In the phase III KAITLIN trial reported in the Journal of Clinical Oncology, Ian E. Krop, MD, and colleagues found that adjuvant ado-trastuzumab emtansine (T-DM1) plus pertuzumab did not improve invasive disease–free survival vs a taxane plus trastuzumab/pertuzumab, both following anthracycline-based chemotherapy, in patients with high-risk HER2-positive breast cancer in either the node-positive or total study population.

As stated by the investigators, “We aimed to improve efficacy and reduce toxicity of high-risk HER2-positive early breast cancer treatment by replacing taxanes and trastuzumab with [T-DM1].”

Ian E. Krop, MD

Study Details

The open-label trial included 1,846 patients with hormone receptor–negative disease and tumor size > 2 cm from sites in 36 countries. They were randomly assigned between January 2014 and June 2015 to receive 3 or 4 cycles of anthracycline-based chemotherapy followed either by 18 cycles of T-DM1 plus pertuzumab given every 3 weeks (AC-KP, n = 928) or by 3 or 4 cycles of taxane chemotherapy concurrently with trastuzumab plus pertuzumab every 3 weeks followed by 18 cycles of trastuzumab/pertuzumab given every 3 weeks (AC-THP, n = 918).

Anthracycline and taxane treatment was selected by investigators prior to random assignment. Adjuvant radiotherapy and endocrine therapy were permitted.

The co-primary endpoints were invasive disease–free survival in the intention-to-treat node-positive and overall populations with hierarchic statistical testing.

Invasive Disease–Free Survival

Median follow-up was 57.0 months (interquartile range [IQR] = 52.1–59.8 months) in the AC-KP group and 57.1 months (IQR = 52.1–60.1 months) in the AC-THP group. A total of 167 patients switched from trastuzumab emtansine to trastuzumab.

The node-positive population consisted of 1,658 patients (89.8%), including 832 in the AC-KP group and 826 in the AC-THP group. As of data cutoff (November 2019), invasive disease–free survival events had occurred in 9.6% of patients in the AC-KP group vs 9.9% of the AC-THP group, with no significant benefit of AC-KP (stratified hazard ratio [HR] = 0.97, 95% CI = 0.71–1.32, P =.83). At 3 years, invasive disease–free survival was 92.8% (95% CI = 91.0%–94.5%) with AC-KP vs 94.1% (95% CI = 92.5%–95.7%) with AC-THP.

In the overall population, invasive disease–free survival events occurred in 9.3% vs 9.6% of patients (stratified HR = 0.98, 95% CI = 0.72–1.32), with 3-year rates of 93.1% (95% CI = 91.4%–94.7%) vs 94.2% (95% CI = 92.7%–95.8%).

Overall survival data were not mature. Death had occurred in 4.7% vs 3.6% of patients.

Adverse Events

Treatment completion rates were 65.0% in the AC-KP group vs 88.4% in the AC-THP group, with the difference largely reflecting discontinuation of T-DM1 in 12.5% of patients due to laboratory abnormalities. Grade ≥ 3 adverse events occurred in 51.8% vs 55.4% of patients, most commonly neutropenia (16.6% vs 19.4%) and febrile neutropenia (5.7% vs 9.6%).

Serious adverse events occurred in 21.4% vs 23.3% of patients. Adverse events led to discontinuation of trastuzumab in 4.0% of patients and to discontinuation of T-DM1 in 26.8%.

Adverse events led to death in five patients in the AC-KP group (pneumonia in two, and colon neoplasm, suicide, and metabolic acidosis in one each) and two patients in the AC-THP group (pneumonia/hydrothorax and uterine leiomyosarcoma in one each), with no deaths considered related to treatment. KP was associated with a decrease in clinically meaningful deterioration in global health status vs THP (stratified HR = 0.71, 95% CI = 0.62–0.80).

The investigators concluded, “The primary endpoint was not met. Both arms achieved favorable invasive disease–free survival. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive early breast cancer.”

Dr. Krop, of Dana-Farber Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by F. Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit ascopubs.org.