Current treatment options for high-risk HER2–positive early breast cancer have limitations in terms of efficacy and tolerability. The KAITLIN trial assessed whether trastuzumab emtansine (T-DM1) could provide a better alternative to taxane-plus-trastuzumab in this setting. Unfortunately, this novel approach did not yield a clinically meaningful improvement in efficacy. Consequently, trastuzumab plus pertuzumab plus chemotherapy remains the standard of care in this patient population.
The standard of care for adjuvant treatment of high-risk human epidermal growth factor receptor 2 (HER2)–positive early breast cancer (EBC) is chemotherapy plus one year of HER2-directed therapy. However, these treatments have limitations in terms of efficacy and tolerability, the latter primarily because of toxicities associated with chemotherapy. In the metastatic and neoadjuvant settings, the addition of pertuzumab to trastuzumab and chemotherapy resulted in improved outcomes. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of the cytotoxic agent DM1 linked to trastuzumab. The phase III KAITLIN trial analysed if T-DM1 plus pertuzumab could provide an alternative to taxanes plus trastuzumab and pertuzumab to improve safety and efficacy in patients with high-risk HER2-positive EBC.
KAITLIN is a phase III, randomised, multinational, open-label study conducted in 36 countries. Eligible patients had newly diagnosed and operable HER2-positive EBC, had node-positive disease (pN ≥ 1), with any tumour size except T0 and any hormone receptor status, or node-negative disease (pN0) with the pathologic tumour size > 2.0 cm and negative for oestrogen receptor (ER) and progesterone receptor (PgR). Post-surgery, patients were randomised (1:1) to anthracycline-based chemotherapy (three-four cycles) and then eighteen cycles of T-DM1 plus pertuzumab (AC-KP), or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary endpoints were invasive disease-free survival (IDFS) in the node-positive and overall populations with hierarchical testing.
Between January 2014 and June 2015, 1,846 patients were enrolled. Of these, 1,658 (89.8%) comprised the node-positive subpopulation. The median follow-up was 57.1 months for AC-THP (N= 918) and 57.0 months for AC-KP (N= 928). As of November 2019, among the intention-to-treat lymph node–positive subpopulation, 9.9% and 9.6% of the IDFS events had occurred in the AC-THP and the AC-KP arm, respectively. Treatment with AC-KP did not reduce the risk of an IDFS event compared with AC-THP in the node-positive subpopulation (stratified HR[95%CI]:0.97[0.71-1.32]; p= 0.83) so hierarchical testing was stopped. The 3-year IDFS rates were 94.1% with AC-THP and 92.8% with AC-KP. In the overall population, 9.6% and 9.3% of the IDFS events occurred in the AC-THP and AC-KP arms, respectively. AC-KP did not reduce the risk of an IDFS event compared with AC-THP (stratified HR[95%CI]: 0.98[0.72-1.32]. Three-year IDFS rates were 94.2% with AC-THP and 93.1% with AC-KP. Sites of recurrence were similar in each arm. Rates of secondary nonprimary breast cancer, disease-free survival, and distant recurrence-free interval were similar between treatment arms. OS data were immature with event rates of 3.6% and 4.7% in patients receiving AC-THP and AC-KP, respectively. Treatment completion rates (i.e., 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP.
Similar rates of grade ≥ 3 (55.4% vs. 51.8%) and serious adverse events (23.3% vs. 21.4%) occurred with AC-THP and AC-KP. Deaths related to an adverse event occurred in 0.2% and 0.5% of the patients receiving AC-THP and AC-KP, respectively. Adjudicated primary cardiac events occurred in 1.1% of patients receiving AC-THP and 0.4% receiving AC-KP. No cardiac deaths occurred. The risk of experiencing a clinically meaningful deterioration in global health status from the start of HER2-targeted therapy was reduced by 29% in the AC-KP versus AC-THP arm (stratified HR[95%CI]: 0.71[0.62-0.80]), with the majority of the deterioration occurring during the first five cycles of HER2-targeted therapy.
Adjuvant AC-KP did not result in statistically significant or clinically meaningful improvement in IDFS compared with AC-THP in the node-positive subpopulation or overall population with high-risk EBC. There was a lower risk of deterioration in quality of life with AC-KP, likely accounted for by taxanes in the AC-THP arm. The approach for management of high-risk HER2-positive breast cancer remains initial treatment with neoadjuvant trastuzumab/pertuzumab and chemotherapy, and escalation to adjuvant T-DM1 for residual disease.
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