ABSTRACT
Background: HER2+ mBC remains incurable, with a need for new HER2-directed therapies and regimens, including chemotherapy-free options. Zanidatamab (zani) is a novel HER2-targeted bispecific antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of antitumor activity, including complement-dependent cytotoxicity. A CDK4/6 inhibitor combined with endocrine therapy is an approved treatment for HER2-negative/HR+ mBC and this combination has also demonstrated encouraging antitumor activity when paired with HER2-targeted therapy(ies) in HER2+/HR+ mBC. Here, we report results from ZWI-ZW25-202 (NCT04224272), an ongoing singlearm phase 2 study of zani combined with palbociclib (palbo) and fulvestrant (fulv) in pts with HER2+/HR+ mBC. Method(s): Eligibility requirements include: HER2+/HR+ unresectable, locally advanced BC or mBC;ECOG PS of 0 or 1;prior treatment with trastuzumab, pertuzumab and T DM1 (additional prior HER2-targeting agents are permitted);and no prior treatment with CDK4/6 inhibitors. Part 1 of the study evaluated the safety and tolerability of the zani/palbo/fulv combination and determined the recommended doses for use in Part 2, where the antitumor activity of the combination is being evaluated. Endpoints include safety outcomes, progression-free survival at 6 months (PFS6), confirmed objective response rate (cORR) per RECIST v1.1;disease control rate (DCR=complete response [CR] plus partial response [PR] plus stable disease [SD]);duration of response (DOR);PFS;and overall survival. Result(s): As of 24 Feb 2022, 34 pts (33 HER2+/HR+ per central analysis) with a median age of 52 (range 36-77) have been treated. In the metastatic setting, pts had received a median (range) of 4 (1-10) prior systemic regimens, including 3 (1-8) different prior HER2 targeted therapies, and 1 (0-4) endocrine therapy. Seven pts (20%) had prior T DXd treatment and 7 pts had prior fulv treatment. All pts received zani (20 mg/kg Q2W) and standard doses of palbo and fulv. Eighteen pts (53%) remained on treatment;median duration of zani treatment was 6.9 mo (range 0.5- 16.3). A dose-limiting toxicity (DLT) of neutropenia occurred in 1 of 7 DLT-evaluable pts in Part 1. Among all pts (n=34), the most common (>20%) treatment (zani, palbo and/or fulv)-related adverse events (TRAEs) were diarrhea (74%), neutrophil count decreased/neutropenia (62%), stomatitis (41%), asthenia (26%), nausea (24%), and anemia (21%). Grade (Gr) >=3 TRAEs in 2 or more pts included neutrophil count decreased/neutropenia (50%), anemia (6%), diarrhea (6%), and thrombocytopenia (6%). AEs of special interest were all Gr <=2 and included 4 pts with cardiac events (LVEF decrease of >=10% from baseline) and 1 pt with infusion-related reaction. There were no treatment-related serious AEs. Palbo was discontinued for 1 pt due to an AE (AST increase);no pt discontinued zani treatment as a result of AEs. Two deaths occurred: 1 due to disease progression and 1 due to an unrelated AE of pneumonia caused by COVID-19. In 29 pts with measurable disease, the cORR was 34.5% (95% CI: 17.9, 54.3), all responses were cPRs, of which 1 is pending CR confirmation. DOR ranged from 2.3 to 14.9+ mo, with 8 confirmed responses ongoing, and the DCR was 93.1% (95% CI: 77.2, 99.2). Interim median PFS was 11.3 mo (range 0.03-16.7;95% CI: 5.6, not estimable). PFS6 analysis is planned following the completion of enrollment. Conclusion(s): Zani in combination with palbo and fulv shows encouraging antitumor activity with durable responses in heavily pretreated pts and a manageable safety profile. This regimen has the potential to be a chemotherapy-free treatment option in pts with HER2+/HR+ mBC. Enrollment in the study is continuing.
ABSTRACT
The increasing use of pre-operative systemic therapy has resulted in more limited information about axillary lymph node status, both from the impact of systemic therapy itself as well as from less extensive axillary surgery. Decisions about the use of adjuvant endocrine therapy have not been majorly affected, but information on the presence and number of involved lymph nodes can have a significant influence on the use of adjuvant chemotherapy and HER-2 targeted therapies. In addition, lymph node information can also impact decisions around radiation therapy, making multidisciplinary discussions highly relevant when planning therapy. Patients with hormone receptor positive breast cancer may be treated with pre-operative endocrine therapy. This strategy was often used in early stage breast cancer during the COVID pandemic due to delays in surgery. Although an effective approach, pre-operative endocrine therapy may impact nodal status at surgery, information which is important when deciding on the use of OncotypeDX testing in premenopausal women. Similarly, in postmenopausal women, the presence and number of lymph nodes involved is a critical factor in determining the appropriateness of OncotypeDx testing. This nodal information may be lost in the setting of pre-operative therapy and would alter decisions regarding adjuvant chemotherapy. For patients with HER2 positive breast cancer, the presence of nodal disease remains critical for adjuvant decision making. In the situation of small (up to 3 cm) node negative cancers, up front surgery is preferred, because pathologic confirmation of the tumor size and node negative status may make patients eligible for a de-escalated approach of adjuvant paclitaxel and trastuzumab. Patients with more advanced HER2 positive disease are good candidates for preoperative chemotherapy and HER2 targeted therapy. If they have residual disease at surgery, they can be offered trastuzumab emtansine, which was shown in the KATHERINE trial to improve outcomes. In both situations, accurate information about the presence of disease in the axillary lymph nodes determines the most effective treatment approach. Finally, accurate information about nodal status is also relevant to decisions in patients with triple negative breast cancer. Patients who are treated with pre-operative chemotherapy and have residual disease in either the breast or axillary lymph nodes may be offered adjuvant capecitabine, based on the CREATE-X study, which indicated improved survival outcomes in those patients with residual disease who received adjuvant capecitabine. As in HER2 positive breast cancer, the presence of residual disease (including in the lymph nodes) after preoperative therapy will influence the adjuvant therapy recommendation. Thus, when considering de-escalation approaches in axillary management, the impact on systemic therapy decision making must be carefully considered, as these additional adjuvant therapies may improve survival for patients. Conflict of Interest: No significant relationships.