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Benefit Holds Up for Dual Adjuvant HER2 Treatment in Updated Trial Results

SAN ANTONIO — New data has reiterated that adding pertuzumab (Genentech's Perjeta) to the legacy HER2 inhibitor trastuzumab (Herceptin), along with chemotherapy in the adjuvant setting, improves breast cancer outcomes for patients with HER-2-positive early-stage breast cancer over the previous standard of just trastuzumab and chemo.

The results, presented today at the 2019 San Antonio Breast Cancer Symposium, come from a six-year analysis of a Phase III clinical trial called APHINITY, which randomized nearly 5,000 patients with early HER2-positive breast cancer to either the new regimen of dual HER2 treatment plus chemo, or the current standard chemotherapy with just trastuzumab.

Despite the fact that the addition of trastuzumab to chemotherapy after surgery has revolutionized treatment outcomes for patients with these tumors, "roughly 30 percent of patients will still experience recurrence of their disease," Martine Piccart, cofounder of the Breast International Group and scientific director at the Institut Jules Bordet in Brussels, said in a statement accompanying the presentation. "By adding a different yet complementary HER2 inhibitor, pertuzumab, to this treatment regimen, we [hoped] to further reduce the risk of recurrence and advanced disease in this patient population," she added.

A previous readout from APHINITY showed that patients treated with the dual-HER2 strategy had improved rates of estimated three-year invasive disease-free survival compared with those in the placebo, or trastuzumab-only arm (94.1 percent versus 93.2 percent, respectively). The addition of pertuzumab reduced the relative risk of recurrence by 19 percent.

After six years of follow up, Piccart and colleagues have now updated their conclusions, reporting today that patients in the pertuzumab arm of the trial now show a reduced relative risk of breast cancer recurrence or death by 24 percent compared with the placebo arm.

Reflecting signs from their previous analysis, Piccart and colleagues also found that patients whose cancer had spread to their lymph nodes appear to derive greater clinical benefit from the addition of pertuzumab. In the six-year data, patients with node-positive disease in the pertuzumab arm had IDFS averaging 87.9 percent compared to 83.4 percent in the placebo arm, representing a 4.5 percent improvement.

Investigators calculated that adding pertuzumab has reduced risk of recurrence by 28 percent for this node-positive subset based on the outcomes so far. 

In the early breast cancer setting where the intent of therapy is to cure patients or prevent relapse/recurrence and survival rates are already relatively high, benefits for new regimens can seem small when plotted on a graph. But Piccart argued that for node-positive patients the benefit being seen should be "considered of really significant clinical value."

In contrast, she said, there has been "no treatment effect detected" for the trial's node-negative population, potentially because this group is already at such a low risk of recurrence.

In her presentation, Piccart said that though added HER2 inhibition doesn't seem to add benefit to node-negative women, the mechanisms aren't fully understood. But, "when you [consider] the excellent outcome in node-neg patients, you can see that it might be very difficult to show any further improvement," she added. Based on results like what the team is seeing in APHINITY, this could mean that it doesn't make sense to keep trying therapy intensification in this subset.

"Probably this trial signals the end of escalation attempts in these women and perhaps the time to start looking at cautious de-escalation," she said.

Interestingly, and encouraging, she added, while the prior APHINITY analysis had also shown a greater benefit for hormone receptor-negative patients compared to hormone receptor-positive patients, the second group has been catching up as the trial has matured further. In the new six-year analysis, HR-negative patients continued to show benefit with a hazard ratio of 0.83, Piccart said at the conference. But a benefit is also "emerging there clearly" for the HR-positive with a hazard ratio of 0.73.

Finally, investigators also updated their calculations of adverse events in the trial. "Benefits have to be balanced, of course, against potential harm … but here's the great news: [there were] no new cardiac safety issues with 2.5 more years follow up," Piccart said. 

At the six-year point, there was one additional primary cardiac event in the pertuzumab arm, and one additional secondary event in each arm. But even with these additions, the incidence of primary cardiac events in the trial still remains less than one percent.

According to Piccart, "The evidence is now even stronger that adding pertuzumab to the previous standard of care reduces the risk of disease recurrence for patients with HER2-positive breast cancer,” she added.

That said, the data, though updated, still remain immature and do not yet offer definitive evidence of improved overall survival, investigators cautioned. As of the six-year analysis, there had been 272 deaths, about 42 percent of the 640 deaths needed for a definitive overall survival analysis.

During her presentation, Piccart reported that 125 patients have died in the pertuzumab group and 147 in the placebo group, representing a hazard ratio of 0.85 in favor of the dual treatment arm. But, this is not a statistically significant finding with such a small proportion of the overall 640 deaths yet recorded.

Authors reported that the trial's next interim analysis is scheduled to take place in 2022.