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Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial

ABSTRACT: HER2-targeted therapy dramatically improves outcomes in early breast cancer. Here we report the results of two HER2-targeted combinations in the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence: ado-trastuzumab emtansine plus pertuzumab (T-DM1/P) and paclitaxel, trastuzumab and pertuzumab (THP). Eligible women have >2.5 cm clinical stage II/III HER2+ breast cancer, adaptively randomized to T-DM1/P, THP, or a common control arm of paclitaxel/trastuzumab (TH), followed by doxorubicin/cyclophosphamide, then surgery. Both T-DM1/P and THP arms ‘graduate’ in all subtypes: predicted pCR rates are 63%, 72% and 33% for T-DM1/P (n = 52), THP (n = 45) and TH (n = 31) respectively. Toxicity burden is similar between arms. Degree of HER2 pathway signaling and phosphorylation in pretreatment biopsy specimens are associated with response to both T-DM1/P and THP and can further identify highly responsive HER2+ tumors to HER2-directed therapy. This may help identify patients who can safely de-escalate cytotoxic chemotherapy without compromising excellent outcome. HER2-targeted therapy improves patient’s outcome in early breast cancer. Here, the authors present the efficacy and biomarker analysis of two HER2-targeted combinations (ado-trastuzumab emtansine plus pertuzumab and paclitaxel, trastuzumab and pertuzumab) in the context of the neoadjuvant I-SPY2 phase 2 adaptive platform trial for early breast cancer at high risk of recurrence.

SUBMITTER: Clark A

PROVIDER: S-EPMC8571284 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CALGB 40601 was activated as a 3-arm study (paclitaxel + trastuzumab + lapatinib [THL], paclitaxel + trastuzumab [TH] and paclitaxel + lapatinib [TL]). In December 2010, twoneoadjuvant studies were presented at the Cancer Therapy and Research Center-American Association for Cancer Research (CTRC-AACR) San Antonio Breast Cancer Symposium that affected the scientific and practical enthusiasm for the TL arm. For this reason the CALGB 40601 has been amended to omit the TL treatment arm (arm 3). In the Geparquinto trial, patients with HER2-positive breast cancer received epirubicin/cyclophosphamide followed by docetaxel combined either with trastuzumab (EC-DOC-H) or lapatinib (EC-DOC-L) neoadjuvantly, then trastuzumab for a total of 12 months adjuvantly [34]. Pathologic complete response (pCR) in breast and axilla was the primary endpoint. Among 620 patients randomized, there was a higher pCR rate (31% vs 22%) and lower toxicity with fewer discontinuations (10% vs 16%) among patients on the trastuzumab arm than the lapatinib arm. The first results of the NeoALTTO trial were similar [35]. Approximately 450 women with HER2-positive breast cancer received a lead-in phase of 6 weeks of biologic therapy withlapatinib (L), trastuzumab (H), or both, then paclitaxel was added for an additional 12 weeks prior to surgery. All drugs were given at doses similar to CALGB 40601. Postoperative adjuvant therapy included additional chemotherapy and biologic therapy, however, the presentation focused solely on the primary endpoint of pCR in the breast at surgery; no longterm outcomes were presented. There were more grade > 3 adverse events in the lapatinib arm compared with the trastuzumab arm, including diarrhea (23% vs 2%), hepatic abnormalities (13% vs 1%), and neutropenia (16% vs 3%). The only death occurred in the combined biologic (LH) arm. Failure to complete treatment as planned was higher in the L (34%) and LH arms (39%) that in the H arm (u%). PCR was highest with LH-paclitaxel (51%), followed by H-paclitaxel (30%), and L-paclitaxel (25%). Based on the inferior results and higher toxicity of the investigational lapatinib arms of these studies and in discussion with CTEP, in January 2011 it was decided to amend CALGB 40601 to omit Arm 3 (TL). Those patients on this arm will complete protocol therapy as perthe original study design. In CALGB 40601, it is recommended that all patients receive trastuzumab adjuvantly for 1 year, hence all of the patients including those previously randomized to the TL neoadjuvant arm, will be able to receive the known benefit of trastuzumab. After local IRB approval of Update #5, the remainder of the patients will be enrolled and randomized to Arm 1 (THL) and Arm 2 (TH) in a 2:1 fashion. Given that TH isthe standard regimen, and is also clearly the best tolerated, we will continue that arm of thestudy as the comparator, with THL as the only investigational arm.

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Neoadjuvant T-DM1/pertuzumab and paclitaxel/trastuzumab/pertuzumab for HER2+ breast cancer in the adaptively randomized I-SPY2 trial

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