plus atezolizumab. Error bars represent standard error of pCR rate.

Fig. 6. Clinical trial schema outlining treatment arm, randomization, collection of biopsies, and adjuvant treatment.

AUC area under the curve, dd dose dense.