Tailoring systemic therapy for HER2+ early breast cancer—The CompassHER2 Trials

The advent of the human epidermal growth factor receptor 2 (HER2)-targeted monoclonal antibody trastuzumab significantly improved disease-free survival and overall survival for patients with breast cancer whose tumors overexpress the HER2 receptor (that is, HER2-positive [HER2+] breast cancer). A recent meta-analysis of 13,864 patients with HER2+ early-stage breast cancer revealed that the addition of trastuzumab to chemotherapy reduced breast cancer recurrence and mortality by one-third.¹ Chemotherapy regimens included in the analysis were doxorubicin and cyclophosphamide followed by a taxane,^2,3 and docetaxel plus carboplatin.³ Risk ratios appeared to favor regimens that omitted anthracyclines because they are similar in efficacy but result in lower rates of acute toxicities, cardiotoxicity, and leukemia.³ Given that many patients with HER2+ early-stage breast cancer have an excellent prognosis with standard systemic therapy, tailoring therapy to maintain or improve survival outcomes in patients with higher-risk disease while avoiding unnecessary chemotherapy-related toxicities in patients with lower-risk disease has become a central goal for managing patients with HER2+ breast cancer.

CompassHER2 Trials

Neoadjuvant (or preoperative) systemic therapy has become the standard of care for treating patients with clinical stage II–III HER2+ breast cancer. The phase II NeoSphere trial (Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation) randomized patients to one of four preoperative treatments: trastuzumab plus docetaxel, trastuzumab and pertuzumab plus docetaxel, trastuzumab plus pertuzumab, and pertuzumab plus docetaxel. All patients subsequently underwent surgery, followed by anthracycline-based chemotherapy. The trastuzumab and pertuzumab plus docetaxel arm out-performed the other treatment arms, with a pathologic complete response (pCR) rate of 45.8 percent (95 percent CI 36.1–55.7).⁴ The DAPHNE trial (De-escalation to Adjuvant Antibodies Post-pCR to Neoadjuvant THP) recently demonstrated physician and patient willingness to omit additional adjuvant chemotherapy for patients with clinical stage II–III HER2+ breast cancer who had a pCR after preoperative paclitaxel, trastuzumab, and pertuzumab (THP).⁵

The aim of the CompassHER2-pCR trial (EA1181) (COMprehensive use of PAthologic response asseSSment to optimize therapy in HER2-positive breast cancer; NCT04266249) is to assess outcomes in patients with HER2+ breast cancer who have a pCR after THP chemotherapy and received no further adjuvant chemotherapy. CompassHER2-pCR is a single-arm prospective trial, led by the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network, for patients with anatomic stage II–IIIa HER2+ breast cancer (either estrogen receptor-positive [ER+] or ER-) who receive 12 weeks of preoperative THP. The trial will enroll 1,250 patients, and the primary objective is a three-year recurrence-free survival greater than 92 percent for patients who have a pCR and do not receive adjuvant chemotherapy. Patients receive radiation and/or endocrine therapy as appropriate. Patients with residual invasive breast cancer are mandated to receive the additional chemotherapy that was omitted from the preoperative regimen, chosen by the treating oncologist.

Though many patients do well with a de-escalated regimen, patients who receive preoperative chemotherapy and are found to have invasive residual disease (RD) at surgery are at higher risk for recurrence,^6,7 and additional systemic treatment escalation is warranted. The KATHERINE trial (A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients with HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes following Preoperative Therapy) randomized 1,486 patients with HER2+ early-stage breast cancer treated with a standard preoperative taxane- (+/- anthracycline-) based regimen plus trastuzumab, and who had RD at the time of surgery to adjuvant trastuzumab or the antibody-drug conjugate T-DM1. Patients who received T-DM1 after surgery had a significantly improved invasive disease-free survival compared with patients who received trastuzumab (hazard ratio for invasive disease or death, 0.50; 95 percent confidence interval, 0.39 to 0.64; P<0.001).⁸ These results were practice-changing and have further underscored the value of response information obtained from surgery after neoadjuvant therapy.

The CompassHER2 RD trial (A011801), or CompassHER2 Residual Disease (RD), a Double-Blinded, Phase III Randomized Trial of T-DM1 and Placebo Compared With T-DM1 and Tucatinib (ClinicalTrials.gov Identifier: NCT04457596), aims to build on the findings from the KATHERINE trial by evaluating T-DM1 plus the HER2-specific tyrosine kinase inhibitor tucatinib compared with T-DM1 plus placebo. This is based on the finding that capecitabine, trastuzumab, and tucatinib significantly improved one-year progression-free survival (hazard ratio for disease progression or death, 0.54; 95 percent confidence interval, 0.42 to 0.71; P<0.001) compared with capecitabine, trastuzumab, and placebo in patients with HER2+ metastatic breast cancer who previously received trastuzumab and T-DM1.⁹ The CompassHER2 RD trial, led by the Alliance for Clinical Trials in Oncology, will enroll 1,031 patients with HER2+ early-stage breast cancer who have invasive RD after preoperative chemotherapy and HER2-directed therapy (ER- or ER+ RD with nodal involvement at surgery) and who have completed at least six cycles of chemotherapy. Eligible patients are randomized to T-DM1 plus placebo, or to T-DM1 plus tucatinib. The primary objective is to determine if the invasive disease-free survival is at least 5 percent higher with the addition of tucatinib to T-DM1.

A common goal

The CompassHER2 trials share a common scientific mission—to optimize systemic therapy for patients with clinical stage II–III HER2+ early-stage breast cancer based on their pathologic response to preoperative systemic therapy. CompassHER2-pCR aims to avoid excess toxicity from unnecessary chemotherapy in patients who have a pCR to THP, and CompassHER2 RD aims to escalate therapy for patients who are at high risk because of the presence of invasive RD after preoperative systemic therapy. These trials are poised to change practice for patients with HER2+ breast cancer and will provide a framework for future clinical trial design.

References

1. Trastuzumab for early-stage, HER2-positive breast cancer: A meta-analysis of 13,864 women in seven randomised trials. Lancet Oncol. 2021;22(8):1139-1150.
2. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.
3. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-1283.
4. Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.
5. Waks AG, Desai NV, Li T, et al. Abstract PD3-05: The DAPHNE trial: A feasibility study of chemotherapy de-escalation based on response to neoadjuvant paclitaxel-HP (THP) in HER2-positive breast cancer. 2020 San Antonio Breast Cancer Symposium.
6. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172.
7. Symmans WF, Wei C, Gould R, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol. 2017;35(10):1049-1060.
8. von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.
9. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609.