Neoadjuvant atezolizumab (atezo) and nab-paclitaxel (nab-p) in patients (pts) with triple-negative breast cancer (TNBC) with suboptimal clinical response to doxorubicin and cyclophosphamide (AC).
Authors: Yam Clinton , Mittendorf Elizabeth A. , Sun Ryan , Huo Lei , Damodaran Senthil , Rauch Gaiane M , Candelaria Rosalind P , Adrada Beatriz E , Seth Sahil , Symmans William Fraser , Murthy Rashmi Krishna , White Jason B , Ravenberg Elizabeth , Clayborn Alyson , Prabhakaran Sabitha , Valero Vicente , Thompson Alastair Mark , Tripathy Debu , Moulder Stacy L. , Litton Jennifer Keating 
Published: June 2021

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Background: Neoadjuvant anti-PD-(L)1 therapy confers an improvement in pathological complete response (pCR) rate in unselected TNBC. However, given the potential for long-term morbidity from immune related adverse events (irAE), it is important to optimize the risk-benefit ratio for the use of these novel agents in the curative neoadjuvant setting. Suboptimal clinical response to neoadjuvant therapy (NAT) by sonography is associated with low rates of pCR rate (2-5%, GeparTrio and Aberdeen trials). Here, we report the results of a single arm phase II study of atezo and nab-p as the second phase of NAT in pts with TNBC with suboptimal clinical response to AC (NCT02530489). Methods: Pts with stage I-III TNBC showing suboptimal response to 4 cycles of doxorubicin and cyclophosphamide (AC), defined as disease progression or a <80% reduction in tumor volume by sonography, were eligible. Pts received atezo (1200mg IV, Q3 weeks x 4), and nab-p (100mg/m2 IV, Q1 week, x 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezo (1200mg IV, Q3 weeks, x 4 cycles). This single arm, two-stage Gehan-type study was designed to detect an improvement in pCR from 5% to 20% in order to deem the regimen worthy of further study in a large, randomized, phase II/III trial; success was defined as pCR in 8 out of 37 pts enrolled. In a subset of pts, sufficient baseline tumor tissue was available for stromal TIL assessment (n=29). Results: 34 pts were enrolled from 2/2016-12/2020. Among the 33 pts who have completed NAT, the pCR rate was 30% (10/33, 95% CI: 16-49%) and the pCR/RCB-I rate was 42% (14/33, 95% CI: 25-61%). Clinicopathological characteristics are described in the table below. Treatment-related adverse events (all grades) occurring in ≥ 20% of pts include fatigue (73%), anemia (55%), peripheral sensory neuropathy (55%), neutropenia (48%), rash (42%), ALT elevation (39%), AST elevation (33%), nausea (30%), anorexia (24%), diarrhea (21%), myalgia (21%). Discontinuation of atezo due to irAEs occurred in 4 pts (12%, nephritis [n=2]; adrenal insufficiency [n=1]; hepatitis [n=1]); 2 of these pts had pCR. Conclusions: This study met its primary endpoint, demonstrating a promising signal of activity in this high risk pt population (pCR=30% vs 5% in historical controls). The 12% discontinuation rate due to irAEs confirms that further evaluation of a strategy administering immunotherapy only to pts with high risk disease not responding to AC warrants further investigation. Exploratory genomic and immunological correlative studies are ongoing. Clinical trial information: NCT02530489. [Table: see text]