Martine J. Piccart, MD, PhD, FASCO, reported that at 6-year follow-up of the APHINITY trial there was a modest, but not statistically significant, overall survival benefit for the addition of pertuzumab to chemotherapy plus trastuzumab vs chemotherapy/trastuzumab as adjuvant therapy in patients with early HER2-positive breast cancer. Dr. Piccart, of the Institut Jules Bordet, Brussels, and lead author of the study, presented the updated analysis at the 2019 San Antonio Breast Cancer Symposium.¹  She noted that the benefit was seen mainly in patients with node-positive disease and was observed regardless of hormone receptor status.

Martine J. Piccart, MD, PhD, FASCO

“At this second analysis of overall survival in the APHINITY trial, we found fewer deaths in the pertuzumab-containing arm, with a 0.9% difference that was not statistically significant. We plan another analysis in 2.5 years. The clinical benefit of pertuzumab was mainly seen in node-positive patients. No benefit can be claimed in node-negative patients [with HER2-positive early breast cancer],” Dr. Piccart said.

“No new cardiac safety events were noted, and the incidence of primary cardiac events was low, < 1% in both arms,” she told the audience.

APHINITY Trial

The multicenter, double-blind, placebo-controlled APHINITY trial enrolled 4,805 women with early HER2-positive breast cancer and randomly assigned them 1:1 to receive chemotherapy, trastuzumab, and pertuzumab vs chemotherapy, trastuzumab, and placebo. Only patients with primary breast cancer were included. Patients were stratified according to nodal status, hormone receptor status, chemotherapy regimen, and geographic region. Primary results were published in The New England Journal of Medicine in 2017.²

Standard anthracycline and nonanthracycline regimens were allowed. Pertuzumab and trastuzumab were given for 1 year concurrent with the start of chemotherapy.

In the first interim analysis, with a median follow-up of 45.4 months, no overall survival benefit was significantly associated with the addition of pertuzumab to chemotherapy plus trastuzumab.

At that time, pertuzumab added to standard chemotherapy plus 1 year of trastuzumab as adjuvant therapy was associated with a modest but statistically significant 19% relative reduction in the risk of an invasive disease–free survival event compared with  chemotherapy plus trastuzumab, and placebo (P = .04). Also at that time, the effect was more robust in node-positive patients, with a 23% relative improvement in invasive disease–free survival and a 24% relative improvement in hormone receptor–negative patients.

Second Interim Overall Survival Analysis

Both arms of the study were well balanced. Two-thirds of participants were node-positive, close to 80% received anthracycline-based chemotherapy, and 64% had hormone receptor–positive disease.

At a median follow-up of 74 months, invasive disease–free survival was significantly improved with pertuzumab, and node-positive patients continued to derive the greatest benefit with the addition of pertuzumab. At the time of the 2019 San Antonio meeting, 272 deaths had occurred, which comprised 42.5% of deaths required for a definitive overall survival analysis.

“Overall survival was excellent in both arms,” Dr. Piccart said. A total of 94.8% of patients were alive in the pertuzumab arm compared with 93.9% in the placebo arm, a difference that was not statistically significant. Dr. Piccart emphasized that “a very stringent P value of .0012” was required for statistical significance in this second interim overall survival analysis.

A total of 508 patients had an invasive disease–free survival event. In a descriptive analysis, invasive disease–free survival rates were 90.6% for pertuzumab vs 87.8% for placebo in the intent-to-treat population. Dr. Piccart noted that this absolute difference of about 2.8% was driven by a reduction in distant and locoregional recurrence. There was no difference between the two study arms in the rate of central nervous system metastases, contralateral invasive breast cancers, and death.

“Node-positive patients continued to derive clear benefit from the addition of pertuzumab, with an absolute 4.5% improvement in 6-year invasive disease–free survival: 87.9% with pertuzumab vs 83.4% with placebo, representing a 28% relative reduction.” No treatment effect was observed in the node-negative population in the two arms: 95% and 94.9%, respectively.

“The 6-year invasive disease–free survival rate in the node-positive group is outstanding,” Dr. Piccart noted.

The first interim analysis showed an enhanced benefit of pertuzumab in the hormone receptor–negative group. In the latest analysis, after 74.1 months of follow-up, the benefit of pertuzumab for invasive disease–free survival was seen regardless of hormone receptor status.

“The clinical benefit of adjuvant anti-HER2 therapy plus chemotherapy must be balanced against potential harm. The good news is there are no new cardiac safety concerns with an additional 2.5 years of follow-up,” Dr. Piccart stated.

“With additional follow-up, the results are stronger now in favor of adding pertuzumab. Probably, we did our first analysis too early,” she added.

De-escalation of Treatment?

“With such excellent outcomes in node-negative patients with early HER2-positive breast cancer, it will be difficult to show an improvement with any new therapy. This trial may signal the end of escalation of treatment and instead signal the time to look at de-escalation of treatment,” Dr. Piccart told listeners.

Dr. Piccart explained that it is not clear that all patients need 1 year of treatment with two anti-HER2 antibodies. She said there were problems with the studies that have tried to explore shorter courses of trastuzumab. She and her colleagues are planning trials to evaluate less intensive chemotherapy for HER2-positive early breast cancer in the neoadjuvant setting.

In the United States, the COMPASS trial will enroll patients who have been given a taxane with no anthracycline plus the two anti-HER2 antibodies prior to surgery (ie, neoadjuvant therapy). If patients achieve a pathologic complete response, they will have no further chemotherapy. The BIG trialists in Europe will also study a similar approach in the ­DECRESCENDO trial.

“There is no reason to give this intense therapy to node-negative patients, based on these results. But only one biomarker [ie, nodal status] is not sufficient for decision-making. We are developing a composite risk score that takes into account nodal status, tumor size, grade, tumor-infiltrating lymphocytes, and number of HER2 gene copies. With this score, we plan to divide HER2-positive patients into risk groups, which will be a better way to decide who will benefit from dual HER2 blockade. We may find [with this score] that some node-positive patients don’t need this therapy and some node-negative patients do,” Dr. Piccart said. 

DISCLOSURE: Dr. Piccart has served as a consultant/received honoraria from AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Genentech, Huya, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Periphagen, Pfizer, Roche, and Seattle Genetics; has received institutional research funding from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, and Synthon; and has served as a scientific board member for Oncolytics.

REFERENCES

1. Piccart M, Procter M, Fumagalli D, et al: Interim overall survival analysis of APHINITY (BIG 4-11): A randomized, multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab vs chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-04. Presented December 11, 2019.

2. von Minckwitz G, Procter M, de Azambuja E, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med 377:122-131, 2017.