Failed ATEMPT: T-DM1 no safer in early HER2+ breast cancer

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.

SAN ANTONIO – Nice try, ATEMPT investigators, but trastuzumab emtansine (T-DM1) does not have a disease-free survival or safety advantage over paclitaxel plus trastuzumab in the adjuvant setting for patients with stage 1 HER2-positive breast cancer.

For 497 patients randomized on a 3:1 basis to receive either T-DM1 every 3 weeks for 17 cycles or paclitaxel plus trastuzumab (TH) weekly for 12 cycles followed by trastuzumab every 3 weeks for an additional 13 cycles, there were no significant between-regimen differences in the co-primary endpoints of 3-year disease-free survival (DFS) or clinically relevant toxicities, reported Sara M. Tolaney, MD, MPH of Dana-Farber Cancer Institute, Boston.

“While there was no difference in the overall incidence of clinically relevant toxicities between the two arms, there were differences in the toxicity profiles that were seen between T-DM1 and TH. It’s also important to know that not all toxicities that are significant for our patients are captured in this clinically relevant toxicity endpoint, such as alopecia, and patient-reported outcomes should be considered when assessing the tolerability of therapy,” she said at the San Antonio Breast Cancer Symposium.

For patients with stage 1, HER2-positive breast cancer at high risk of recurrence, paclitaxel and trastuzumab is associated with a 93% disease survival rate.

T-DM1, an drug antibody conjugate of trastuzumab and DM1, a cytotoxic agent, is active against metastatic HER2-positive breast cancer and in patients with residual disease after neoadjuvant HER2-directed therapy.

“Importantly, T-DM1 has been associated with less toxicity when compared to chemotherapy with trastuzumab,” said Dr. Tolaney.

To see whether T-DM1 could be a less toxic treatment option for patients with stage 1 HER2-positive breast cancer at risk for recurrence, the investigators enrolled 512 patients who were within 90 days of surgery, had N0 or microscopic N1 disease, left ventricular ejection fraction (LVEF) of 50% or greater, and no prior invasive breast cancer.

The patients were stratified by age (younger than 55 or 55 and older), planned radiation (yes or no), and planned hormonal therapy (yes or no), and then randomly assigned on a 3:1 basis to receive either T-DM1 3.6 mg/kg intravenously every 3 weeks for 17 cycles, or TH, consisting of paclitaxel 80 mg/m² plus trastuzumab 2 mg/kg intravenously weekly for 12 cycles, followed by trastuzumab 6 mg/kg every 3 weeks for an additional 13 cycles.

A total of 383 patients assigned to T-DM1 and 114 assigned to TH were included in the intention-to-treat analysis.

The study arms were well balanced by tumor size, histologic grade, hormone receptor status, and HER2 status by fluorescent in situ hybridization (1+, 2+, 3+ or not performed).

Three-year disease-free survival with was 97.7% with T-DM1 and 93.2% with TH, but the study was not powered to detect efficacy differences between the two adjuvant regimens, Dr. Tolaney noted.

In all, 46% of patients in each arm had clinically relevant toxicities. Grade 3 or greater nonhematologic toxicities were seen in 10% of those on T-DM1, vs. 11% of those on TH. Grade 2 or greater neurotoxicity was seen in 11% of patients and 23%, respectively.

Four patients on T-DM1 had grade 4 hematologic toxicity vs. none on TH. Febrile neutropenia was not seen among patients on T-DM1, but occurred in two patients on TH.

The incidence of toxicity requiring a dose delay was 28% and 26%, respectively, while nearly 3 times as many patients on T-DM1 had toxicities requiring early discontinuation (17% vs. 6%).

T-DM1 was also associated with higher incidences of grade 2 or greater thrombocytopenia (11% vs. 1%), alanine aminotransferase elevation (9% vs. 4%), and bilirubin increase (5% vs. 1%).

Three patients on T-DM1 and one on TH had symptomatic heart failure. Asymptomatic declines in LVEF were seen in five and seven patients, respectively.

“Given the low event rate seen in this trial, T-DM1 may be considered an alternative treatment approach to TH for select patients with stage 1 HER2-positive disease who are concerned about specific TH-related side effects and who understand the potential for T-DM1 toxicities. There may be some patients and physicians, however, who will want longer follow-up before adopting such an approach,” Dr. Tolaney said.

In the question and response session, an audience member said, “I would like to add one more toxicity that has not been considered, which is financial toxicity. There’s a huge difference in the price of both regimens, and the total cost of care.”

Dr. Tolaney replied that “certainly we did consider this and we had our pharmacist do some calculations looking at this financial toxicity, and it is true that a year of T-DM1 does cost a little more than two times as much as TH.”

She agreed that financial toxicity is a very important consideration when making treatment decisions, “but I think there are differences in toxicity profiles that do need to be considered when making individual decisions for our patients.”

Invited discussant A. Jo Chien, MD of the University of California, San Francisco noted that 75% of all patients enrolled in ATEMPT had hormone receptor positive disease “and therefore 3 years median follow-up is relatively short for this cohort.

“Due to the high rates of discontinuation in the T-DM1 arm, it is important to remember that duration of toxicity is a contributor to overall tolerability, which often is not well characterized by standard toxicity assessments, which often just report highest-grade toxicity at one point in time. High-grade toxicities that are short-lived may be acceptable, but low-grade toxicities for longer duration may not,” she said.

The ATEMPT trial was funded by Genentech. Dr. Tolaney has disclosed advisory board participation, institutional research funds, honoraria, and travel expense reimbursement from the company. Dr. Chien disclosed institutional research funding from Merck, Puma, Seattle Genetics, Astellas, and Amgen.

SOURCE: Tolaney SM et al. SABCS 2019, Abstract GS1-05.