Adjuvant trastuzumab (Herceptin, Roche) can be safely given to HER2+ early breast cancer patients for 6 rather than 12 months, with no impact on treatment efficacy, according to a UK individual patient data analysis of five major trials.
Professor Helena Earl, department of oncology, Addenbrooke's Hospital, Cambridge, and colleagues, combined data on more than 11,000 patients who were treated with trastuzumab for 9 weeks or 6 months versus the current standard of 12 months.
They found that treating HER2+ early breast cancer patients for 6 months was non-inferior to continuing treatment for 12 months, with no significant difference in 5-year invasive disease-free survival (IDFS) rates.
However, when 9 weeks of trastuzumab was compared with 12 months, the IDFS rates were lower with the shorter duration of treatment, and over the pre-specified non-inferiority limit, indicating that it did not perform as well.
The research was presented at the European Society for Medical Oncology (ESMO) Annual Meeting 2021 on September 17.
What Happens Next?
"There is non-inferiority of 6 months of trastuzumab compared with 12 months, and this has been confirmed," Prof Earl said, but the non-inferiority of 9 weeks versus 12 months has "not been confirmed".
The key question, however, is: "What is going to happen now?"
She explained that there is a "prior outcome preference, which is quite strong, that 12 months should remain the standard treatment, so there will be significant statistical criticism of our analysis".
Prof Earl said that there are other factors that could weigh against clinicians changing their practice in response to their findings, including "loss aversion" and "entrenched behaviour".
"So the implications for practice in countries providing 12 months of trastuzumab" is that "we should be considering guideline changes to empower personalised patient choice".
She suggested that patients on single agent trastuzumab after 6 months of treatment be "shown the evidence that to continue to 12 months provides only marginal additional benefit".
Then "patients, with their oncology [physicians], can choose whether to continue to 12 months", Prof Earl said.
Great Value
Dr Antonio Llombart-Cussac, Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain, who was not involved in the study, welcomed the analysis.
He commented however that, for a clinical decision to be taken on the duration of trastuzumab, a meta-analysis taking into account classical prognostic factors "would be of great value".
He also noted that there is evidence to show that chemotherapy may be de-escalated in low-risk HER2+ early breast cancer against a backdrop of 12-month trastuzumab, but no trial is currently exploring "concomitant chemotherapy and trastuzumab de-escalation".
Dr Llombart-Cussac wondered: "Is the combination of weekly paclitaxel and trastuzumab [for] 6 months a reasonable option, despite not being tested in a clinical trial?"
He also pointed out that numerous studies have looked at combination approaches, including the antibody-drug conjugate trastuzumab emtansine (Kadcyla, Roche), where the benefits are "by far higher than the absolute differences observed between the 6 and 12 months of trastuzumab".
Overall, Dr Llombart-Cussac believes that treatment intensity and duration "must be modulated" by risk criteria, with lower intensity therapy considered "standard" in low-risk disease, while drug sensitivity/resistance must be taken into account in high-risk patients.
He added that if clinicians want to "push" the 6-month strategy for trastuzumab, they need to convince the regulators, because if the US Food and Drug Administration or European Medicines Agency "do not accept that that could be a reasonable control arm…it will be difficult to continue to build a strategy in the future".
On Twitter, Nagi S. El-Saghir, professor of medicine at the Naef K. Basile Cancer Institute, American University of Beirut Medical Center, Beirut, Lebanon, described the meta-analysis as "very important".
He agreed that with Prof Earl that 6-month duration of trastuzumab should be discussed with individual patients and "deserves to be in the guidelines for lower risk patients".
However, he warned that "de-implementing" a treatment "is harder than implementing" it.
Study Details
Prof Earl explained that, for their analysis, the team examined data from five non-inferiority randomised controlled trials of trastuzumab duration in HER2+ early breast cancer.
Three of them compared 12 months and 6 months of treatment: PERSEPHONE, with 4088 patients; PHARE, with 3380 patients; and HORG, which included 493 patients. The two remaining studies looked at 12 months versus 9 weeks of trastuzumab: SOLD, with 2174 patients; and SHORT-HER, with 1254 patients.
Overall, 11,389 patients were included in the analysis, and the team conducted an individual patient data intention to treat analysis, timed from the start of protocol treatment.
A random effects model showed that, for all five trials combined, the 5-year IDFS rate was 88.46% for a treatment duration of 12 months versus 86.87% for shorter treatment periods.
The adjusted hazard ratio for 12 months versus shorter duration of trastuzumab was a non-significant 1.14 (95% credibility interval [CrI] 0.88–1.47), where the non-inferiority limit was 1.19 (p=0.37).
Looking next at the 12 months versus 6 month trials, the team found that for the combined results of the three trials, 5-year IDFS rates were 89.26% and 88.56%, respectively, at a non-significant adjusted hazard ratio of 1.07 (95% CrI 0.98–1.17).
Prof Earl pointed out that this "is significantly less than the non-inferiority limit" of 1.20 (p=0.02).
On the other hand, the two trials of 12 months versus 9 weeks combined indicated that the 5-year IDFS rates were 91.40% and 89.22%, respectively, at a significant adjusted hazard ratio of 1.27 (95% CrI 1.07–1.49).
This, Professor Earl said, is "well over" the non-inferiority limit of 1.25 (p=0.56).
The study was funded largely by the UK government.
Prof Earl declares relationships with the Asian Society for Continuing Medical Education, Intas Pharmaceuticals.
Dr Llombart-Cussac declares relationships with MedSIR, Initia Research, Eisai, Celgene-BMS, Lilly, Pfizer, Roche, Novartis, MSD, Tesaro-GSK, Pierre-Fabre, Genomic Health.
ESMO Congress 2021: Abstract LBA11. Presented September 17.
