TCbHP/T-DM1+P Sequence Shows Promise in HER2+ Primary Breast Cancer

Standard therapy with docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta) (TCbHP) followed by trastuzumab emtansine (T-DM1; Kadcycla) and pertuzumab (T‑DM1+P) out-performed TCbHP alone in a new phase II neoadjuvant study of patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer.¹

The study, published in the journal Breast Cancer Research and Treatment,also suggests that personalization of the T-DM1+P regimen could help minimize toxicity without affecting efficacy.

Corresponding author Masakazu Toi, MD, PhD, of the Graduate School of Medicine at Kyoto University, in Japan, wrote that the current standard of care in the neoadjuvant setting for patients with HER2-positive primary breast cancer is dual HER2-targeted therapy. The problem, though, is that treatment-related toxicity can be high, and pathological complete response (pCR) rates need improvement, particularly in luminal HER2-positive cases.

Toi and colleagues designed a randomized, phase II study, dubbed Neopeaks (Japanese Breast Cancer Research Group-20), to evaluate 3 treatment variations, including a control group receiving TCbHP, and a group that started with T-DM1+P with personalization based on initial response. The groups were broken down as follows:

• Group A: 6 cycles of TCbHP
• Group B: 4 cycles of TCbHP followed by 4 cycles of T-DM1+P
• Group C: 4 cycles of T-DM1+P followed by an assessment of clinical response using MRI and/or core needle biopsy.

In the latter group, those who responded well continued on T-DM1+P for up to 6 cycles; those who did not respond were switched to 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC). The primary end point was pCR.

A total of 236 patients were enrolled in the study, and 204 were randomized 1:1:2 between the 3 groups. Half were assigned to either group A (51 patients) or group B (52 patients). The remaining 101 were placed in arm C of the trial. Of those, 80 responded well to treatment and continued on T-DM1+P; the remaining 21 switched to FEC.

The results showed that patients who were put on the B regimen had a pCR rate of 71%, while those on standard TCbHP had a pCR rate of 57%. Those in the T-DM1+P group also had an overall pCR rate of 57%, though it was higher in the responders (63%) than in the nonresponders (38%). pCR rates were the same (57%) after the initial 4 cycles of treatment with both the T-DM1+P and the standard TCbHP regimens.

The study also confirmed earlier research² that showed that pCR rates are higher in patients with estrogen receptor (ER)–negative tumors compared with ER-positive tumors, with pCR rates of 67% to 76%.1 Among patients with ER-positive tumors, those in group B had the highest rate of pCR (69%), compared with groups A (43%) and C (51%).

In an email to Targeted Oncology, Toi said it was notable that group B had the highest pCR rate. He said that the 69% pCR rate among the ER-positive/HER2-positive subgroup “would be probably the highest pCR rate ever reported for ER-positive/HER2-positive disease, although the sample size is small.”

Toi noted that the toxicity profile of the group B regimen also appeared to be “slightly” less toxic than the control regimen, group A.

More broadly, Toi said the data suggest the group B regimen of 4 cycles of TCbHP followed by 4 cycles of T-DM1+P might be a promising new regimen, particularly in cases of ER-positive/HER2-positive disease.

“A sequence of cytotoxic regimens like TCbHP and less cytotoxic antibody–drug conjugated regimens like T-DM1+P has not been studied much in the neoadjuvant setting,” he said. “These sequences need to be studied further.”

As for group C, Toi said the response rates in group C1 (those who responded to the initial 4 cycles of T-DM1+P therapy) had impressive pCR rates in both the ER-negative/HER2-positive subgroup (72%) and in the ER-positive/HER2-positive subgroup (55%). “These data seem to be impressive,” he said.

Toi added that the group C regimen may be an intriguing subject for further research, since the toxicity of the responders was minor.

“It is much easier for the patients compared with cytotoxic regimens,” he said. “In the C2 group [T-DM1+P nonresponders who subsequently received FEC], we could see some benefit from the FEC therapy, as planned. The group C strategy may also be a therapeutic option for [patients with] HER2-positive primary breast cancer.”

_References:

_{1. Masuda N, Ohtani S, Takano T, et al. A randomized, 3-arm, neoadjuvant, phase 2 study comparing docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP), TCbHP followed by trastuzumab emtansine and pertuzumab (T-DM1+P), and T-DM1+P in HER2-positive primary breast cancer. Breast Cancer Res Treat. 2020;180:135-146. doi: 10.1007/s10549-020-05524-6.}

_{2. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284. doi: 10.1093/annonc/mdt182.}