Antibody drug conjugate induces responses in heavily pretreated TNBC

BOSTON – An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.

BOSTON – An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.

BOSTON – An antibody conjugated to the active metabolite of irinotecan was associated with a good overall response rate in patients with heavily pretreated triple-negative breast cancer, with lower toxicities than seen with systemic irinotecan therapy, investigators reported.

Among 54 patients with triple-negative breast cancer (TNBC) in a phase II trial who had undergone a median of six prior lines of therapy, treatment with the conjugate, labeled IMMU-132 (sacituzumab govitecan) was associated with a 31.5% overall response rate, including two complete responses, reported Dr. Aditya Bardia of Massachusetts General Hospital, Boston, and his colleagues, at the AACR–NCI–EORTC International Conference on Molecular Targets and Cancer Therapeutics.

The compound consists of a monoclonal antibody (RS7-3G11) targeted to the Trop-2/EGP-1 panepithelial cancer antigen that is conjugated with the active metabolite of irinotecan (SN-38). The antibody has been shown in preclinical studies to bind to human breast, lung, colon, renal, prostate, and urothelial cancer and other solid malignancies. Trop-2 is expressed in more than 80% of triple-negative breast cancers, said coauthor Dr. David M. Goldenberg, chairman of Immunomedics, the maker of the compound.

“What distinguishes this antibody-drug conjugate, or ADC, is that we have used the active metabolite of irinotecan, which is 100 to 1,000 times more toxic than its parent drug, and the reason it’s tolerated is that it’s conjugated to the antibody, and we have shown preclinically that we can deliver approximately 136 times more SN-38 to the cancer cell than if you give irinotecan and measure how much SN-38 gets to the tumor,” he said at a briefing.

The conjugate has good activity in patients who have experienced relapses after multiple prior lines of therapy, and it can be delivered repeatedly over a long course of therapy with toxicities that are manageable, he noted.

The compound was found to have good activity in several solid tumors in a phase I trial, which led to an expanded phase II trial including, as of May 10, 2015, a total of 56 patients with TNBC, 2 of whom had received fewer than three doses of the study drug by the data cutoff, and therefore were not included in the efficacy analysis.

Patients received IMMU-132 intravenously in doses of 8 or 10 mg/kg on days 1 and 8 of each 21-day cycle, which could be repeated until progression or unacceptable toxicity.

Among 54 assessable patients, the overall response rate (percentage change from baseline according to RECIST [Response Evaluation Criteria in Solid Tumors] 1.1 guidelines) was 31.5%, (17 of 54) consisting of 2 confirmed complete responses and 15 partial responses. Additionally, there were 24 cases of stable disease (4 confirmed), 9 of which had a greater than 20% regression of tumor, but had not met the definition of a partial response by the time of the analysis.

The combined clinical benefit rate, a composite of complete and partial responses and stable disease for 6 months or more, was 44%.

Median progression-free survival in an intent to treat analysis was 7 months. Median overall survival had not been reached, with 87% of patients alive at the data cutoff.

Among all patients in the study, including those with TNBC and other tumors, adverse events at the 10 mg/kg dose included diarrhea in 37% (grade 3 or 4 in 6%); Dr. Goldenberg noted that severe diarrhea is one of the common adverse effects of the parent compound irinotecan, earning it a black-box warning. Other common adverse events associated with irinotecan were neutropenia in 26% (grade 3 or 4 in 15%), febrile neutropenia, all grade 3 or 4, in 4%, and anemia in 20% (grade 3/4 in 6%).

“I have to say that for me, SN-38 was a brilliant idea,” commented Dr. Lee J. Helman, a sarcoma specialist at the National Cancer Institute in Bethesda, Md.

He said that the data showing less severe diarrhea with IMMU-132 than with the parent irinotecan are encouraging, because it may allow more patients to benefit from the therapy.

“This is a very active drug, irinotecan. It gets activated to SN-38 through enterohepatic metabolism, and therefore, it has a very difficult toxicity, which is diarrhea. In fact, I’ve had patients who are responding, who have come off the drug because they can’t stand the diarrhea,” he said.

Dr. Helman moderated a briefing in which Dr. Goldenberg presented the data but was not involved in the study.