Updated APHINITY Supports Benefit of Dual HER2 Blockade

Pam Harrison

December 11, 2019

SAN ANTONIO, Texas — An updated analysis of the APHINITY trial strengthens earlier findings showing the addition of pertuzumab (Perjeta, Roche) to trastuzumab (Herceptin, Genentech) plus chemotherapy provides meaningful clinical benefit over trastuzumab plus chemotherapy alone in women with operable HER2-positive early breast cancer.

Median study follow-up is now approximately 6 years.

"As far as the updated descriptive analysis is concerned, I think we can say that the clinical benefit of pertuzumab in HER2-positive, early breast cancer is strengthened in node-positive patients and very importantly, after a median follow-up of 74.1 months, the benefit of pertuzumab was seen regardless of hormone receptor status," said Martine Piccart, MD, PhD, scientific director, Institut Jules Bordet, Brussels, Belgium.

She spoke at a press briefing here at the San Antonio Breast Cancer Symposium 2019.

"These results demonstrate the importance of longer follow-up of APHINITY and further confirm the pertuzumab-based regimen as the standard-of-care for people with HER2-positive early breast cancer at high risk of recurrence, such as those with lymph node-positive disease," she added in a statement.

Between November 2011 and August 2013, 2400 women were randomly assigned to chemotherapy and the two monoclonal antibodies while another 2405 patients were randomized to chemotherapy plus trastuzumab alone.

Patients may have been treated upfront with an anthracycline, as Piccart noted, but regardless of what the initial chemotherapy regimen was, they all received a taxane plus one or both monoclonal antibodies concurrently. Both trastuzumab and pertuzumab were given for a total of 52 weeks.

The primary analysis of APHINITY showed that at a median follow-up of 45.4 months (3 years, 9 months), the addition of pertuzumab to the chemotherapy plus trastuzumab backbone reduced the relative risk of recurrence by 19%, at a hazard ratio (HR) of 0.81 compared with chemotherapy plus trastuzumab alone.

At the same time point, estimated 3-year invasive disease-free survival (IDFS) rates were 94.1% vs 93.2% respectively (P = .04), Piccart noted.

"The magnitude of treatment effect was modest," Piccart acknowledged.

"However, it was more pronounced at that time in patients at high-risk of relapse," she added.

At the same median follow-up of 45.4 months, the treatment effect was also similar in node-positive patients as well as hormone-receptor negative disease, where the absolute benefit from additional pertuzumab was 1.8% and 1.6%, respectively.

Node-Negative News

At a median follow-up of 74.1 months, the node-positive cohort continued to derive clear benefit from the addition of pertuzumab. That is, in this cohort of patients, there was an absolute difference in the event-free survival rate between the two treatment groups of 4.5%, at an HR of 0.72 in favor of additional pertuzumab.

Specifically, at approximately 6 years of follow-up, IDFS rates were 87.9% in pertuzumab-treated patients vs 83.4% of those in the standard-of-care group.

In contrast, no treatment effect from additional pertuzumab was observed in the node-negative cohort, suggesting that "there is absolutely no reason to give additional pertuzumab to node-negative patients," Piccart told Medscape Medical News. 

There is absolutely no reason to give additional pertuzumab to node-negative patients. Dr Martine Piccart

HR Status News

With longer follow-up, the benefit of additional pertuzumab also no longer appeared to depend on the patient's hormone receptor status, investigators observed.

The relative risk of being free of invasive disease was 27% higher in hormone-receptor positive patients treated with pertuzumab compared with the standard-of-care group (91% vs 88.7%; HR, 0.73)

Among hormone-receptor negative patients, the risk of being free of invasive disease was 17% greater for pertuzumab-treated patients compared with those in the standard-of-care group (88.9% vs 86.7%; HR, 0.83)

"Pertuzumab reduced the risk of distant recurrence as well as locoregional recurrence and contralateral invasive breast cancer recurrence," Piccart observed.

Table. Site of first occurrence of an IDFS event at a median
follow-up of 74.1 months



No Pertuzumab

Distant recurrence






Contralateral invasive




Indeed, the benefit of additional pertuzumab was seen across all subgroups with the exception of patients with node-negative disease.

There was also a 2.8% absolute improvement in OS with pertuzumab at the end of the same extended analysis, Piccart noted.

Great Cardiac News

The "great news" to emerge from the longer-term analysis of APHINITY was that no new cardiac safety issues were seen over the additional 2.5 years of follow-up, Piccart emphasized.

One additional cardiac event was reported in the pertuzumab group, but the rate of severe cardiac events was under 1% in both groups (0.8% for pertuzumab, 0.3% for no pertuzumab).

Other side effects included grade 3 diarrhea, which occurred in 10% of patients, Piccart noted.

However, as she pointed out, if diarrhea occurs, it occurs mainly during the administration of chemotherapy and resolves very rapidly after treatment is completed.

Piccart also noted that APHINITY investigators are currently developing a composite risk score that takes into account not only a patient's nodal status but tumor size, patient age, hormone receptor status and tumor-infiltrating lymphocytes, as well as the degree of HER2 amplification.

"We hope with this composite risk score that we can better define individual patient risk and then see if the treatment protocol works in the patient's favor," Piccart said.

A third interim analysis of APHINITY is scheduled to take place in another 2.5 years.

Further Improvement

Asked by Medscape Medical News to comment on the findings, Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center in Boston, noted that patients such as the ones in APHINITY can absolutely be treated with intent to cure.

"This what we saw initially with adjuvant trastuzumab. We saw that there was an increase in the cure rate for early breast cancer and the number of patients who had disease recurrence decreased dramatically with the addition of adjuvant trastuzumab — and now we are seeing a further improvement in disease-free survival (DFS) with the addition of pertuzumab as well," said Bardia, who is not involved with APHINITY.

On the other hand, the relative risk of recurrence or death was 50% lower among patients with residual disease following neoadjuvant chemotherapy following treatment with trastuzumab emtansine (TDM-1) compared with trastuzumab alone in the KATHERINE trial.

This has essentially transformed treatment of early HER2-positive breast cancer to one favoring neoadjuvant therapy first, Bardia pointed out. 

"Thus, the applicability of APHINITY in an era when we are using neoadjuvant therapy does come into question," he cautioned.

However, Bardia did note that if a patient has a very small HER2-positive, lymph node-negative tumor and undergoes surgery first, oncologists might consider giving trastuzumab along with paclitaxel if the patient is left with small amounts of residual disease.

The study was funded by Roche/Genentech. Piccart has served as a consultant on the scientific advisory board at Roche, for which she has received honoraria. Additionally, Piccart is a consultant for the advisory boards of AstraZeneca, Camel-IDS, Crescendo Biologics, Debiopharm, G1 Therapeutics, Huya Bioscience International, Immunomedics, Eli Lilly, The Menarini Group, Merck, Novartis, Odonate Therapeutics, PeriphaGen, Pfizer, and Seattle Genetics. She is also a scientific board member for Oncolytics and Radius. Piccart's institution receives funding from Eli Lilly, Merck, Pfizer, Radius Health, Roche/Genentech, AstraZeneca, Novartis, Servier Pharmaceuticals, and Synthon Pharmaceuticals.

Bardia reports that he has served as a consultant or served on the advisory board for Genentech, Roche, Pfizer, Novartis, Merck, Daiichi, Immunomedics, and Sanofi.

San Antonio Breast Cancer Symposium (SABCS) 2019: Abstract GS1-04. Presented December 11, 2019.

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