Trastuzumab-Containing Regimens and Novel Drugs Mark the Precision Medicine Era of HER2-Positive Breast Cancer

Kari B. Wisinski, MD

The aggressiveness of early breast cancer and the overall prognosis of patients with the disease is highly dependent on the presence of aberrations in the tumor. HER2 overexpression, in particular, is found in 10% to 40% of breast tumors, which make tumors with these characteristics less responsive to the hormone therapy and cytotoxic agents most commonly used for the treatment of breast cancer.1

Although HER2 positivity has been identified as a predictive factor of response to chemotherapy, it remains controversial considering that responses to chemotherapy can vary in patients with certain disease characteristics. Once trastuzumab (Herceptin), the first targeted therapy for HER2-positive breast cancer entered the paradigm, it was clear that patients had more options,1,2 but, experts were unaware of how far targeted therapies could go in terms of improving outcomes.

“Treatment should be individualized based on the patient’s presenting characteristics, including tumor size, lymph node status, and hormone receptor status,” Kari B. Wisinski, MD, medical oncologist, UW Health and the University of Wisconsin Carbone Cancer Center, told Targeted Oncology, in an interview.

“Individualizing therapy for our patients with HER2-positive disease can help us improve outcomes and decrease toxicity for our patients,” added Sara Tolaney MD, MPH, associate director, Susan F. Smith Center for Women's Cancers, director, Clinical Trials, Breast Oncology, and senior physician, at the Dana-Farber Cancer Institute, and assistant professor of medicine, at Harvard Medical School.

Before the Agent Boom in HER2-Positive Breast Cancer

As a newly introduced targeted therapy in the field of HER2-positive breast cancer in 1998, trastuzumab added to cytotoxic chemotherapy demonstrated a significant improvement in disease-free survival (DFS) in patients with HER2-positive breast cancer, according to results from the N9831 trial (NCT00005970). The result was a 10-year DFS rate of 73.7% with the addition of trastuzumab compared with 62.2% with chemotherapy alone (HR, 0.60; 95% CI, 0.53-0.78) and the 10-year OS rate achieved was 84% versus 75.2% (HR, 0.63; 95% CI, 0.54-0.73).3

As scientific advances were made, trastuzumab continued to be used with chemotherapy, but novel targeted therapies also emerged in the landscape.2

The Thriving Targeted Therapy Research in HER2-Positive Breast Cancer

Many targeted therapies are now FDA approved as treatment of patients with early HER2-positive breast cancer and, unsurprisingly, many of the regimens used in clinical trials for these patients include trastuzumab or are intended to be administered after trastuzumab treatment is completed.

“Several new targeted therapies have emerged in the last several years for HER2-positive breast cancer. First of all, we have pertuzumab [Perjeta], the anti-HER2 monoclonal antibody, which has been supported in the neoadjuvant setting as well as in the adjuvant setting. There is neratinib [Nerlynx], which is an oral tyrosine kinase inhibitor that is now approved as an extended duration anti-HER2 treatment following completion of 1 year of trastuzumab in the adjuvant setting,” Wisinski explained. “Lastly, we have recent data for T-DM1 [trastuzumab emtansine; Kadcyla], which is now FDA approved in the post-neoadjuvant setting in patients with residual disease after standard upfront chemotherapy and anti-HER2 directed therapy. Each of these 3 medications has significantly changed our landscape.”

One of the most revolutionary clinical trials exploring the use of novel targeted therapies in patients with breast cancer is the I-SPY-2 platform trial, which includes a subset of patients with HER2-positive disease. I-SPY-2 is a series of mini studies of novel drugs combined with chemotherapy compared with single-agent standard of care, which is the combination of paclitaxel plus trastuzumab followed by doxorubicin and cyclophosphamide. The trial includes 4000 patients.

The combination treatment arms being explored in I-SPY-2 include AMG 386 with or without trastuzumab, AMG 479 (Ganitumab) plus metformin, MK-2206 with or without trastuzumab, T-DM1 plus pertuzumab, pertuzumab plus trastuzumab, talazoparib (Talzenna) plus irinotecan, patritumab plus trastuzumab, durvalumab (Imfinzi) plus olaparib (Lynparza), and cemiplimab (Libtayo) plus durvalumab plus olaparib. The monotherapy arms include ganetespib, ABT-888, neratinib, PLX3397, pembrolizumab (Keytruda), SGN-LIV1A, tucatinib (Tukysa), and cemiplimab, in all breast cancers.4

Aside from the I-SPY-2 trial, vaccine therapies including the HER2-sensitized dendritic

cell vaccine (NCT03387553), the dendritic cell vaccine compared to the WOKVAC vaccine (NCT03384914), and TPIV100, another HER2 vaccine (NCT04197687) are under investigation in phase 1/2 clinical trials.

There have also been studies of combination chemotherapy like trastuzumab plus chemotherapy (NCT03894007), which is a phase 2 study evaluating treatment before surgery in patients with HER2-amplified early breast cancer. Therapeutic strategies that are even further along in the pipeline are immune checkpoint inhibitor monotherapy and immunotherapy and chemotherapy combination that first demonstrated efficacy in other diseases.

The immunotherapy agents and combinations currently under investigation for early HER2-positive breast cancer include the phase 2, open-label, randomized, multicenter trial of paclitaxel plus pembrolizumab versus pembrolizumab alone (NCT03747120); the phase 2 trial of doxorubicin, cyclophosphamide, and paclitaxel plus nivolumab (Opdivo; NCT03742986) in inflammatory breast cancer, which includes patients with HER2-positive disease in 1 arm who will be treated with added trastuzumab and pertuzumab; as well as the single-arm, open-label study of M7824 ahead of standard neoadjuvant therapy (NCT03620201), which is evaluating patients with stage II or III HER2-positive breast cancer.

Expanding the Possibilities of Trastuzumab

Trastuzumab is considered a standard chemotherapy backbone in the landscape of HER2-positive breast cancer.1 To keep the efficacy going, Wiscinski suggests using trastuzumab not only to escalate but also to de-escalate treatment.

“One of the strategies that still needs to be considered is not just escalating treatment with these newer agents, but also the idea of deescalating for smaller HER2-positive breast cancer. In particular, I am thinking about either the regimen of paclitaxel with trastuzumab or T-DM1 as a single-agent,” Wiscinski stated. “Overall, the escalation treatment strategy is sometimes appropriate, but other times, de-escalation is a critical thing for treating HER2-positive breast cancer.”

Tolaney also noted, during an interview, that de-escalation plays a critical role in how patients with HER2-positive breast cancer are treated.

“By tailoring adjuvant therapy based on response to preoperative therapy, we are able to escalate therapy for patients with residual disease, and de-escalate for patients with pathologic complete response,” Tolaney stated.

The de-escalation strategy is an area of active research as well. Currently, the CompassHER2-pCR study (NCT04266249), the PALTAN study (NCT02907918), and the TOUCH trial (NCT03644186) are all investigating de-escalation of trastuzumab-containing regimens.

Wiscinski noted, however, that challenges do exist with this strategy and should be explored future.

“An unmet need is having better predictors of who needs an escalation treatment and who can have their treatment de-escalated. For example, right now we rely a lot on nodal status and tumor size, but there could potentially be genomic markers or diagnostic tests that could help us identify which patients have very HER2-sensitive disease and potentially could be treated with less chemotherapy,” she explained.

_References:

_{1. Kurebayashi J. Biological and clinical significance of her2 overexpression in Breast Cancer. Breast Cancer. 2001;8(1):45-51. doi:10.1007/BF02967477}

_{2. Sharifi M, Wisinski KB. Advances in the treatment of early-stage her2-positive breast cancer. Clin Adv Hematol Oncol. 2020;18(8):482-492.}

_{3. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-3752. doi:10.1200/JCO.2014.55.5730}

_{4. The I-SPY 2 Trial. I-SPY2 website. Accessed October 2, 2020. https://bit.ly/36qn2Kk}