KATHERINE (NCT01772472) was a randomized, multicenter, open-label trial of 1486 patients with HER2-positive, early breast cancer. Patients were required to have had neoadjuvant taxane and trastuzumab-based therapy with residual invasive tumor in the breast and/or axillary lymph nodes. Patients received radiotherapy and/or hormonal therapy concurrent with study treatment as per local guidelines. Breast tumor samples were required to show HER2 overexpression defined as 3+ IHC or ISH amplification ratio ≥ 2.0 determined at a central laboratory using Ventana's PATHWAY anti-HER2-/neu (4B5) Rabbit Monoclonal Primary Antibody or INFORM HER2 Dual ISH DNA Probe Cocktail assays. Patients were randomized (1:1) to receive KADCYLA or trastuzumab. Randomization was stratified by clinical stage at presentation, hormone receptor status, preoperative HER2-directed therapy (trastuzumab, trastuzumab plus additional HER2-directed agent[s]), and pathological nodal status evaluation after preoperative therapy.

KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on Day 1 of a 21-day cycle. Patients were treated with KADCYLA or trastuzumab for a total of 14 cycles unless there was recurrence of disease, withdrawal of consent, or unacceptable toxicity. At the time of the major efficacy outcome analysis, median treatment duration was 10 months for both KADCYLA- and trastuzumab-treated patients. Patients who discontinued KADCYLA for reasons other than disease recurrence could complete the remainder of the planned HER2-directed therapy with trastuzumab if appropriate based on toxicity considerations and investigator discretion.

The major efficacy outcome of the study was invasive disease-free survival (IDFS). IDFS was defined as the time from the date of randomization to first occurrence of ipsilateral invasive breast tumor recurrence, ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. Additional efficacy outcomes included IDFS including second primary non-breast cancer, disease free survival (DFS), and overall survival (OS).

Patient demographics and baseline tumor characteristics were generally balanced between treatment arms. The median age was approximately 49 years (range 23-80 years), 73% were White, 9% were Asian, 6% were American Indian or Alaska Native and 3% were Black or African American. Most patients (99.7%) were women. Enrollment by region was as follows: 23% in North America, 54% in Europe and 23% throughout the rest of the world. Tumor prognostic characteristics including hormone receptor status (positive: 72%, negative: 28%), clinical stage at presentation (inoperable: 25%, operable: 75%) and pathological nodal status after preoperative therapy (node positive: 46%, node negative or not evaluated: 54%) were similar across study arms.

The majority of patients (77%) had received an anthracycline-containing neoadjuvant chemotherapy regimen. Twenty percent of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy; 94% of these patients received pertuzumab.

After a median follow-up of 40 months, a statistically significant and clinically meaningful improvement in IDFS was observed in patients who received KADCYLA compared with trastuzumab in patients with HER2-positive EBC with residual disease after completion of neoadjuvant treatment. The OS data were not mature at the time of the IDFS analysis (98 deaths [6.6%] occurred in 1486 patients).

After a median follow-up of 101 months, the final descriptive IDFS analysis indicated the observed benefit of KADCYLA is maintained over time and the second interim analysis of OS demonstrated a statistically significant and clinically meaningful improvement in OS for KADCYLA compared with trastuzumab. In the final descriptive IDFS analysis, KADCYLA reduced the risk of an IDFS event by 46% compared with trastuzumab (unstratified HR=0.54; 95% CI: 0.44–0.66). Estimates of IDFS event free rates at 7 years were 80.8% (95% CI: 77.86, 83.78) vs. 67.1% (95% CI: 63.49, 70.65) in the KADCYLA and trastuzumab arms, respectively. IDFS results at the final descriptive IDFS analysis were consistent with the primary analysis. The efficacy results from KATHERINE are summarized in Table 8, Figure 3, and Figure 4.

Consistent results were observed with KADCYLA in terms of IDFS and OS across subgroups based on stratification factors, key baseline demographic and disease characteristics, and prior treatments.

Figure 3 Kaplan-Meier Curve of Invasive Disease-Free Survival in KATHERINE

Figure 4 Kaplan-Meier Curve of Overall Survival in KATHERINE (Updated Analysis)