Background: Triple negative breast cancers of high proliferation or grade are a subgroup characterized by very poor prognosis, rapid progression to metastatic stage and rapid onset of resistance to chemotherapy after initial response. As a whole, triple negative breast cancer (TNBC) represents a specific area of medical need, in which new therapeutic approaches deserve appropriate test. Retrospective data showed that a subset of patients have an ongoing immune response within the tumor microenvironment, and that PD-L1 expression is an adaptive method of tumor resistance to tumor infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, the data suggests a role for immune regulation of response to chemotherapy, and support the concept that blockade of immune check-points may favor the achievement of durable response by immune mechanisms themselves, and in combination with classical chemotherapy. Methods: In this multicenter open label study (NCT002620280), a total of 280 patients with TNBC were randomized to neoadjuvant carboplatin AUC 2 and abraxane 125 mg/m2 iv on days 1 and 8, with or without atezolizumab 1200 mg iv on day 1. Both regimens were given every 3 weeks for 8 cycles and were followed by surgery and by 4 cycles of an anthracycline regimen as per investigator choice. The primary aim of the study is to compare event-free survival 5 years after randomization of the last patient. Important secondary aim is the rate of pCR (defined as absence of invasive in breast and lymph nodes). The comparison among treatments will be carried out by a two-sided Cochran-Mantel-Haenszel test, controlling for disease stage (early high-risk vs locally advanced) and PD-L1 expression (positive vs negative). The primary population for all efficacy endpoints will be the ITT (intent-to-treat) population, the safety population is defined as all randomized patients who received at least one dose of either regimen. pCR and safety data will be presented at the meeting. Patients will continue to be followed up to allow for assessing comparative long-term event-free and overall survival analyses. Supported in part by unrestricted grants from Hoffman-La Roche, Ltd, Switzerland and Celgene International Sarl, Switzerland Citation Format: Luca Gianni, Chiun-Sheng Huang, Daniel Egle, Begona Bermejo, Claudio Zamagni, Marc Thill, Antonio Anton, Stefania Zambelli, Giampaolo Bianchini, Stefania Russo, Eva Ciruelos, Richrad Greil, Vladimir Semiglazov, Marco Colleoni, Catherine Kelly, Gabriella Mariani, Lucia Del Mastro, Ilaria Maffeis, Pinuccia Valagussa, Giuseppe Viale. Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michelangelo randomized study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS3-04.

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LBA1010 Background: Taxane-based chemotherapy (CT) improves progression-free survival (PFS) in patients (pts) with newly diagnosed HER2-negative metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor (MTKI), demonstrated antitumor activity in combination with D in a phase I/II study in pts with MBC. A randomized, open-label, multicenter phase III trial in pts with newly diagnosed ABC tested the hypothesis that addition of a MTKI to D improves PFS vs. D alone. Methods: Eligible pts (female; ≥18 yrs) had an ECOG PS ≤1, and newly diagnosed HER2-negative MBC or ABC. If (neo)adjuvant therapy included a taxane, relapse must have occurred ≥12 mos after CT. Pts were randomized (1:1) to treatment (tx) with D 75 mg/m2 iv on day 1 and SU 37.5 mg/day po from day 2–15 q3w (Schedule 2/1; Arm A), or to D 100 mg/m2 iv 1-hr infusion q3w (Arm B) that could be given until progression. If D was discontinued in Arm A for reasons other than progressive disease (PD), single-agent SU 37.5 mg daily was permitted until PD. Median, independently assessed, PFS (primary endpoint) was compared between tx arms using stratified and unstratified log-rank tests. Overall objective response rate (ORR), overall survival (OS), pt-reported outcomes, and safety were secondary endpoints. Results: As of the data cutoff (February 1, 2010), the ITT population comprised 593 pts (SU+D, n=296; D, n=297). The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment or in prolonging OS. Baseline characteristics were well balanced. Median relative dose intensity (RDI) was 94.2% and 92.4% for SU+D, and 92.6% for D arms, respectively. Median PFS was 8.6 mos (95% CI 8.2–10.3) in the SU+D arm vs 8.3 mos (95% CI 7.7–9.6) for the D arm (HR 0.922). Median OS was 24.8 mos (95% CI 21.5–33.1) in SU+D arm vs 25.5 mos (95% CI 22.8–27.8) for D arm (HR 1.207). ORR was significantly better for SU+D (51%) vs. D (39%) (p=0.0018). Frequent all causality grade 3/4 adverse events (≥10%) were neutropenia (46%), hand–foot syndrome (17%), and fatigue (12%) in the SU+D arm and neutropenia (44%) in the D arm. Conclusions: Based on these data, SU+D is not a recommended treatment option for patients with newly diagnosed ABC. Strategies using antiangiogenic TKIs that increase RR but not OS may need to be revisited. [Table: see text]

Background: H + taxane is an established and effective first-line treatment for HER2−positive LR/mBC. Preclinical data provide the rationale for combining BEV and H in HER2−positive LR/mBC but clinical data in this setting are limited to single-arm phase II studies. AVEREL is the first randomized trial of BEV in HER2−positive LR/mBC. Methods: Eligible patients had measurable or evaluable HER2−positive LR/mBC (centrally confirmed IHC 3+ or FISH/CISH +), ECOG performance status 0/1, and had received no prior chemotherapy for advanced disease. Prior adjuvant H/taxanes were permitted unless disease had recurred <6/<12 months after the last dose, respectively. Patients with CNS metastases were excluded. Patients were stratified according to adjuvant H, prior (neo)adjuvant taxane (further stratified by time to relapse since last dose of [neo] adjuvant chemotherapy/no chemotherapy), hormone receptor status, and measurable disease, and were randomized to receive either H (8 mg/kg → 6 mg/kg q3w) + DOC (100 mg/m2 q3w) or H + DOC + BEV (15 mg/kg q3w). H and BEV were given until disease progression; DOC was given for a planned minimum of 6 cycles unless progression or unacceptable toxicity mandated earlier discontinuation. The primary endpoint was progression-free survival (PFS). Additional endpoints included overall survival (OS), overall response rate (ORR; assessed by RECIST 1.0), duration of response, time to treatment failure, safety (NCI CTCAE v3.0 adverse events [AEs] and AEs of special interest for BEV), quality of life (FACT-B), and translational research. The primary analysis of PFS was prespecified after 310 investigator-assessed PFS events. The statistical design provided 90% power to detect a PFS hazard ratio (HR) of 0.69 (median PFS 11→16 months) with α=0.05. Results: Between Sep 2006 and Feb 2010, 424 patients were enrolled from 60 centers; 421 received treatment. Baseline characteristics were generally well balanced in the H + DOC and H + DOC + BEV arms: median age 55 and 53 years, respectively; visceral metastases 71% and 77%; prior adjuvant H 12% and 13%; disease-free interval <12 months 43% in both arms; measurable disease 85% in both arms. Median follow-up was 26 months in both arms. Efficacy results are summarized in the table. No new safety signals were observed. The following grade ≥3 AEs were more common in the BEV-containing arm than the H + DOC arm: congestive heart failure (5.1% vs 2.9%, respectively); febrile neutropenia (11.6% vs 8.7%); hypertension (11.6% vs 0.5%). Grade 5 AEs occurred in 1.4% of the H + DOC + BEV arm vs 1.9% of the H + DOC arm. Conclusions: The addition of BEV to H + DOC improved PFS without reaching statistical significance according to investigator assessment (unstratified HR 0.82; 95% CI 0.65−1.02). The improvement as assessed by Independent Review Committee was statistically significant. Evaluation of biomarkers is ongoing to try to identify those patients who may benefit from first-line BEV-containing therapy for HER2−positive LR/mBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-8.

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