Exploration of neoadjuvant chemotherapy with anti-HER2 therapy to achieve higher pathological complete response (pCR) is important. We focused on trastuzumab emtansine (T-DM1), pertuzumab (P) and tailored response guided therapy in HER2+ primary breast cancer (cT1c–T3, cN0–N1, M0, tumor ≤ 7 cm).
This randomized phase II study evaluated efficacy and safety of 3 regimens, A) 6 cycles TCbHP, B) 4 cycles TCbHP followed by 4 cycles T-DM1+P, and C) 6 cycles T-DM1+P: responders to 4 cycles T-DM1+P were assigned to 2 more cycles [C1] or non-responders were assigned to 4 cycles FEC [C2] (Table). Responders: ≥30% decrease in tumor size (MRI) and Ki67 ≤10% or no cancer cells in core needle biopsy. ER(+) patients received anti-hormonal therapy concurrent to T-DM1+P. HER2, ER and Ki-67 were assessed in a central laboratory. Primary endpoint was pCR rate (yT0-is, yN0; centrally confirmed). Secondary endpoints were safety, ORR and breast conservation rate.
A total of 206 patients were enrolled (Aug 2014-Feb 2016; full analysis set, n = 204). Patient characteristics were comparable among all groups (median age 53.0 y, post-menopause 53.9%, T2 70.6%, median tumor size 26 mm, N0 63.2%, ER(+) 57.8%). In group C, 80 (79.2%) patients continued T-DM1+P due to favorable response. pCR rate in group A, B, and C was 56.9%, 71.2%, and 57.4%. By exploratory analyses, pCR rate was higher for groups B and C1 than A in ER(+), but comparable in ER(-) patients. No significant differences in secondary endpoints. No treatment discontinuation due to AEs and similar drug-related SAE profile were seen among groups. Of specific mention: low drug-related alopecia in group C1 (5.0%) than A, B or C2 (81%–94%) and less febrile neutropenia in C1 (0%) than A, B or C2 (15%–33%).Table:
159PD Summary of response
|Variable||Group A (6-cycle TCbHP) % (n = 51)||Group B (4-cycle TCbHP switched to 4-cycle T-DM1+P) % (n = 52)||Group C1 (4-cycle T-DM1+P continued 2-cycle T-DM1+P) % (n = 80)||Group C2 (4-cycle T-DM1+P switched to 4-cycle FEC) % (n = 21)||Group C % (n = 101)|
|pCR rate, Overall||56.9 (29/51)||71.2 (37/52)||62.5 (50/80)||38.1 (8/21)||57.4 (58/101)|
|pCR rate, ER (-)||76.2 (16/21)||73.9 (17/23)||72.2 (26/36)||33.3 (2/6)||66.7 (28/42)|
|pCR rate, ER (+)||43.3 (13/30)||69.0 (20/29)||54.5 (24/44)||40.0 (6/15)||50.8 (30/59)|
|ORR||96.1 (49/51)||86.5 (45/52)||88.8 (71/80)||85.7 (18/21)||88.1 (89/101)|
|cCR||47.1 (24/51)||51.9 (27/52)||38.8 (31/80)||38.1 (8/21)||38.6 (39/101)|
|Breast conservation rate||52.0 (26/50)||51.9 (27/52)||54.4 (43/79)||38.1 (8/21)||51.0 (51/100)|
|Breast conservation rate from planned mastectomy||34.4 (11/32)||38.7 (12/31)||36.7 (18/49)||14.3 (2/14)||31.7 (20/63)|
Dose was administered every 3 weeks as adjuvant therapy. ER (+) patients received concurrent endocrine therapy during T-DM1 treatment. ER, estrogen receptor; FEC, 5-fluorouracil/epirubicin/cyclophosphamide; ORR, overall response rate; pCR, pathological complete response; TCbHP, docetaxel/carboplatin/trastuzumab + pertuzumab; T-DM1+P, trastuzumab emtansine + pertuzumab
Addition of T-DM1+P to standard TCbHP regimen may be possibly superior to TCbHP. Tailored T-DM1+P is a promising approach with mostly equal efficacy and less toxicity compared to TCbHP.
Clinical trial identification
Legal entity responsible for the study
Japan Breast Cancer Research Group
Japan Breast Cancer Research Group and Chugai Pharmaceutical Co., Ltd.
N. Masuda: Honorarium from Chugai and AstraZeneca. T. Takano, M. Toi: Funding from Chugai. Y. Ito: Funding from MSD, AstraZeneca, Novartis, Parexel, Chugai, and Lilly. H. Kasai: Consulting fee/honorarium from Chugai. T. Takasuka: Employee and stock options with Chugai. S. Morita: Consultancy for Chugai. All other authors have declared no conflicts of interest.