Impact of HER2 heterogeneity on treatment response of early-stage HER2-positive breast cancer: phase II neoadjuvant clinical trial of T-DM1 combined with pertuzumab

532 Background: T-DM1 has demonstrated clinical activity as a single agent in patients (pts) with previously untreated MBC. In a previous phase II randomized trial of T-DM1 vs trastuzumab + docetaxel, T-DM1 had no clinically significant cardiac events, no cases of post-baseline left ventricular ejection fraction (LVEF) ≤40%, and fewer grade ≥3 adverse events (AEs; Hurvitz, ESMO 2011). This phase II study assessed the clinical safety and feasibility of T-DM1 following anthracycline-based chemotherapy in the adjuvant or neoadjuvant setting for early-stage HER2-positive breast cancer. Methods: TDM4874g (NCT01196052) is a phase II single-arm, open-label study of T-DM1 (3.6 mg/kg q3w IV; up to 17 cycles) following completion of doxorubicin/cyclophosphamide (AC; q2w or q3w for 4 cycles), or 5-fluorouracil/epirubicin (100 mg/m2)/cyclophosphamide (FEC; q3w for 3-4 cycles) chemotherapy in pts with early-stage HER2-positive breast cancer. Pre-chemotherapy LVEF by MUGA/ECHO ≥55% was required for enrollment. Co-primary endpoints are safety and rate of pre-specified cardiac events following initiation of T-DM1 treatment. An interim analysis was planned for the first 60 pts evaluable for cardiac safety (received ≥1 T-DM1 dose). Results: For pts in the interim analysis (20 received AC, 40 FEC), the most common all-grade T-DM1-related AEs were nausea (n=20), asthenia (n=17), and headache (n=17); 8 pts had grade 3/4 T-DM1-related AEs (including 3 with grade 3 increased aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT]). No deaths occurred. Two pts had AEs leading to T-DM1 discontinuation (grade 3 AST and grade 2 ALT increase; grade 3 thrombocytopenia). No pre-specified cardiac events occurred; no pts delayed or discontinued T-DM1 due to cardiac AEs; there were no reports of grade ≥2 left ventricular systolic dysfunction, heart failure, or LVEF <50%. Results will be updated with data from all 153 enrolled pts. Conclusions: T-DM1 following anthracycline-based chemotherapy was not associated with cardiac toxicity in pts with early-stage HER2-positive breast cancer; this study continues without modification.

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Abstract OT1-1-12: NSABP FB-7 Trial: A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel and Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer

10.1158/0008-5472.sabcs12-ot1-1-12 ◽

2012 ◽

Author(s):

J Lu ◽

SA Jacobs ◽

ME Buyse ◽

S Paik ◽

N Wolmark

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Neoadjuvant Therapy ◽

Randomized Clinical Trial ◽

Phase Ii ◽

Locally Advanced ◽

Weekly Paclitaxel ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

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Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

Nature Communications ◽

10.1038/s41467-020-19494-2 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Sara A. Hurvitz ◽

Jennifer L. Caswell-Jin ◽

Katherine L. McNamara ◽

Jason J. Zoeller ◽

Gregory R. Bean ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Phase Ii ◽

Early Stage ◽

Pathologic Complete Response ◽

Early Assessment ◽

Her2 Positive ◽

Time Of Surgery ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

AbstractIn this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.

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Trial in progress: A phase II open-label, randomized study of PARP inhibition (olaparib) either alone or in combination with anti-PD-L1 therapy (atezolizumab) in homologous DNA repair (HDR) deficient, locally advanced or metastatic non-HER2-positive breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps1102 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS1102-TPS1102

Author(s):

Patricia LoRusso ◽

Mary Josephine Paula Pilat ◽

Cesar Augusto Santa-Maria ◽

Roisin M. Connolly ◽

Erin Elizabeth Roesch ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Dna Repair ◽

Phase Ii ◽

Locally Advanced ◽

Parp Inhibition ◽

Her2 Positive ◽

Open Label ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

TPS1102 Background: While immunostimulatory therapies have shown great success, a major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The DNA repair proficiency of a tumor may impact its potential for immune recognition and sensitivity to immune checkpoint blockade. Preclinically, PARP inhibition in HDR-deficient tumors has been shown to trigger antitumor immunity through a STING-dependent antitumor immune response. Effects of PARP inhibitors were augmented when combined with PD-1 blockade. We hypothesize that enhanced DNA damage and cell death induced by PARP inhibition in tumors with homology directed repair (HDR) deficiency will enhance adaptive anti-tumor immune responses and increase sensitivity to PD-1 axis blockers. Methods: This is a randomized, open-label phase II clinical trial exploring the PARP inhibitor olaparib either alone or in combination with the anti-PD-L1 human monoclonal antibody atezolizumab in BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. HDR deficiency is defined as the presence of deleterious BRCA 1/2 mutations. Randomization occurs in a 1:1 fashion to two arms: (1) olaparib 300 mg PO bid continuously in 21-day cycles or (2) olaparib 300 mg PO bid continuously in combination with atezolizumab 1200 IV every 3 weeks in 21-day cycles. Patients undergo baseline evaluations and pre-treatment biopsy within 2 weeks of starting therapy. Repeat biopsies are required at the time of first tumor assessment scan (6 weeks from the start of treatment) and in the event of disease progression. Correlative studies, including detailed analysis of the genomic profile and tumor immune contexture, will be performed at each biopsy time point. The primary objective is to compare progression free survival between the study arms. If progression occurs on the olaparib monotherapy arm, cross-over to the combination arm is allowed. This study began enrolling in August 2018; 47 of the planned 72 patients have been registered. Clinical trial information: NCT02849496 .

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