The addition of pertuzumab (Perteza, Genentech) to standard trastuzumab (Herceptin, Genentech) therapy in patients with early HER2-positive breast cancer led to modest improvements and increased side effects according to results of the Adjuvant Pertuzumab and Herceptin in Initial Therapy (APHINITY) trial.
The study, presented here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting and published in the New England Journal of Medicine, raises questions about the future of trials that build on trastuzumab's success.
"APHINITY should be the last trial of its generation," writes Kathy Miller, MD, from Indiana University Melvin and the Bren Simon Cancer Center, Indianapolis, in an accompanying editorial in the NEJM. "It simply is not feasible to add more and more therapy for patients with HER2-positive disease who are selected only on the basis of anatomy. The toxic effects (and cost) are too great for too many to benefit too few."
Indeed, the cost implications of adding pertuzumab to the mix are "quite substantial," noted Carey Anders, MD, ASCO's discussant of the study, from the University of North Carolina at Chapel Hill.
In her discussion of the article, Dr Anders described how, on the basis of Medicare estimates, 1 year of pertuzumab therapy would increase the cost of standard trastuzumab plus chemotherapy from approximately $56,000 to $150,500.
Details of Results
The APHINITY trial was conducted in 4805 patients after undergoing surgery for HER2-positive cancer. The patients received 1 year of chemotherapy and trastuzumab, plus either pertuzumab or placebo.
Chemotherapy consisted of a number of standard anthracycline-taxane sequences or a nonanthracycline (TCH) regimen.
For the primary endpoint of invasive disease-free survival (IDFS), after a median follow-up of 45.4 months, the intent-to-treat analysis showed a 19% relative risk reduction in the pertuzumab arm at 3 years (94.1% vs 93.2%; stratified hazard ratio [HR], 0.81; P = .045), reported study investigator Gunter von Minckwitz, MD, PhD, president of the German Breast Group in Neu-Isenburg, Germany.
These data indicate that 112 patients would need to be treated with pertuzumab to avoid one invasive disease relapse, he said.
About two thirds of study patients were node positive. A predefined subgroup analysis of patients by nodal status showed a 23% reduction in relative risk among the patients treated with pertuzumab vs placebo (92% vs 90.2%; unstratified HR, 0.77; P = .019), with a number needed to treat of 56, he said.
Similarly, among roughly one third of patients who were hormone-receptor-negative, treatment with pertuzumab was associated with a relative risk reduction of 24% compared to placebo (3-year IDFS rates of 92.8% vs 91.2%; unstratified HR, 0.76; P = .085), with a number needed to treat of 63.
In hormone-receptor-positive patients, there was no difference between treatment arms.
Cardiac safety was a primary safety endpoint. Cardiac events occurred at double the rate in patients who were treated with pertuzumab (n = 17) compared to patients who received placebo (n = 8). However, the absolute difference between the groups was not statistically significant, and many of the events were temporary drops in left ventricular ejection fraction, he reported.
The biggest safety difference between the groups was in diarrhea, with 9.8% of the pertuzumab group experiencing grade 3 diarrhea or higher vs 3.7% of the placebo group. This was largely confined to the chemotherapy period of treatment, between weeks 18 and 24, he said.
Asked to comment on the findings, George Sledge, MD, from Stanford University Medical Center, in California, told Medscape Medical News that the trial demonstrates how hard it has become to study breast cancer in the adjuvant setting. "Thousands were randomized to demonstrate a truly modest difference in outcomes," he said, adding, "If the new therapy becomes a standard-of-care approach, then we will clearly be overtreating the vast majority of patients."