Shorter Duration of Trastuzumab Noninferior to Standard 12 Months in Early HER2+ Breast Cancer

Helena M. Earl, MBBS, PhD

Helena M. Earl, MBBS, PhD

In patients with HER2-positive early breast cancer, 6 months of adjuvant treatment with trastuzumab (Herceptin) was noninferior for disease-free survival (DFS) compared with the standard 12-month schedule, according to findings from the phase III PERSEPHONE trial presented ahead of the 2018 ASCO Annual Meeting.¹

With 5 years of follow-up, results of the randomized trial showed the 4-year DFS rate was 89.8% with 12 months of trastuzumab compared with 89.4% with the 6-month course, which met the criteria for noninferiority (HR, 1.07; 90% CI, 0.93-1.24;P= .01). In addition to improvements in DFS, the number of patients stopping treatment due to cardiac toxicity was cut in half with the shorter duration of trastuzumab.

"The PERSEPHONE Trial Group of investigators and patients successfully completed this large trial, which shows exciting first results, and we are confident we’ll mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer," said lead investigator Helena M. Earl, MBBS, PhD, professor of Clinical Cancer Medicine, Honorary Consultant Medical Oncologist, University of Cambridge, United Kingdom. "We hope, that for many women, this will become the standard of care."

The PERSEPHONE trial randomized 4088 patients across 152 sites in the United Kingdom to receive trastuzumab for 6 months (n = 2043) or 12 months (n = 2045). Adjuvant chemotherapy could be administered 3 cycles prior to initiation of trastuzumab and could be continued sequentially during the first 3 cycles with the HER2-targeted monoclonal antibody. Randomization to the 6-month arm or 12-month group could be delayed until cycle 9 of treatment, which represented the 6-month mark.

Two-thirds of patients (69%) in the trial were both HER2-positive and estrogen receptor-positive. Overall, 85% of patients also received adjuvant chemotherapy, which consisted of an anthracycline alone (41%), anthracycline and taxane (49%), or a taxane alone (10%).

The study assessed left ventricular ejection fraction (LVEF) every 3 months until month 12, with continued quality of life and health economic assessments beyond month 12 at months 18 and 24. Findings for quality of life, patient-reported outcomes, and health economic assessments remained ongoing, Earl noted.

Overall, 8% of those enrolled in the 12-month group discontinued treatment with trastuzumab due to cardiotoxicity compared with just 4% in the 6-month group (P<.0001). Across both groups, cardiac function, as measured by LVEF, recovered within a few months following treatment with trastuzumab (P<.0001). In general, however, patients in the 6-month group had a more rapid recovery compared with the standard of care arm (P= .02), Earl noted.

Other adverse events commonly associated with trastuzumab were lower in the 6-month group versus the standard arm. Grade 3/4 cough, fatigue, pain, chills, and palpitation were more common in the 12-month group compared with the 6-month arm.

"Patients treated with the 6-month treatment were able to return more quickly to their normal lives," she said. "6-month compared with 12-month treatment reduces cardiac and other toxicities and [reduces] costs both to patients and healthcare systems."

Several prior trials have sought to uncover the optimal duration of treatment with adjuvant trastuzumab. In the phase III HERA trial,²the 12-month standard was compared with a 2-year course of trastuzumab. After a median follow-up of 11 years, there was not an improvement in DFS with the 2-year dose compared with 12 months (HR, 1.02; 95% CI, 0.89-1.17). Adding to this, cardiotoxicity led to more treatment discontinuations in the 2-year group versus the 1-year arm (9.4% vs 5.2%, respectively).

Other previous studies have assessed a shorter duration of adjuvant trastuzumab for HER2-positive breast cancer, without the demonstration of positive findings. Notably, in the PHARE trial,³3384 patients were randomized to 6 or 12 months of trastuzumab. After 3.5 years of follow-up, the shorter treatment duration failed to show noninferiority to the standard 12 months (HR, 1.28; 95% CI, 1.05-1.56;P= .29), although cardiotoxicity was lower.

Additionally, in findings presented at the 2017 ASCO Annual Meeting from the phase III Short-HER trial,⁴a 9-week schedule of trastuzumab failed to meet the criteria for noninferiority compared with the 12-month dose (HR, 1.15; 90% CI, 0.91-1.46). A similar scenario was repeated in findings from the phase III SOLD study,⁵which also failed to show noninferiority for the 9-week dose versus 12 months of trastuzumab (HR, 1.39; 90% CI, 1.12-1.72).

Given the lack of efficacy in other trials, the experts discussing the research were hesitant to support a shorter duration of trastuzumab as a new standard of care until findings for overall survival were available. The PERSEPHONE study, which began enrolling in 2007, will continue to follow patients for this endpoint.

At the 5-year assessment, there had been 319 deaths in the study (8%). With this small sample size, the researchers noted that survival findings were currently congruent with the DFS results, with some heterogeneity observed based on stratification variables.

"Important translational research will be carried out analyzing blood and tumor samples to look for biomarkers to identify subgroups of different risk where shorter / longer durations of trastuzumab might be tailored," Early noted.

References:

1. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): Randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results.J Clin Oncol. 2017;36 (suppl; abstr 506).
2. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial.Lancet. 2017; 389(10075):1195-1205.
3. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial.Lancet Oncol. 2013;14(8):741-748.
4. Conte PF, Bisagni G, Frassoldati A, et al. 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER.J Clin Oncol. 2017;35 (suppl; abstr 501).
5. Joensuu H, Fraser J, Wildiers H, et al. A randomized phase III study of adjuvant trastuzumab for a duration of 9 weeks versus 1 year, combined with adjuvant taxane-anthracycline chemotherapy, for early HER2-positive breast cancer. The Synergism Or Long Duration (SOLD) trial. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS3-04.