Two Anti-HER2 Drugs Slightly Better Than One

CHICAGO -- A large study showing a small improvement in the outcome of HER2-positive breast cancer could lead to a major change in the way the disease is treated, experts meeting here agreed.

Patients with early-stage HER2-positive breast cancer had less than a 1% absolute improvement in 3-year overall survival (OS) rate when they received two anti-HER2 drugs -- pertuzumab (Perjeta) and trastuzumab (Herceptin) -- after surgery, instead of the current standard of trastuzumab alone. Patients with positive lymph nodes or hormone receptor-negative disease derived greater benefit, on the order of 1.5% to 2.0% in absolute terms.

The combination might be hard to justify for all patients with early HER2-positive breast cancer, but a stronger case can be made for selected patients with higher-risk disease, specialists said at the American Society of Clinical Oncology meeting.

"It's always an issue with adjuvant treatment that if you report the early results, you don't have the full view on the efficacy," said study investigator Gunter von Minckwitz, MD, PhD, president of the German Breast Group in Neu-Isenberg. "From a statistical point of view, we don't see a difference in efficacy in the node-positive versus node-negative patients or with regard to hormone-receptor status. But with the data we have right now, these results support the use more in the higher-risk patients: node positive and receptor negative."

U.S. breast cancer specialists acknowledged the study, known as the APHINITY trial, as an advance in the treatment of HER2-positive breast cancer but agreed that patient selection will be a key issue.

"The differences were small but statistically significant and the trial did meet its primary endpoint," said Leif William Ellisen, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston. "However, in the larger picture, we have to see who is this trial actually going to apply to. The fact that differences were small and that these are very expensive drugs that do cause some additional toxicity, suggests that this regimen might be better suited for higher risk patients, including those who have estrogen receptor-negative disease and those who have node-positive disease. This will be fleshed out as we get more information on the study as the years go by."

Additionally, the results need to be considered within the context of the dramatic improvement in breast cancer treatment and survival that has occurred over the years, said Lisa Carey, MD, of the University of North Carolina in Chapel Hill.

"Results of APHINITY and [other recent trials] of newer HER2-targeted regimens highlight that you can improve outcome past trastuzumab-based regimens," she told MedPage Today. "The 'however' is that patients are doing so much better now. The transformation of prognosis for HER2-positive breast cancer that was created by the first generation of HER2-targeted drugs means that many of these patients are doing great.

"We have almost a splintering of approaches where we can lay on dual and sequential targeting in very high-risk patients, if we can figure out who they are, and we can reduce drugs in low risk, but at the moment we're not very good at it. I think the take-home message from all of this is that we can gild the lily with incremental advances but maybe not very large incremental advances, if you take the whole population."

Improved use of new HER2-targeted strategies will come with the development of genomic testing to identify high- and low-risk groups, as has already occurred with HER2-negative breast cancer, she added.

The APHINITY trial involved 4,800 women with untreated early-stage HER2-positive breast cancer. Following surgery, they received standard chemotherapy and trastuzumab and were randomized to receive pertuzumab, in addition to trastuzumab, or to placebo.

The trial had a primary endpoint of invasive disease-free survival (IDFS) at 3 years. The trial had the statistical power to detect a 25% reduction in the hazard ratio, assuming a 3-year IDFS of 89.2% in the placebo group and 91.8% in the pertuzumab group.

The 3-year IDFS was higher than expected in both arms, as the 0.9% difference in IDFS in favor of pertuzumab represented a 19% reduction in the hazard ratio (95% CI 0.66-1.00, P=0.045). An extensive subgroup analysis generally exhibited trends in favor of pertuzumab but yielded only one statistically significant difference: Patients with positive lymph nodes had a 23% reduction in the hazard ratio with pertuzumab (92.0% versus 90.2%, HR 0.77, 95% CI 0.62-0.96, P=0.019).

Patients with HR-negative breast cancer derived 24% benefit at 3 years with pertuzumab (92.8% versus 91.2%), but the difference did not achieve statistical significance (95% CI 0.56-1.04, P=0.085).

Both of the anti-HER2 drugs carry a risk of cardiotoxicity, and the primary safety endpoint of combined heart failure/cardiac death was slightly higher in the pertuzumab group (0.7% versus 0.4%). An excess of heart failure accounted for all of the difference (0.6% versus 0.2%). Seven patients in the pertuzumab arm had recovery of left ventricular ejection fraction as compared with four in the placebo group.

Grade 3/4 adverse events generally occurred in a similar proportion of patients in each group, the notable exception being diarrhea, which occurred more often with pertuzumab (9.8% versus 3.7%). Von Minckwitz noted that the frequency of diarrhea was affected by the type of chemotherapy chosen by treating physicians and drug sequencing.

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