For Adjuvant Trastuzumab, 6 Months Is Noninferior to 12 Months

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The noninferiority phase III Persephone trial could shake up the standard of care for adjuvant trastuzumab (Herceptin), showing that patients with early-stage HER2-positive breast cancer derived as much benefit from 6 months of trastuzumab as 12 months, according to research from the United Kingdom to be reported at the 2018 ASCO Annual Meeting.1

This is a real-world result…. But we need to be very careful and cautious about saying at this point that 6 months of trastuzumab is enough.
— Helena Margaret Earl, MBBS, PhD

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“The first results of Persephone demonstrate that 6 months of adjuvant trastuzumab is noninferior to 12 months. Given the cardiac and other toxicities during months 7 to 12 of treatment, our results would support a reduction of standard trastuzumab duration to 6 months,” said Helena Margaret Earl, MBBS, PhD, of the University of Cambridge and the National Institute for Health Research Cambridge Biomedical Research Center in the United Kingdom.

Interest in the study was high during a press briefing in advance of the ASCO meeting. The press conference moderators maintained that longer follow-up and a closer look at the data are needed before oncologists change practice. 

Richard L. Schilsky, MD, FACP, FASCO

Richard L. Schilsky, MD, FACP, FASCO

“Personally, I find the results quite compelling, and I think they will likely signal a shift in the U.S. oncology community toward shorter duration of therapy,” said Richard L. Schilsky, MD, FACP, FASCO, Chief Medical Officer for ASCO. But he thought a more detailed analysis is warranted, especially to identify women who would benefit more from 12 months of trastuzumab. He suggested that oncologists hold off on changing practice, pending revisions to the current practice guidelines.

Bruce E. Johnson, MD, FASCO, ASCO President, agreed. “Declaring victory with only 8% of deaths and 12% of recurrences may be a bit early—too early to make a definite change in practice,” he said, though he acknowledged that the benefit in terms of cardiac toxicity is clear.

Dr. Earl did not disagree. “This is a real-world result…. But we need to be very careful and cautious about saying at this point that 6 months of trastuzumab is enough,” she said. “The due process is that we present our results at ASCO, then in a peer-reviewed publication, and then they will undergo rigorous scrutiny alongside other available data…. But what we hope is that for many women, 6 months of trastuzumab will become the standard of care.”

Persephone Details

Persephone was a randomized phase III noninferiority trial comparing 6 months of trastuzumab to the standard 12 months in 4,088 patients enrolled from 152 sites in the United Kingdom between 2007 and 2015. The study “mapped into standard practice,” she said, randomly assigning to 6 or 12 months of trastuzumab, any time until after cycle 9.

Declaring victory with only 8% of deaths and 12% of recurrences may be a bit early—too early to make a definite change in practice.
— Bruce E. Johnson, MD, FASCO

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The size of the population enabled the trial to assess noninferiority, which was defined as “no worse than 3% below the assumed 4-year disease-free survival of 80% in the 12-month arm.” The preplanned definitive disease-free survival analysis required 500 events. The investigators emphasized that although a few other studies have evaluated shorter durations of trastuzumab, Persephone is the largest noninferiority trial to do so.

The HER2-positive population was largely estrogen receptor–positive (69%), and most patients (89%) had received chemotherapy, including anthracycline-based regimens (41%), anthracycline-plus-taxane–based regimens (49%), and taxane-based regimens (10%). Trastuzumab was given sequentially in 54% of cases.

Noninferior Outcomes  

After 4.9 years’ median follow-up, 8% of the patients had died and 12% had relapsed, with no significant differences between the groups. With a 4-year disease-free survival rate of 89.8% in the 12-month arm and 89.4% in the 6-month arm, the hazard ratio of 1.07 (95% confidence interval = 0.93–1.24; P = .01 for noninferiority) was well within the noninferiority limit set at 1.29, Dr. Earl reported.

Congruent results were found for overall survival and for the preplanned disease-free survival and overall survival landmark analyses (after 6 months of trastuzumab), but these details will not be reported at this year’s ASCO Annual Meeting.

Less Cardiac Toxicity in 6-Month Arm

Importantly, there were fewer cardiac events in the 6-month arm. As the investigators previously reported for the first 2,000 participants, treatment discontinuation due to cardiotoxicity occurred in 4% of the 6-month arm vs 8% of the 12-month arm (P < .0001).2 Between 7 and 12 months, 8% of the 12-month arm had left-ventricular ejection fractions < 50%, compared to 5% of the 6-month arm (= .004). Although cardiac function often recovered after trastuzumab was stopped, the recovery was more rapid in the 6-month arm (P = .02). 


  • The randomized phase III Persephone trial, conducted in 4,088 patients with early-stage HER2-positive breast cancer patients in the United Kingdom, evaluated 6 months of adjuvant trastuzumab vs the standard 12 months’ duration.
  • Persephone found that 6 months of trastuzumab was noninferior to 12 months and was associated with less cardiotoxicity.
  • Disease-free survival at 4 years was 89% in each arm.
  • Treatment discontinuation due to cardiac toxicity was documented for 8% of the 12-month arm and 4% of the 6-month arm.

The shorter duration was also associated with a reduction in other toxicities, including grade 3 or 4 cough, fatigue, chills, and palpitations. “They were at a low level, certainly as compared to chemotherapy, but patients tell us [these toxicities] impact their lives. More importantly, patients undergoing 6 months of treatment can return more quickly to their normal lives,” she commented.

Dr. Earl said translational research is underway to look for biomarkers of recurrence risk, which could help determine the optimal trastuzumab duration for an individual patient. ■

DISCLOSURE: Dr. Earl has consulting or advisory roles with or has received honoraria from Celgene, Pfizer, Roche, AstraZeneca, Daiichi Sankyo, and Amgen. Dr. Schilsky reported no conflicts of interest. Dr. Johnson has stock and other ownership interests with the KEW Group; has received honoraria from Merck and Chugai Pharma; has a consulting or advisory role with Novartis, AstraZeneca, KEW Group, Merck, Transgene, Clovis Oncology, Genentech, Lilly, Chugai Pharma, Boehringer Ingelheim, and Amgen; has received research funding from Novartis; has patents, royalties, and other intellectual property with royalties from Dana-Farber Cancer Institute; and has provided expert testimony for Genentech. 


1. Earl HM, Hiller L, Vallier A-L, et al: Persephone: 6 versus 12 months of adjuvant trastuzumab in patients with HER2 positive early breast cancer: Randomized phase 3 non-inferiority trial with definitive 4-year disease-free survival results. 2018 ASCO Annual Meeting. Abstract 506. To be presented June 4, 2018.  

2. Earl HM, Vallier A-L, Dunn J, et al: Trastuzumab-associated cardiac events in the Persephone trial. Br J Cancer 115:1462-1470, 2016.

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