Abstract PD14-09: Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC)

Abstract

Background Inhibition of PD-L1 with atezolizumab combined with chemotherapy has shown acceptable safety and improved survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Patients with TNBC who do not achieve a pathological complete response (pCR) to neoadjuvant chemotherapy have a high risk of disease recurrence and death. This randomized, open-label, phase 2 trial evaluates neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with previously untreated clinical stages II and III TNBC. Methods Women aged ≥18 years with clinical stage T2-T4c, any N, M0 primary tumor by AJCC 7th edition staging TNBC; ECOG PS 0-2; and no prior systemic therapy for the indexed breast cancer were eligible. Patients were randomized in a 1:2 ratio to carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 (Arm A), or carboplatin AUC5 q 3 weeks x 4 + paclitaxel 80 mg/m2 q week x 12 + atezolizumab 1200 mg q3 weeks x 4 (Arm B). Surgery was 3-6 weeks following neoadjuvant chemotherapy. Adjuvant dose-dense doxorubicin and cyclophosphamide was administered q2 weeks with growth factor support to all patients as per routine care. pCR and tumor infiltrating lymphocyte (TIL) percentages are the co-primary endpoints. pCR-evaluable population includes all eligible women who have been randomized and received at least one dose of combination therapy, while the TIL-evaluable population includes all eligible women who have evaluable TIL percentage after one cycle of therapy. A sample size of 67 (22 in Arm A, and 45 in Arm B) provided 80% power at 1-sided alpha = 0.10 to detect a minimum of 15% difference in TIL and 29% improvement (40% vs. 69%) in pCR, respectively. Herein, we report pCR results in the per protocol modified intent-to-treat population (mITT), which includes all eligible patients who were randomized and received at least one dose of combination therapy. Results Sixty-seven patients were randomized between 8/2017 and 9/2019. Six patients randomized to Arm A withdrew consent; 2 of these received protocol therapy but are excluded from the mITT analyses as they are not evaluable because definitive pathology reports are not available. Median follow up is 6 months (range 0.3 - 12.6 months). Median age is 52 years (range 25 - 78). Forty-three (64.2%) were Caucasian and thirteen (19.4%) were African American. Twenty-five (37.3%) were pre-menopausal. 67.2% and 32.8% had stages II and III disease respectively. Nine (13.4%) had a germline mutation in either BRCA1 or BRCA2. In the mITT population, 3 of 16 patients achieved pCR in Arm A - 18.8% (95% CI 4.0%- 45.6%), versus 25 of 45 patients in Arm B - 55.6% (95% CI 40.0%-70.4%); p value 0.018. pCR in those with BRCA mutations was 50% and 80% in Arm A and Arm B, respectively. Treatment delays were observed in 9 patients (40.9%) in Arm A, and 20 (44.4%) in Arm B; dose reductions occurred in 4 patients (18.1%) in Arm A, and in 6 (13.3%) in Arm B. There were 4 SAEs in Arm A and 10 in Arm B. One patient in Arm B had grade 3 adrenal insufficiency. One patient in Arm B died from recurrent disease during the follow-up period. Conclusions: The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in an increased pCR rate in patients with clinical stages II and III TNBC. However, the pCR in the control Arm A was lower than expected, possibly due to the absence of neoadjuvant anthracyclines. The high pCR rate observed in the experimental arm of this study is similar to that observed in other neoadjuvant trials utilizing anthracyclines, taxanes, and carboplatin in TNBC. Clinical trial information: NCT02883062. Citation Format: Foluso O Ademuyiwa, Feng Gao, Ina Chen, Donald W Northfelt, Robert Wesolowski, Mili Arora, Adam Brufsky, Claire Dees, Cesar A Santa-Maria, Roisin M Connolly, Jeremy Force, Alvaro Moreno-Aspitia, Sarah Larson, Elad Sharon, William Gillanders. Nci 10013 - A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel, with or without atezolizumab in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-09.

Immune Checkpoint Inhibitors Plus Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

“…Through comprehensive database retrieval, a total of 983 research records were determined. According to the inclusion and exclusion criteria, six studies with 2,142 patients were included in this meta-analysis; four studies had full text [17][18][19][20], and two studies were published in the form of abstracts (NeoTRIPaPDL1 and Nci 10013 ) [21][22]. Figure 1 A total of six RCTs were included in this meta-analysis, and the characteristics of each study are shown in Table 1.…”

“…There were six RCTs included in our meta-analysis (N = 2142) [17][18][19][20][21][22], and the results showed that immunotherapy combined with chemotherapy signi cantly improved pCR rates (OR: 1.91; 95% CI: 1.32-2.78, P < 0.001). The pCR rates were increased by 16.5% in IMpassion031, [20]13.6% in KEYNOTE-522 17 , and 36.8% in Nci 10013 [22]. However, the negative result in NeoTRIPaPDL1 [21] may be associated with the enrolled population being at high risk, the disease stage being late, and the immune induction effect of the chemotherapy regimens in the study design being insu cient.…”

“…For other relevant studies, a systematic hand search was conducted, and the abstracts and full texts were carefully read for screening. A total of 2142 patients from six randomized controlled trials (RCTs) were included in this metaanalysis [17][18][19][20][21][22][23]. The keywords used in the search were "immunotherapy" or "immune check-point inhibitors" or "PD-1" or "PD-L1" or "Pembrolizumab" or "Atezolizumab" or "Durvalumab" or "neoadjuvant chemotherapy" or "preoperative" and "breast cancer" or "triple negative breast cancer" or "TNBC" or "breast tumor" or "breast neoplasm."…”

“…A total of six studies were included in this meta-analysis [17,22], 865 early TNBC patients received NACT plus ICIs and 692 early TNBC patients received NACT. The results showed that patients with TNBC who received NACT plus immunotherapy had a signi cant improvement in pCR compared with NACT alone in ITT populations (OR:1.91; 95% CI: 1.32-2.78, P < 0.001).…”

“…The results of IMpassion 130 and Keynote-355 suggested that immune checkpoint inhibitors (ICIs) plus chemotherapy are effective in patients with advanced TNBC and predicted that it would yield promising results in patients with early TNBC [15,16]. Based on the research prospects, a number of studies on neoadjuvant chemotherapy (NACT) plus ICIs in patients with early TNBC are ongoing, but the outcome is controversial to date, which needs to be con rmed by further meta-analysis [17][18][19][20][21][22][23]. Therefore, our meta-analysis aimed to further con rm the e cacy of NACT plus immunotherapy.…”