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SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.
The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.
“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.
Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.
Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.
“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.
Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.
Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.
In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.
The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
Study details
DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.
As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.
ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.
The median time to response was 1.6 month, and the median duration of response was 14.8 months.
The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.
Interstitial lung disease
After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.
A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.
In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.
The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.
However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.
“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.
The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.
SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.
SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.
The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.
“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.
Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.
Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.
“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.
Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.
Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.
In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.
The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
Study details
DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.
As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.
ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.
The median time to response was 1.6 month, and the median duration of response was 14.8 months.
The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.
Interstitial lung disease
After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.
A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.
In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.
The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.
However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.
“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.
The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.
SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.
SAN ANTONIO –A novel antibody-drug conjugate pairing trastuzumab (Herceptin) with a topoisomerase I inhibitor as the toxic payload was associated with a good overall response rate in patients with heavily pretreated HER2-positive metastatic breast cancer.
The confirmed overall response rate among 184 patients treated with trastuzumab deruxtecan and followed for a median of 11.1 months was 60.9%, consisting of 6% complete responses and 54.9% partial responses, reported Ian Krop, MD, PhD, from the Dana-Farber Cancer Institute in Boston.
“These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer,” he said at a briefing prior to presentation of the data at the San Antonio Breast Cancer Symposium.
Results of the open-label phase 2 DESTINY-BREAST01 study were also published online in the New England Journal of Medicine.
Although the antibody-drug conjugate was associated with a good response rate among heavily pretreated patients (median of six prior lines of therapy), it was also associated with interstitial lung disease (ILD), including 4 fatalities among 184 patients who received the drug at the recommended study dose of 5.4 mg/kg.
“ILD is confirmed as an important risk of trastuzumab deruxtecan, it can be severe, and requires careful monitoring and prompt intervention,” Dr. Krop said.
Trastuzumab deruxtecan is composed of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab, and exatecan derivative as the topoisomerase I inhibitor payload conjugated by a tetrapeptide-based cleavable linker.
Although topoisomerase I inhibitors are not commonly used in breast cancer because of limited activity in clinical trials and toxicities when used systemically, the rationale for using a topoisomerase I inhibitor in this setting is that the toxic effects can be largely confined to the local tumor environment.
In addition, “this is an agent that the cancers generally haven’t been exposed to, so there is the hope this will be non–cross-resistant,” Dr. Krop said at the briefing.
The product has a high drug molecule-to-antibody ratio or approximately 8:1, which is higher than that seen with other antibody-drug conjugates, and the topoisomerase inhibitor payload is membrane permeable, giving it extra potency.
Study details
DESTINY-BREAST01 is an open-label, multicenter, phase 2 study consisting of a dose-finding phase and a continuous phase. Dr. Krop reported on all 184 patients who have been treated at the recommend 5.4-mg/kg dose.
As noted, the patients had received a median of 6 prior lines of therapy, with at least one patient receiving a staggering 27 prior lines. All had previously received trastuzumab and a different antibody-drug conjugate, ado-trastuzumab emtansine (T-DMI; Kadcyla). Two-thirds of patients (65.8%) had received pertuzumab (Perjeta), 54.3% received other anti-HER2 therapies. 48.9% had received hormone therapy, and 99.5% had received other systemic therapies.
ORR by independent review, the primary endpoint, was as noted before. In addition to the 60.9% ORR, 36.4% of patients had stable disease, for a disease control rate of 97.3%.
The median time to response was 1.6 month, and the median duration of response was 14.8 months.
The median progression-free survival at follow-up was 16.4 months. The median overall survival had not been reached at the time of data cutoff in August 2019.
Interstitial lung disease
After a median treatment duration of 10 months, all but one patient had at least one drug-related adverse event. Grade 3 or greater drug-related adverse events occurred in 48.4% of patients, and serious drug-related events occurred in 12.5%.
A total of 25 patients had ILD of any grade, including 5 with grade 1, 15 with grade 2, 1 with grade 4, and the aforementioned 4 patients who died from the disease.
In the four patients with fatal ILD, onset ranged from 63-146, with the deaths occurring 9-60 days after ILD diagnosis. Three of the patients had received steroids as part of their ILD treatment.
The investigators recommend close monitoring of patients for signs and symptoms of lung disease, including fever, cough, or dyspnea. They also recommend that patients with suspected ILD be evaluated with high-resolution CT and testing for pulmonary function and oxygen saturation, ideally under consultation with a pulmonologist.
However, despite the known cardiotoxic effects of trastuzumab, there were no reported cases of heart failure with decline in left ventricular ejection fraction, and only three patients had a decrease in left ventricular ejection fraction, none of which grade 4.
“The response rate and overall efficacy observed with trastuzumab deruxtecan in this study appear to substantially exceed those of currently available HER2-directed regimens and new agents in development, although cross-trial comparisons must be interpreted with caution,” the investigators wrote in the New England Journal of Medicine.
The study was funded by Daiichi Sankyo and AstraZeneca. Dr. Krop disclosed consulting fees, honoraria from each company, and research support from Genentech/Roche and Pfizer.
SOURCE: Krop I et al. SABCS 2019, Abstract GS1-03.
REPORTING FROM SABCS 2019