Shorter-term Herceptin Sufficient?
No Agreement

Kristin Jenkins

June 14, 2019

Despite extensive research, the debate over the optimal duration of systemic therapy for early human epidermal growth factor receptor 2 (HER2 )-positive breast cancer shows no signs of being resolved any time soon.

Much-anticipated results from the two largest phase 3 randomized European trials to determine whether 6 months of adjuvant trastuzumab (Herceptin, Genentech/Roche) is better than the 12-month standard of care have led researchers to draw opposing conclusions.

This could be the result of using different margins to demonstrate non-inferiority, according to one of the research teams.

"The choice of the non-inferiority margin remains inherently controversial, especially in the context of oncology trials in which the primary outcome is survival," say Xavier Pivot, MD, PhD, of the Centre Paul Strauss in Strasbourg, France, and colleagues.

Pivot and colleagues analyzed findings from the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial, and concluded that the adjusted hazard ratio [HR] for disease-free survival in the 12-month group vs the 6-month group was 1.08 (P = .39).

This does not demonstrate the non-inferiority of 6 months vs 12 months of adjuvant trastuzumab, they conclude in a study published online June 6 in The Lancet. Hence, they recommend keeping the 12-month treatment standard.

Despite various subgroup analyses, the treatment effect remained the same, Pivot told Medscape Medical News. "We cannot identify a subset which benefits from a shorter duration of trastuzumab," he said.

We cannot identify a subset which benefits from a shorter duration of trastuzumab. Dr Xavier Pivot

Because there has been some evidence that a shorter trastuzumab treatment might be sufficient to prevent disease recurrence, "the failure to demonstrate the non-inferiority between 6- and 12-months duration might appear surprising," Pivot admitted.

Huge Trial Confirms Non-inferiority

Meanwhile, the multicenter PERSEPHONE trial in 4088 women has shown  that disease-free survival was comparable whether patients were treated with 6 or 12 months of adjuvant trastuzumab.

The study, led by Helena M. Earle, MBBS, PhD, professor of clinical cancer medicine at the University of Cambridge, United Kingdom, was also published online June 6 in The Lancet.

"We confirm non-inferiority of 6 months trastuzumab compared with 12 months, according to our statistical plan," Earle told Medscape Medical News.

We confirm non-inferiority of 6 months trastuzumab compared with 12 months. Dr Helena Earle

"This data can now be added to all existing data on adjuvant Herceptin to be scrutinized by the wider breast cancer community for consideration of changes to practice," she said in a statement.

The study showed that the 4-year disease-free survival was 89.4% in the 6-month treatment group and 89.8% in the group receiving 12 months of trastuzumab (hazard ratio [HR], 1.07; non-inferiority P = .011).

However, women treated with a 6-month regimen had significantly reduced treatment-related side effects. They also had less cardiotoxicity than those treated for 12 months (3% vs 8%, respectively), and the cost of treatment was substantially reduced.

The absolute difference in 4-year disease-free survival was only 0.4% whether trastuzumab was given for 6 or 12 months, the authors point out.

"This result signals the potential of reducing treatment duration to 6 months and, thereby, [reducing] toxicity and cost, while obtaining similar efficacy for at least some women with HER2-positive breast cancer," they write.

However, the PERSEPHONE trial also produced evidence to suggest that in some women, longer treatment may be needed. "Women taking the medication should not change their treatment without seeking advice from their doctor," Earle advised.

Currently, the UK researchers are analyzing blood and tissue samples from trial participants to identify biomarkers that can be used to determine which women might benefit from shorter or longer adjuvant treatment, Earle said.

"[D]espite years of research, we haven't been able to establish the optimal duration of Herceptin treatment, either to delay cancer coming back or to cure patients with early HER2-positive breast cancer following surgery," said Charles Swanton, MD, PhD, of Cancer Research UK, in a press statement.

"The important next steps are to work out which patients can stop Herceptin at 6 months and which need extended therapy," he said.

Conclusions are "Entirely Discordant"

In an accompanying editorial, Sara Hurwitz, MD, of the David Geffen School of Medicine at the University of California, Los Angeles notes that the conclusions reached by the PERSEPHONE and PHARE research teams are "entirely discordant."

In spite of the near equivalence of the HRs in both studies (1.08 in PERSEPHONE and 1.07 in PHARE), she suggests that "[u]nderstanding these seemingly contradictory interpretations requires a closer look at the endpoints chosen."

The PERSEPHONE trial had a prespecified non-inferiority margin of less than 3% (HR, 1.32) and the PHARE trial had a non-inferiority margin of 1.15, Hurwitz noted. In an oncology setting, "the margin for equivalence is quite subjective," she said.

Unlike PERSEPHONE, the PHARE trial found no change in cardiac safety between the 6- and 12-month treatment groups.

The incidence of cardiac events was limited and the vast majority were reversible, said Pivot. Although most occurred during treatment with trastuzumab and rarely after completion of therapy, an early treatment interruption as a result of cardiac events had limited impact on the outcome, he added.

Pivot recommended stopping trastuzumab should cardiac function dramatically decrease after 6 months of treatment.

In their report, the PHARE researchers suggest that shorter treatment may be more about reducing costs than reducing adverse events associated with the duration of adjuvant trastuzumab.

"Without any safety concerns related to adjuvant trastuzumab, a pharmacoeconomic model of the cost savings with a shorter treatment duration seems to be the criterion supporting the decrease in duration," they write.

In fact, the UK researchers estimate that the cost savings for patients taking adjuvant trastuzumab for 6 months instead of 12 months would be about £9,699 ($12,244) per patient. A more detailed cost effectiveness analysis is underway, said Earle.

"Given that HER2-positive breast cancer represents a significant global burden of the disease, 6 months adjuvant treatment would translate into potential global savings of hundreds of millions of dollars annually," she pointed out.

"Worldwide, this will have a huge impact in middle and low income countries," Earle continued, "since it will facilitate Herceptin treatment (a World Health Organization designated essential medicine) for many more women with HER2-positive early breast cancer."

Many other de-escalation studies have been unable to demonstrate the non-inferiority of shorter duration trastuzumab. These include the HORG study, the Short-HER trial , the SOLD trial, and the E2198 trial.

The PERSEPHONE trial "is the only reduced-duration study to show non-inferiority for shorter adjuvant trastuzumab treatment," Earle and colleagues say, predicting that it "will stimulate substantial debate."

Nevertheless, as early as 2006, results from the FinHer trial sparked interest in shortening the duration of adjuvant trastuzumab treatment, they point out.

As previously reported by Medscape Medical News, the trial showed that 9 weeks of treatment with trastuzumab fell a small margin short of being non-inferior to 1 year of treatment. However, there was a statistically significant improvement in disease-free survival in patients randomly assigned to adjuvant chemotherapy with 9 weeks of concurrent trastuzumab (HR, 0.29; P = .002).

Until more is known, Hurwitz suggests that the use of an anthracycline-free treatment regimen might improve the therapeutic index for adjuvant trastuzumab. The risk of symptomatic cardiomyopathy would be about 0.5%, she points out.

About 90% of patients in both the PHARE and PERSEPHONE trials received anthracycline-based treatment, putting them at increased risk of cardiac toxicity, Hurwitz notes.

"In an era in which non–anthracycline-based regimens are increasingly being used, and our ability to risk-stratify patients for the selection of additional therapies has improved, the benefit, if any, of reducing the duration of trastuzumab is not clear," she writes.

Like many other experts, Hurwitz believes that long-term follow-up likely holds the key.

"In future years, it will indeed be important to follow the data of PERSEPHONE as they mature," she writes.

The PERSEPHONE trial was funded by the National Institute of Health Research. Earle reported relationships with Roche, sanofi-aventis, Daiichi Sankyo, AstraZeneca, Pfizer, Amgen, and Prime Oncology. A number of coauthors also disclosed relationships with industry.

The PHARE trial was funded by the The French National Cancer Institute. Pivot reported relationships with Amgen, Samsung Bioepis, and Roche. A number of coauthors also disclosed relationships with industry.

Hurvitz reported relationships with Ambrx, Amgen, Bayer, BI Pharma, Biomarin, Cascadian, Daiichi Sankyo, Dignitana, Genentech, GlaxoSmithKline, Immunomedics, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Pieris, PUMA, Roche, and Seattle Genetics.

The Lancet. Published online June 6, 2019. PERSEPHONE study, PHARE study, Editorial

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