Relationship between tumour biomarkers and efficacy in EMILIA trial identified women most likely to benefit from T-DM1

Biomarker subanalysis of the phase III clinical study of T-DM1 in HER2-positive metastatic breast cancer

Patients in all biomarker subgroups in the EMILIA study had longer progression-free survival and overall survival with T-DM1 vs lapatinib plus capecitabine. In a biomarker subanalysis, patients with tumours expressing high HER2 mRNA levels derived even greater overall survival benefit from T-DM1. Lapatinib plus capecitabine-treated patients with PIK3CA mutations had worse outcomes than those with wild type PIK3CA. T-DM1-treated patients with PIK3CA mutations had a similar treatment benefit as those without, suggesting that the unique mechanism of action of T-DM1 may overcome PIK3CA mutation resistance. The findings were presented by Dr José Baselga, physician-in-chief at Memorial Sloan-Kettering Cancer Centre in New York, USA, at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

EMILIA was a landmark phase III clinical study, which showed that T-DM1 prolonged progression-free survival and overall survival and was less toxic in patients with positive metastatic breast cancer that had been previously treated with trastuzumab and a taxane chemotherapy compared with lapatinib plus capecitabine. Also, it provided proof-of-concept that a new class of drugs, antibody-drug conjugates can benefit patients.

The antibody-drug conjugate T-DM1 retains the mechanisms of action of trastuzumab, including HER2 targeting and interruption of HER2 signalling, and provides a means of delivering the cytotoxic agent DM1 directly to HER2-positive tumours. Activating mutations of PIK3CA may lead to resistance to currently available HER2-directed therapies, and therefore the relationship between treatment efficacy and tumour HER2 mRNA expression or PIK3CA mutation status was examined in this biomarker analysis.

Tumour tissue collected for HER2 testing was also used for HER2 mRNA analysis by qRT-PCR and for PIK3CA assessment (with additional consent), using a PIK3CA Mutation Detection Kit.

Median mRNA concentration ratios and PIK3CA mutation frequency were similar across treatment arms and consistent with data previously reported. T-DM1 demonstrated superior progression-free survival and overall survival vs lapatinib-capecitabine in all biomarker subgroups. The hazard ratio of overall survival was less for patients with high (>median) vs. low tumour HER2 mRNA levels. For patients treated with lapatinib-capecitabine, PIK3CA mutations were associated with shorter median progression-free survival and overall survival; PIK3CA mutations did not significantly affect T-DM1 treatment outcomes.

Consistent with the prior analysis, the researchers found that all patients treated with T-DM1 had significantly longer progression-free and overall survival compared with those treated with lapatinib and capecitabine (9.6 months progression-free survival vs. 6.4 months; and 30.9 months for overall survival vs. 25.1 months).

Patients with tumours expressing higher levels of HER2 derived greater benefit from treatment with T-DM1 compared with patients with tumours expressing lower levels of HER2; overall survival was 34.1 months for those with high levels of HER2 vs. 26.5 months. For patients with tumours expressing higher levels of HER2, those receiving T-DM1 had a 47% decreased risk for death compared with those receiving lapatinib and capecitabine.

The researchers also investigated whether tumour mutations in the PIK3CA gene affected treatment response. According to the researchers, patients with PIK3CA-mutated, HER2-positive breast cancer normally do not respond as well to treatment with conventional HER2-targeted therapies such as trastuzumab compared with patients without PIK3CA mutations in their tumours. However, for patients treated with T-DM1, PIK3CA mutation status did not significantly decrease progression-free survival.

The study researchers hope that these data will help them in identifying a panel of molecular features that they can use to make informed treatment decisions.