The awaited long-term results came with the publication of APHINITY.8 The trial randomly assigned patients to pertuzumab (2400 patients) or placebo (2405 patients) added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. Disease recurrence was noted in 7.1% of patients assigned to pertuzumab and 8.7% of patients assigned to placebo (HR, 0.81; 95% CI, 0.66-1.00; P = .045). Among the 63% of patients with node-positive disease, the 3-year rate of invasive disease-free survival was 92.0% with pertuzumab compared with 90.2% with placebo (HR, 0.77; 95% CI, 0.62-0.96; P = .02).
Based on these results, the FDA granted pertuzumab in combination with trastuzumab and chemotherapy full regular approval for the adjuvant treatment of HER2-positive breast cancer. The results are, however, somewhat controversial: in an editorial accompanying the results of APHINITY, Kathy D. Miller, MD, of the Indiana University Melvin Bren Simon Cancer Center in Indianapolis, wrote that the results were a “disappointment.9
“The addition of pertuzumab resulted in an absolute 0.9-percentage-point lower rate of recurrence or death at 3 years. Although the absolute benefit was larger in patients with lymph-node involvement, even in these patients the rate of invasive-disease–free survival was a mere 1.8 percentage points lower in the pertuzumab group than in the placebo group,” Dr Miller wrote, adding that the “totality of evidence” from the trial did not yet support the use of pathological complete response as a surrogate endpoint for disease-free survival.
According to Dr DeMichele, it is the small effect size that makes the results controversial.
“The trial fell just short of what it was powered to show, which was a small improvement with the addition of pertuzumab,” Dr DeMichele said. “The question is whether the additional cost, time, and toxicity — even though it is not very toxic — is really worth the increase that you get.”
The small effect size has more to do with trial design than the drug itself, Dr DeMichele said. Specifically, the trial was conducted in a group of patients that generally do very well and are already receiving a good treatment with trastuzumab and chemotherapy.
“There was not a lot of room to improve things,” she said. “Less than 10% of patients relapsed regardless of what you gave them.”
Another criticism is the follow-up period of the trial. The median follow-up was about 45 months, or almost 4 years.
“This was reasonable because the time horizon for HER2-positive disease relapse is 5 years or 60 months,” Dr DeMichele said. “It would be nice to have gotten 60 months, but 45.4 months is going to capture the majority of relapses that would have happened.”
Pertuzumab is approved with a boxed warning for cardiomyopathy and embryo-fetal toxicity. In neoadjuvant trials of pertuzumab, an increased rate of left ventricular ejection fraction decline was observed. There were also observations of oligohydramnios, delayed renal development, and embryo-fetal death in animal studies of the drug.
“Physicians will have to consider when to use this drug so that it adds benefit over and above trastuzumab and standard chemotherapy, and whether that benefit is enough to offset the additional cost and toxicity,” Dr DeMichele said. “Only the highest-risk patients are likely to get some net benefit when taking that into account, such as those who are hormone receptor–negative and/or node-positive.”
- FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer [news release]. Silver Spring, MD: US Food and Drug Administration; December 20, 2017. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm. Accessed January 3, 2018.
- Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med.2001;344:783-92.
- FDA approval for pertuzumab. National Cancer Institute website. https://www.cancer.gov/about-cancer/treatment/drugs/fda-pertuzumab#Anchor-MetastatiHER2. Updated October 1, 2013. Accessed January 3, 2018.
- Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-19.
- Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372:724-34.
- Gradishar WJ. HER2 therapy — an abundance of riches. N Engl J Med.2012;366:176-8.
- Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomized multicenter, open-label, phase 2 trial. Lancet Oncol. 2012;13:25-32.
- von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med.2017;377:122-31.
- Miller KD. Questioning our APHINITY for more. N Engl J Med. 2012;377:186-7.