APHINITY Trial in Patients With HER2-Positive Early Breast Cancer: Update at 8 Years

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Updated results from the adjuvant APHINITY trial in HER2-positive early breast cancer, now with a median follow-up of 8.4 years, confirmed the benefit of adding pertuzumab to trastuzumab plus chemotherapy in preventing invasive disease recurrences, but as yet no statistically significant overall survival benefit has emerged, according to Sibylle Loibl, MD, PhD, Chair of the German Breast Group, who presented the findings at a Virtual Plenary session of the European Society for Medical Oncology (ESMO).1

Sibylle Loibl, MD, PhD

Sibylle Loibl, MD, PhD

The long-term outcomes of both arms remain very good, with more than 92% of patients alive at 8 years. The overall survival analysis remains immature, but the difference of 0.7% numerically favors the pertuzumab arm, Dr. Loibl noted.

Investigators have previously reported the results of two prior analyses of APHINITY. At the ESMO session, Dr. Loibl presented the third prespecified analysis of overall survival and updated descriptive analyses of invasive disease–free survival.

Key Findings

“In the third interim analysis, fewer deaths were seen in the pertuzumab arm compared with the placebo arm,” Dr. Loibl said. By January 10, 2022, deaths totaled 168 in the pertuzumab arm (7.0%) and 202 in the placebo arm (8.4%). The 8-year overall survival percentages were 92.7% vs 92.0%, respectively—a 0.7% difference (hazard ratio [HR] = 0.83; P = .078; 95% confidence interval [CI] = 0.68–1.02).

For invasive disease–free survival, the primary endpoint, the updated descriptive analysis revealed a 2.6% absolute benefit for pertuzumab (HR = 0.77; 95% CI = 0.66–0.91), consistent with the 2.8% increase from the 6-year analysis,2 she further reported.

Of note, the sustained benefit with pertuzumab was driven by its impact on the node-positive cohort. The absolute benefit of dual HER2 blockade in this cohort was 1.9% for overall survival and 4.9% for invasive disease–free survival. In contrast, patients with node-negative disease derived no additional benefit from the second anti-HER2 agent. Interestingly, although not shown in previous analyses, the addition of pertuzumab conferred an advantage in both hormone receptor–negative and –positive patients.

Dr. Loibl emphasized two key takeaways from the latest findings: “The node-positive cohort derives benefit from adding pertuzumab. And with longer follow-up beyond the first 3 years, the data clearly show that hormone receptor status should not guide pertuzumab treatment decisions.”


Between 2011 and 2013, the global randomized, phase III APHINITY trial enrolled 4,805 patients with HER2-positive operable breast cancer. Patients were assigned to receive adjuvant treatment with dual or single HER2 blockade plus chemotherapy. Treatment consisted of pertuzumab at 840 mg followed by 420 mg, or placebo, plus 8 mg/kg of trastuzumab followed by 6 mg/kg every 3 weeks for 1 year in combination with chemotherapy.

The groups were well balanced in terms of nodal status (34% node-negative), hormone receptor status (64% hormone receptor–positive), and adjuvant chemotherapy regimen (78% received anthracyclines). The primary endpoint was invasive disease–free survival (which did not include second non–breast cancer primary tumors).


  • The third interim analysis of the APHINITY trial was performed after 8.4 years’ median follow-up.
  • The benefit of pertuzumab added to trastuzumab/chemotherapy as adjuvant treatment of early HER2-positive breast cancer was confirmed; the risk for an invasive disease event was reduced overall by 23%.
  • Benefit was restricted to the node-positive cohort.
  • Both hormone receptor–negative and hormone receptor–positive patients benefited from the second anti-HER2 agent.
  • Long-term survival was excellent overall, with more than 92% of all patients still alive.

In the primary analysis of APHINITY, reported several years ago, the addition of pertuzumab to trastuzumab plus chemotherapy significantly improved invasive disease–free survival (HR = 0.81; P = .045), leading to a new standard of care for high-risk patients.2 The first interim overall survival analysis and a second prespecified one, however, did not reach statistical significance.3

In the current third interim analysis, median follow-up was 8.4 years, which is 27 months longer than for the second interim analysis. There are now 370 deaths, which is 98 more than for the second one, constituting 57.8% of the 640 deaths needed for the event-driven definitive overall survival analysis. For the current interim analysis, a P value of .0060 was required for statistical significance.

Overall Survival

Key findings for 8-year overall survival from the third interim analysis of APHINITY included the following:

  • Fewer deaths in the pertuzumab arm vs placebo arm: 8-year overall survival was 92.7% vs 92.0% (HR = 0.83; P = 0.78)
  • Trend toward survival benefit was influenced by the node-positive cohort: 91.1% vs 89.2% (HR = 0.80)
  • Node-negative cohort had excellent survival without the addition of pertuzumab: 96.4% vs 95.5% (HR = 0.99).

Invasive Disease–Free Survival

The key findings from the descriptive 8-year invasive disease–free survival analysis in the intent-to-treat population, for the pertuzumab vs placebo arms, included:

  • Sustained benefit with the addition of pertuzumab: 88.4% vs 85.8% (HR = 0.77; 95% CI = 0.66–0.91)
  • Benefit in node-positive cohort: 86.1% vs 81.2% (HR = 0.72; 95% CI = 0.60–0.87)
  • Site of first occurrence in overall population: distant, 6.2% vs 8.5%, and locoregional, 1.3% vs 2.4%
  • Site of first occurrence in node-positive cohort: distant, 8.7% vs 12.3%, and locoregional, 1.5% vs 2.6%
  • Absolute difference favoring pertuzumab was similar for the hormone receptor–negative cohort (2.3%) and the hormone receptor–positive cohort (2.8%).

Elaborating on the sites of first recurrence, Dr. Loibl noted that for both arms, most events were distant metastases, but they were much fewer in the pertuzumab group, both overall and in the node-positive population. Central nervous system metastases were similar between the arms—and rare (approximately 3% node-positive, ≤ 1.0% node-negative). Approximately 2.5% of patients died without a prior event, and this outcome was also similar between the arms.

Nodal and Hormone Receptor Status

Dr. Loibl emphasized the differential impact of pertuzumab based on nodal status (Table 1). Patients with node-positive disease continue to experience a clear reduction in invasive disease–free survival events with the addition of the second anti-HER2 agent. In contrast, in the node-negative cohort, more than 92% of patients were event-free in 8 years; therefore, pertuzumab offered no additional advantage over trastuzumab alone (HR = 1.01).

In the node-positive group, the benefit of -pertuzumab was continuous, even increasing over time, as reflected by an increase over trastuzumab in absolute benefit: from 1.8% at 3 years, to 4.4% at 6 years, to 4.9% at 8 years, now resulting in a 28% reduction in risk (HR = 0.72; 95% CI = 0.60–0.87), Dr. Loibl noted.

Additionally, she said, pertuzumab offered benefit across hormone receptor status (Table 1), which only became apparent after longer follow-up. “The hormone receptor–negative cohort, which was initially the cohort deriving the sole benefit from pertuzumab, continued to derive benefit, with an absolute difference of 2.3%. But the hormone receptor–positive cohort, which initially did not seem to benefit at 3 years, with longer follow-up also derived a large benefit, with an absolute benefit of 2.8% at 8 years. That’s why it’s important to have longer follow-up in our breast cancer trials, especially to see whether there is benefit in hormone receptor–positive patients.”

No Safety Concerns

The safety profile of pertuzumab plus trastuzumab and chemotherapy remained consistent with previous studies. No new cardiac safety issues emerged from this interim analysis, with the incidence of primary cardiac events remaining below 1% in both arms: 0.8% in the pertuzumab arm vs 0.4% in the placebo arm. Class II/IV heart failure or decreased left-ventricular ejection fraction occurred in 0.7% and 0.2%, respectively.

Three additional cardiac deaths were reported, one in the pertuzumab arm and two in the placebo arm, for a total incidence of cardiac deaths in the study of 0.1% and 0.2%, respectively. These deaths all occurred in patients who received anthracyclines.

“Continued follow-up of patients is needed to determine a possible survival benefit and the long-term safety of adding adjuvant pertuzumab to trastuzumab,” Dr. Loibl said. 

DISCLOSURE: Dr. Loibl has received grants or nonfinancial support from or reported other relationships with AbbVie, AstraZeneca, Celgene, Amgen, BMS, Eirgenix, Eisai Europe Ltd, GSK, Lilly, Merck, Pierre Fabre, Relay Therapeutics, Sanofi, Daiichi-Sankyo, Gilead, Novartis, Pfizer, Roche, Molecular Health, and Seagen; and has patents pending (EP14153692.0, EP21152186.9, EP19808852.8), a patent issued (EP15702464.7), and a patent with royalties paid to her institution (Digital Ki67 Evaluator).


1. Loibl S, Jassem J, Sonnenblick A, et al: Updated results of APHINITY at 8.4 years median follow-up. ESMO Virtual Plenary. Abstract VP6-2022l. Presented July 14, 2022.

2. Piccart M, Procter M, Fumagalli D, et al: Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer in the APHINITY Trial: 6 years’ follow-up. J Clin Oncol 39:1448-1457, 2021.

3. 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.

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