EMILIA Study: T-DMI Prolongs Progression-Free and Overall Survival

The investigational drug trastuzumab emtansine, or T-DM1, was well tolerated and was associated with significantly prolonged progression-free survival compared with combination capecitabine/lapatinib (XL) treatment in 978 patients with HER2-positive metastatic breast cancer.

The antibody-drug conjugate, which combines the antitumor activity of the monoclonal antibody trastuzumab with the cytotoxic effects of the maytansine derivative DM1, also improved overall survival.

The median progression-free survival among those randomized to receive T-DM1 was 9.6 months, compared with 6.4 months for those treated with XL (stratified hazard ratio, 0.65) – a difference that was both statistically significant (P less than .0001) and clinically meaningful, said Dr. Mark D. Pegram of Stanford (Calif.) University’s Stanford Cancer Institute.

The findings were noted in the first planned interim analysis of the randomized, open-label, phase III EMILIA study. Overall survival at 1 year was 84.7% and 77% in the T-DM1 and XL groups, respectively, and overall survival at 2 years was 65.4% and 47.5% for the groups, respectively (J. Clin. Oncol. 30, 2012 [suppl 27 abstr 98]). The objective response rate was 43.6% vs. 30.8%, and the duration of response among those with an objective response was a median of 12.6 months vs. 6.5 months, Dr. Pegram said.

The findings were presented at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

The findings with respect to overall survival, based on this analysis, showed a trend in favor of T-DM1 (stratified hazard ratio, 0.621; P less than .0005), but the difference between the two treatment groups did not technically achieve statistical significance, Dr. Pegram said.

However, the overall survival analysis was recently updated, and the latest findings did demonstrate a statistically significant overall survival advantage with T-DM1 treatment, he noted.

The detailed findings from that latest analysis will be reported publicly for the first time at the European Society for Medical Oncology 2012 Congress to be held Oct. 1. Roche/Genentech Inc., maker of T-DM1, resubmitted to the Food and Drug Administration an application for accelerated approval of the agent. The company has said it plans to provide the FDA, which refused to file the initial application for accelerated approval submitted in 2010, with the updated overall survival analysis data when the agency reviews the application.

EMILIA participants were women with confirmed HER2-positive metastatic breast cancer who had been treated previously with trastuzumab and a taxane. They were randomized to receive 3.6 mg/kg of intravenous T-DMI every 3 weeks, or combination therapy with an oral twice-daily dose of 1,000 mg/m² of capecitabine on days 1-4 every 3 weeks and an oral dose once daily of 1,240 mg of lapatinib; the XL combination treatment is currently the only approved combination treatment for trastuzumab-refractory HER2-positive metastatic breast cancer.

Patients in the T-DM1 and XL groups were followed for a median of 12.9 and 12.4 months, respectively, and progression-free survival was determined by independent review.

T-DM1 was well tolerated; no unexpected safety signals emerged. The most common grade 3 or higher adverse events in the T-DM1 patients were thrombocytopenia (12.9% vs. 0.2% of T-DMI vs. XL patients), increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 1.4%). The most common adverse events in the XL patients were diarrhea (20.7% vs. 1.6% of the XL vs. T-DM1 patients), palmar plantar erythrodysesthesia (16.4% vs. 0), and vomiting (4.5% vs. 0.8%).

Dose reductions were required in 16.3% of T-DM1 patients, whereas lapatinib doses were reduced in 27.3% of the XL patients, and capecitabine doses were reduced in 53.4% of the XL patients.

The EMILIA trial is sponsored by Genentech. Dr. Pegram reported serving as a consultant or adviser for Takeda, receiving honoraria from AstraZeneca and GlaxoSmithKline, receiving research funding from Sanofi, providing expert testimony for Novartis, and receiving other remuneration from Bristol-Myers Squibb, Pfizer, and Roche/Genentech.

The investigational drug trastuzumab emtansine, or T-DM1, was well tolerated and was associated with significantly prolonged progression-free survival compared with combination capecitabine/lapatinib (XL) treatment in 978 patients with HER2-positive metastatic breast cancer.

The antibody-drug conjugate, which combines the antitumor activity of the monoclonal antibody trastuzumab with the cytotoxic effects of the maytansine derivative DM1, also improved overall survival.

The median progression-free survival among those randomized to receive T-DM1 was 9.6 months, compared with 6.4 months for those treated with XL (stratified hazard ratio, 0.65) – a difference that was both statistically significant (P less than .0001) and clinically meaningful, said Dr. Mark D. Pegram of Stanford (Calif.) University’s Stanford Cancer Institute.

The findings were noted in the first planned interim analysis of the randomized, open-label, phase III EMILIA study. Overall survival at 1 year was 84.7% and 77% in the T-DM1 and XL groups, respectively, and overall survival at 2 years was 65.4% and 47.5% for the groups, respectively (J. Clin. Oncol. 30, 2012 [suppl 27 abstr 98]). The objective response rate was 43.6% vs. 30.8%, and the duration of response among those with an objective response was a median of 12.6 months vs. 6.5 months, Dr. Pegram said.

The findings were presented at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

The findings with respect to overall survival, based on this analysis, showed a trend in favor of T-DM1 (stratified hazard ratio, 0.621; P less than .0005), but the difference between the two treatment groups did not technically achieve statistical significance, Dr. Pegram said.

However, the overall survival analysis was recently updated, and the latest findings did demonstrate a statistically significant overall survival advantage with T-DM1 treatment, he noted.

The detailed findings from that latest analysis will be reported publicly for the first time at the European Society for Medical Oncology 2012 Congress to be held Oct. 1. Roche/Genentech Inc., maker of T-DM1, resubmitted to the Food and Drug Administration an application for accelerated approval of the agent. The company has said it plans to provide the FDA, which refused to file the initial application for accelerated approval submitted in 2010, with the updated overall survival analysis data when the agency reviews the application.

EMILIA participants were women with confirmed HER2-positive metastatic breast cancer who had been treated previously with trastuzumab and a taxane. They were randomized to receive 3.6 mg/kg of intravenous T-DMI every 3 weeks, or combination therapy with an oral twice-daily dose of 1,000 mg/m² of capecitabine on days 1-4 every 3 weeks and an oral dose once daily of 1,240 mg of lapatinib; the XL combination treatment is currently the only approved combination treatment for trastuzumab-refractory HER2-positive metastatic breast cancer.

Patients in the T-DM1 and XL groups were followed for a median of 12.9 and 12.4 months, respectively, and progression-free survival was determined by independent review.

T-DM1 was well tolerated; no unexpected safety signals emerged. The most common grade 3 or higher adverse events in the T-DM1 patients were thrombocytopenia (12.9% vs. 0.2% of T-DMI vs. XL patients), increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 1.4%). The most common adverse events in the XL patients were diarrhea (20.7% vs. 1.6% of the XL vs. T-DM1 patients), palmar plantar erythrodysesthesia (16.4% vs. 0), and vomiting (4.5% vs. 0.8%).

Dose reductions were required in 16.3% of T-DM1 patients, whereas lapatinib doses were reduced in 27.3% of the XL patients, and capecitabine doses were reduced in 53.4% of the XL patients.

The EMILIA trial is sponsored by Genentech. Dr. Pegram reported serving as a consultant or adviser for Takeda, receiving honoraria from AstraZeneca and GlaxoSmithKline, receiving research funding from Sanofi, providing expert testimony for Novartis, and receiving other remuneration from Bristol-Myers Squibb, Pfizer, and Roche/Genentech.

The investigational drug trastuzumab emtansine, or T-DM1, was well tolerated and was associated with significantly prolonged progression-free survival compared with combination capecitabine/lapatinib (XL) treatment in 978 patients with HER2-positive metastatic breast cancer.

The antibody-drug conjugate, which combines the antitumor activity of the monoclonal antibody trastuzumab with the cytotoxic effects of the maytansine derivative DM1, also improved overall survival.

The median progression-free survival among those randomized to receive T-DM1 was 9.6 months, compared with 6.4 months for those treated with XL (stratified hazard ratio, 0.65) – a difference that was both statistically significant (P less than .0001) and clinically meaningful, said Dr. Mark D. Pegram of Stanford (Calif.) University’s Stanford Cancer Institute.

The findings were noted in the first planned interim analysis of the randomized, open-label, phase III EMILIA study. Overall survival at 1 year was 84.7% and 77% in the T-DM1 and XL groups, respectively, and overall survival at 2 years was 65.4% and 47.5% for the groups, respectively (J. Clin. Oncol. 30, 2012 [suppl 27 abstr 98]). The objective response rate was 43.6% vs. 30.8%, and the duration of response among those with an objective response was a median of 12.6 months vs. 6.5 months, Dr. Pegram said.

The findings were presented at the American Society of Clinical Oncology’s 2012 Breast Cancer Symposium.

The findings with respect to overall survival, based on this analysis, showed a trend in favor of T-DM1 (stratified hazard ratio, 0.621; P less than .0005), but the difference between the two treatment groups did not technically achieve statistical significance, Dr. Pegram said.

However, the overall survival analysis was recently updated, and the latest findings did demonstrate a statistically significant overall survival advantage with T-DM1 treatment, he noted.

The detailed findings from that latest analysis will be reported publicly for the first time at the European Society for Medical Oncology 2012 Congress to be held Oct. 1. Roche/Genentech Inc., maker of T-DM1, resubmitted to the Food and Drug Administration an application for accelerated approval of the agent. The company has said it plans to provide the FDA, which refused to file the initial application for accelerated approval submitted in 2010, with the updated overall survival analysis data when the agency reviews the application.

EMILIA participants were women with confirmed HER2-positive metastatic breast cancer who had been treated previously with trastuzumab and a taxane. They were randomized to receive 3.6 mg/kg of intravenous T-DMI every 3 weeks, or combination therapy with an oral twice-daily dose of 1,000 mg/m² of capecitabine on days 1-4 every 3 weeks and an oral dose once daily of 1,240 mg of lapatinib; the XL combination treatment is currently the only approved combination treatment for trastuzumab-refractory HER2-positive metastatic breast cancer.

Patients in the T-DM1 and XL groups were followed for a median of 12.9 and 12.4 months, respectively, and progression-free survival was determined by independent review.

T-DM1 was well tolerated; no unexpected safety signals emerged. The most common grade 3 or higher adverse events in the T-DM1 patients were thrombocytopenia (12.9% vs. 0.2% of T-DMI vs. XL patients), increased AST (4.3% vs. 0.8%), and increased ALT (2.9% vs. 1.4%). The most common adverse events in the XL patients were diarrhea (20.7% vs. 1.6% of the XL vs. T-DM1 patients), palmar plantar erythrodysesthesia (16.4% vs. 0), and vomiting (4.5% vs. 0.8%).

Dose reductions were required in 16.3% of T-DM1 patients, whereas lapatinib doses were reduced in 27.3% of the XL patients, and capecitabine doses were reduced in 53.4% of the XL patients.

The EMILIA trial is sponsored by Genentech. Dr. Pegram reported serving as a consultant or adviser for Takeda, receiving honoraria from AstraZeneca and GlaxoSmithKline, receiving research funding from Sanofi, providing expert testimony for Novartis, and receiving other remuneration from Bristol-Myers Squibb, Pfizer, and Roche/Genentech.