Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting

TROIKA (NCT03013504) was a multicenter, randomized, phase 3 trial previously detailed in the publication reporting the primary analysis [1]. The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Approval of the study protocol and all accompanying documents provided to the patients was obtained from independent ethics committees at participating institutions, and all patients provided voluntary written informed consent. Key eligibility criteria were age ≥ 18 years; ERBB2-positivity; new diagnosis; unilateral, operable breast cancer; and a baseline left ventricular ejection fraction ≥ 55%.

Patients were enrolled and randomized using a block of 8 in a ratio of 1:1 to receive either HD201 or referent trastuzumab (loading dose: 8 mg/kg; maintenance dose: 6 mg/kg) every 3 weeks, administered concurrently with 8 cycles of chemotherapy (4 cycles of docetaxel [75 mg/m²], followed by 4 cycles of epirubicin [75 mg/m²]/cyclophosphamide [500 mg/m²]) in the neoadjuvant setting. After surgery, patients received an additional 10 cycles of HD201 or referent trastuzumab in the adjuvant setting according to the previous allocation.

Secondary objectives included evaluation of event-free survival (EFS) (defined as the time from randomization to the first observation of disease progression, including local and distant recurrence, second primary cancer, or death due to any cause), overall survival (OS) (defined as the time from randomization to death), safety, and immunogenicity. Exploratory analyses were conducted for EFS including locally assessed tpCR and bpCR as covariates.

Target sample sizes and statistical power calculations for the primary analysis have been reported previously [1]. Statistical analyses were performed with SAS (version 9.4; SAS Institute Inc., NC, USA). Kaplan–Meier analysis was used to estimate EFS and OS rates. Cox proportional hazards regression analyses providing hazard ratios (HRs) and 95% confidence intervals (95% CIs) for EFS adjusted for region, stage, and tumor hormonal receptor status are presented. Survival analyses were conducted in the per-protocol set (PPS), including all patients who received the study treatment (without a major protocol deviation affecting the primary efficacy assessment) and who underwent surgery after the completion of neoadjuvant treatment or did not undergo surgery because of lack of efficacy, and analysis was also performed in the modified full analysis set (mFAS), including all patients who received at least 1 dose of study medication (Fig. 1). Safety analyses were descriptive and conducted in all patients who received at least one dose of treatment. Adverse events (AEs) and serious AEs (SAEs) were recorded and graded per standard common technology criteria for adverse events (CTCAE).

This analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). The mFAS comprised 502 randomized and treated patients, among whom 250 (49.8%) were in the HD201 group and 252 (50.2%) were in the referent trastuzumab group and were included between February 19 and September 21, 2018, across 70 centers in 12 countries. A total of 28 patients with mFAS were excluded from the PPS (12 patients in the HD201 treatment group and 16 patients in the referent trastuzumab group). The PPS thus comprised 238 patients in the HD201 treatment group and 236 patients in the referent trastuzumab treatment group. Baseline demographics and disease characteristics were well balanced between the study arms as reported previously [1].

In the PPS, the 3-year EFS rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (Fig. 2A). The Cox proportional HR adjusted for region, stage, and tumor hormonal receptor status was 1.02 (95% CI: 0.63–1.63; p = 0.945) (Fig. 2A). The 3-year OS rates were comparable for the HD201 (95.5%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606) (Fig. 2B). These results for EFS and OS were similar to those in the mFAS population (Figs. 2E and F). The sensitivity analysis searching heterogeneity of treatment effect according to the disease characteristics did not observed any discordances between the two arms in terms of survival outcomes.

In the PPS, in both treatment arms, 3-year EFS was more better for patients achieving a tpCR (locally assessed) than for those with residual disease, with 10.8% (24/222) versus 17.9% (45/252) of patients with events counting for EFS, respectively (HR 0.53, 95% CI 0.32–0.87; p = 0.013) (Fig. 2C). Similarly, 3-year EFS was more favorable for patients achieving a bpCR (locally assessed) than for those without (HR 0.54, 95% CI 0.33–0.89; p = 0.014) (Fig. 2D).

During the posttreatment follow-up period, PTAEs were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the referent trastuzumab groups, respectively (Table 1). PTAEs with severity grade 3 or higher were reported for 7 (3.0%) patients and 13 (5.4%) patients, and serious PTAEs were reported for 4 (1.7%) patients and 5 (2.1%) patients, respectively. No serious PTAEs related to study treatment were reported during the posttreatment follow-up period. Overall, no noteworthy differences were found between the two groups.