NEW YORK (Reuters Health) - In the EMILIA trial of ado-trastuzumab emtansine (Kadcyla injection, Genentech, Inc.), women with metastatic breast cancer and high tumor expression of HER2 derived a greater benefit in terms of overall survival than women with lower HER expression, new data show.
In February, the U. S. Food and Drug Administration approved Kadcyla for monotherapy in patients with HER2-positive, metastatic breast cancer who had previously received trastuzumab and a taxane, separately or in combination.
In EMILIA, the drug was effective even in women who had PIK3CA mutations, reported Dr. Jose Baselga, from Memorial Sloan-Kettering Cancer Center in New York City, in a presentation at the annual meeting of the American Association for Cancer Research (AACR).
Finding that breast cancer patients with the highest expression of HER2 on their tumors fared the best with ado-trastuzumab emtansine was not all that surprising, Dr. Baselga told Reuters Health.
What was more exciting to his team, he said, was the finding that tumor PIK3CA mutations failed to diminish the tumor response.
Ado-trastuzumab emtansine, an antibody-drug conjugate, retains the mechanisms of action of trastuzumab, including the targeting of HER2 and interruption of HER2 signaling, and provides a means of delivering the cytotoxic agent DM1 directly to HER2-positive tumors.
In the 991-patient EMILIA study, the drug showed a statistically significant progression-free and overall survival benefit, with less toxicity when compared with capecitabine plus lapatinib (XL) in patients with previously treated HER2-positive metastatic breast cancer. This study was the basis for the FDA's approval.
In the current subanalysis, Dr. Baselga and his team analyzed tissue samples from 495 EMILIA participants to see if tumor levels of HER2, as assessed by the amount of HER2 messenger ribonucleic acid (mRNA) affected treatment response.
Patients with tumors expressing greater than the median amount of tumor HER2 mRNA were considered to have high levels of HER2, and those with tumor HER2 expression at or below the median were considered to have low levels of HER2.
Consistent with the prior analysis, the researchers found that all patients treated with ado-trastuzumab emtansine had significantly longer progression-free survival (9.6 vs 6.4 months) and overall survival (30.9 vs 25.1 months) compared to patients treated with lapatinib and capecitabine.
Furthermore, among the group treated with ado-trastuzumab emtansine, overall survival was 34.1 months for those with high levels of HER2 compared with 26.5 months for those with lower levels of HER2.
Patients with high HER2 expression had a 47% lower risk of death if they received ado-trastuzumab emtansine instead of lapatinib and capecitabine.
Importantly, the investigators said, patients with PIK3CA mutations had a similar treatment benefit as those without, suggesting that the drug's mechanism of action overcomes PIK3CA mutation resistance.
"We know that a proportion of tumors that express high levels of HER2 also have a mutation in the P13 kinase gene which keeps the pathway turned on all the time, making the tumors resistant to trastuzumab, pertuzumab, and lapatinib," Dr. Baselga explained.
The new drug, however, "was effective against tumors with this mutation, probably because it is not working through inhibition of the HER2 signaling pathway," Dr. Baselga said.
Commenting on this study for Reuters Health, Dr. Thaer Khoury from Roswell Park Cancer Institute in Buffalo, New York called it "an important step towards treating trastuzumab-resistant breast cancer patients," despite the relatively small improvements in progression-free and overall survival in comparison with lapatinib-based therapy.
Ado-trastuzumab emtansine "improved the progression free and overall survival for only 3.2 months and 4.8 months, respectively compared to lapatinib based therapy," Dr. Khoury pointed out, adding that HER2 breast cancer is a diverse disease. "Some patients will have long survival even without trastuzumab therapy and some will have recurrence early in the course of trastuzumab therapy."
There have been multiple theories about trastuzumab resistance, Dr. Khoury noted.
"Such resistance most likely is multifactorial, and one of the proposed reasons is PIK3CA mutation. The fact that this study showed that this mutation had no effect on the survival when (ado-trastuzumab emtansine) is applied is a good step towards personalized medicine. It would be equally important if the investigators looked into other genes/factors that have been proven to be reasons for trastuzumab resistance, such as IGF, p27, pSRC, p95HER2, pTEN, etc."
The FDA requires that ado-trastuzumab emtansine packaging include a boxed warning describing the risk of hepatotoxicity, reduction in left ventricular ejection fraction, embryo-fetal toxicity and birth defects, and the need for effective contraception prior to starting therapy.
More information is available on the FDA's website, here: http://1.usa.gov/Yb4uVC.
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