SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Dual HER2 targeting with lapatinib added to 16 weeks of trastuzumab significantly improved event-free survival (EFS), compared with trastuzumab alone, among women with HER2-positive breast cancer.

EFS was significantly longer in the combination arm versus single-blockade therapy (hazard ratio, 0.35; 95% confidence interval, 0.15-0.84; P = .013).

“Overall survival was also increased, but the number of events was very small,” said study author Ian E. Krop, MD , of the Dana-Farber Cancer Institute in Boston, who presented the study results at the San Antonio Breast Cancer Symposium .

As expected, and consistent with other studies, the pathologic complete response (pCR) rate with dual blockade was associated with favorable long-term outcomes, and the effect was most pronounced in HR- and HER2 enriched cancers.

However, Dr. Krop cautioned that these results need to be seen in the context of two larger trials that failed to find a benefit for dual-blockade HER2 therapy in either the adjuvant or neoadjuvant setting.

Previous research has shown that trastuzumab and lapatinib are synergistic, potently inhibiting HER2 signaling in preclinical trials. The combination of both agents is also active in both untreated and heavily pretreated HER2+ advanced breast cancer. The addition of lapatinib to trastuzumab plus chemotherapy has also been associated with a pCR rate that was statistically significant in many studies.

But despite this “wealth of evidence,” the largest of these studies, the phase 3 ALTTO study , failed to show a benefit for dual HER2 blockade. The same was true for the neoadjuvant Neo ALTTO study . Both studies failed to show an improvement in EFS or overall survival.

The current trial, CALGB 40601 , a randomized phase 3 trial, assessed the effect of dual HER2 blockade consisting of trastuzumab and lapatinib added to paclitaxel on rates of pCR, and the researchers also looked at tumor and microenvironment molecular features. Dr. Krop noted that they had previously found that rates of pCR were numerically but not significantly increased with combination-blockade therapy; they had also found that the tumor molecular subtype and evidence of immune activation were independent factors affecting rates of pCR.

Dr. Krop presented results from a secondary analysis in which they evaluated the effects of treatment arm and gene expression–defined subgroups on EFS.

A total of 305 patients with stage II and III HER2+ breast cancer were randomized to receive 16 weeks of either paclitaxel plus trastuzumab alone or that combination with lapatinib as well before undergoing surgery. Evaluable information regarding EFS and RNA-sequencing gene expression was available for 265 patients.

“Despite the lack of significant benefits in other studies, we did demonstrate an improvement in EFS,” said Dr. Krop, noting that it was more pronounced in the subset of HR- patients (HR, 0.12; P = .0160).

EFS was also significantly longer among those who achieved pCR than those who didn’t (HR, 0.34; P = .0032).

In an exploratory analysis, Dr. Krop and his colleagues assessed whether there was a difference in rates of pCR by subtype, and they found that luminal A and luminal B did not have much of an effect on rates of pCR. However, patients with HER2-enriched disease who had a pCR had significantly better EFS than those who did not (HR, 0.14; 95% CI, 0.04-0.44; P less than .0001).

Conversely, patients with HER2-enriched disease who did not achieve pCR had a substantial risk of recurrence.

When looking at EFS by intrinsic subtype, the addition of lapatinib had the most effect on luminal A cancers. “This shows that there was some discordance between analyses by pCR and by long-term endpoint,” Dr. Krop said.

Finally, among gene expression signatures, only immune activation measured by an immunoglobulin G signature was associated with an improvement in EFS (HR, 0.70; 95% CI, 0.50-0.98; P = .04).

“These data are hypothesis generating and require validation,” Dr. Krop concluded. He added that a combined analysis of this trial, along with the Neo ALTTO and others, is planned.

SOURCE: Krop IE et al. SABCS 2017 Abstract GS3-02.


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