article_7_hero
article_continue

KADCYLA Clinical Trials

The clinical studies section of the prescribing information provides all the critical information from the pivotal clinical trials that helped bring the drug to FDA approval. For KADCYLA, there were two pivotal clinical trials. EMILIA, which examined KADCYLA in HER2+ MBC for patients who had failed prior taxane and trastuzumab-based therapy, and KATHERINE, which evaluated KADCYLA in patients with HER2+ EBC and residual invasive disease following neoadjuvant taxane and trastuzumab-based treatment.

At a Glance: Primary Results of Pivotal Clinical Trials

14.1 Metastatic Breast Cancer: The EMILIA Trial

Select the tabs below to learn more about the EMILIA clinical trial.

Overview

The EMILIA trial was a randomized, multicenter, open-label trial of 991 patients with HER2+, unresectable locally advanced or metastatic breast cancer. Prior taxane and trastuzumab-based therapy was required before trial enrollment. Patients with only prior adjuvant therapy were required to have disease recurrence during or within a 6‑month period of completing adjuvant therapy. Breast tumor samples were required to show HER2 overexpression. Patients were randomly allocated (1:1) to receive lapatinib plus capecitabine or KADCYLA.

Study Design

KADCYLA was given intravenously at 3.6 mg/kg on Day 1 of a 21-day cycle. Lapatinib was administered at 1250 mg/day orally once per day of a 21-day cycle and capecitabine was administered at 1000 mg/m2 orally twice daily on Days 1-14 of a 21-day cycle. Patients were treated with KADCYLA or lapatinib plus capecitabine until progression of disease, withdrawal of consent, or unacceptable toxicity. At the time of primary analysis, median time on study drug was 5.7 months (range: 0-28.4) for KADCYLA, 4.9 months (range: 0-30.8) for lapatinib, and 4.8 months (range: 0-30.4) for capecitabine.

Endpoints

Primary Endpoint:

Co-primary endpoints for EMILIA were progression-free survival (PFS) based on tumor response assessments by an independent review committee (IRC) and overall survival (OS).

  • PFS was defined as the time from the date of randomization to the date of disease progression or death from any cause
  • OS was defined as the time from the date of randomization to the date of death from any cause

Secondary Endpoints:

  • PFS
  • Objective response rate (ORR)
  • Duration of response
  • Time to symptom progression

Baseline Characteristics

Patient demographics and baseline tumor characteristics were balanced between treatment arms. All patients had metastatic disease at study entry.

  • Median age was ~53 years (range 24-84 years)
  • 74% White, 18% Asian, 5% Black
  • All but 5 patients were women
  • Tumor prognostic characteristics were similar in study arms
  • The majority of patients (88%) had received prior systemic treatment in the metastatic setting
  • 12% of patients had prior treatment only in the neoadjuvant or adjuvant setting and had disease relapse within 6 months of treatment
  • All but one patient received trastuzumab prior to study entry
  • 85% of patients received prior trastuzumab in the metastatic setting
  • Over 99% of patients had received a taxane
  • 61% of patients had received an anthracycline prior to study entry

Efficacy Results

Primary Endpoint Results

  • The randomized trial demonstrated a statistically significant improvement in IRC-assessed PFS in the KADCYLA-treated group compared with the lapatinib plus capecitabine-treated group
  • There was an increase in median PFS of 3.2 months (median PFS of 9.6 months in the KADCYLA-treated group vs 6.4 months in the lapatinib plus capecitabine group)(see Table 1 and Figure 1)
  • At the time of PFS analysis, 223 patients had died. More deaths occurred in the lapatinib plus capecitabine arm (26%) compared with the KADCYLA arm (19%). At the time of the second interim OS analysis, 331 events had occurred.
  • OS was significantly improved in patients receiving KADCYLA. There was a median OS of 30.9 months in the KADCYLA group compared to a median OS of 25.1 months in the lapatinib plus capecitabine group. (see the table and figures below)

Summary of Efficacy from EMILIA

KADCYLA
N = 495 		Lapatinib+Capecitabine
N = 496
Progression-Free Survival (independent review)
Number (%) of patients with event
Median duration of PFS (months) 		265 (53.5%)
9.6		 304 (61.3%)
6.4
Hazard Ratio (stratified*)
95% CI for Hazard Ratio
p-value (Log-Rank test, stratified*) 		0.650
(0.549, 0.771)
< 0.0001
Overall Survival†
Number (%) of patients who died
Median duration of survival (months) 		149 (30.1%)
30.9		 182 (36.7%)
25.1
Hazard Ratio (stratified*)
95% CI for Hazard Ratio
p-value (Log-Rank test*) 		0.682
(0.548, 0.849)
0.0006
Objective Response Rate (independent review)
Patients with measurable disease
Number of patients with OR (%) 		397
173 (43.6%)		 389
120 (30.8%)
Difference (95% CI) 12.7% (6.0, 19.4)
Duration of Objective Response (months)
Number of patients with OR
Median duration (95% CI) 		173
12.6 (8.4, 20.8)		 120
6.5 (5.5, 7.2)
PFS: progression-free survival; OR: objective response
* Stratified by world region(United States, Western Europe, other), number of prior chemotherapeutic regimens for locally advanced or metastatic disease (0-1 vs. > 1), and visceral vs. non-visceral disease.
†The second interim analysis for OS was conducted when 331 events were observed and the results are presented in this table.

Progression-Free Survival for EMILIA

Overall Survival for EMILIA

14.2 Early Breast Cancer: The KATHERINE Trial

Select the tabs below to learn more about the KATHERINE clinical trial.

Overview

KATHERINE was a randomized, multicenter, open-label trial of 1486 patients with HER2+ EBC. 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. Breast tumor samples were required to show HER2 overexpression. Patients were randomized (1:1) to receive KADCYLA or trastuzumab.

Study Design

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 of Day 1 of a 21-day cycle. Patients were treated with KADCYLA or trastuzumab for a total of 14 cycles unless there was a 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.

Endpoints

Primary Endpoint:

  • 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.

Secondary Endpoints:

  • iDFS including second primary non-breast cancer
  • Disease free survival (DFS)
  • Overall survival (OS)

Baseline Characteristics

Patient demographics and baseline tumor characteristics were generally balanced between treatment arms.

  • The median age was ~49 years (range 23-80 years).
  • 73% were White, 9% were Asian, 6% were American Indian or Alaska Native, 3% were Black or African American.
  • 99.7% of patients were women.
  • Tumor prognostic characteristics were similar across study arms.
  • The majority of patients (77%) had received an anthracycline-containing neoadjuvant chemotherapy regimen.
  • 20% of patients received another HER2-targeted agent in addition to trastuzumab as a component of neoadjuvant therapy; 94% of these patients received pertuzumab.

Efficacy Results

Primary Endpoint Results

After a median follow-up of 40 months, there was a statistically significant improvement in iDFS in patients who received KADCYLA compared with trastuzumab. KADCYLA reduced the risk of recurrence by 50% versus trastuzumab (HR, 0.50 [95% CI: 0.39, 0.64; P < 0.0001)]. See the table and figure below for details.

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

Efficacy Results for KATHERINE

KADCYLA
N = 743 		Trastuzumab
N = 743
Invasive Disease-Free Survival (iDFS)1,4
Number (%) of patients with event
Median duration of PFS (months) 		91 (12.2%) 165 (22.2%)
HR [95% CI]2
p-value (Log-Rank test, unstratified) 		0.50 [0.39, 0.64]
< 0.0001
3-year event-free rate, % [95% CI] 83.3 [85.8, 90.7] 77.0 [73.8, 80.7]
iDFS including second primary non-breast cancer
Number (%) of patients with event 95 (12.8%) 167 (22.5%)
HR [95% CI]2 0.51 [0.40, 0.66]
3-year event-free rate, % [95% CI] 87.7 [85.2, 90.2] 76.9 [73.7, 80.1]
Disease-Free Survival (DFS)
Number (%) of patients with event 98 (13.2%) 167 (22.5%)
HR [95% CI]2 0.53 [0.41, 0.68]
3-year event-free rate3, % [95% CI] 87.4 [84.9, 89.9] 76.9 [73.7, 80.1]
HR: Hazard Ratio; CI: Confidence Intervals,
1 Hierarchical testing applied for iDFS and OS
2 Unstratified analysis
3 3-year event-free rate derived from Kaplan-Meier estimates
4 Data from the pre-specified interim analysis (67% of the number of events for the planned final analysis) with the p-value compared with the allocated alpha of 0.0124

iDFS Results for KATHERINE

iDFS Results Across Subgroups

Let's take a closer look at iDFS results across different patient subgroups. The figure below demonstrates that KADCYLA provided a consistent iDFS benefit for patients regardless of stratification factors, key baseline demographics and disease characteristics, and prior treatments. This includes patients with any amount of residual invasive disease, even ≤1 cm. In fact, a benefit was seen in 331 patients with residual invasive disease ≤1 cm in the breast and negative lymph nodes, with invasive-disease events in 17 patients (10.0%) in the KADCYLA group versus 25 patients (15.5%) in the trastuzumab group (HR, 0.60; 95% CI, 0.33 to 1.12).

iDFS Results: Exploratory Analysis of Pre-specified Subgroups

Progress Check