Novel antimetabolite strategy slows progression of deadly mesothelioma

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]

CHICAGO – The arginine depletor ADI-PEG 20 cut the risk of progression in half for patients with malignant pleural mesothelioma in the randomized ADAM trial.

Median progression-free survival improved from 1.9 months with best supportive care (BSC) to 3.2 months with the addition of ADI-PEG 20 (hazard ratio, 0.51; P = .012).

The study was not powered for overall survival, but five patients have lived beyond 2 years, all on the ADI-PEG 20 plus BSC arm, Dr. Peter Szlosarek said at the annual meeting of the American Society of Clinical Oncology.

Mean overall survival was 12.8 months for patients assigned BSC and 14.5 months for those also given ADI-PEG 20 (P = .53). Median survival with this invariably fatal disease is typically 9-12 months.

"Arginine deprivation may have a role in the future management of mesothelioma," said Dr. Szlosarek, a medical oncology consultant at the Barts Cancer Institute and St. Bartholomew’s Hospital in London.

ADI-PEG 20 is one of several arginine-depleting agents in development and has been granted orphan drug status in the U.S. for hepatocellular carcinoma and melanoma.

ADI-PEG 20 is a pegylated arginine deiminase that exerts antitumor activity by depletion of serum arginine, an essential amino acid. Normal cells synthesize arginine from citrulline via the urea cycle enzyme argininosuccinate synthase 1 (ASS1), he explained.

Studies have shown that many malignancies including mesothelial and urological cancers, melanoma, and sarcomas lack ASS1 and therefore obtain arginine from the blood for tumor growth and survival. Recent evidence suggests that expression of argininosuccinate lyase, an enzyme immediately downstream of ASS1, may also play a role in tumor survival.

ADAM (ADI-PEG 20 in Patients with Malignant Pleural Mesothelioma) screened 214 patients with malignant pleural mesothelioma, roughly half of whom who were chemotherapy naive and half of whom were previously treated with platinum combination chemotherapy. Of these, 68 patients had tumors with negative or low ASS1 expression by immunohistochemistry including 24 who were randomly assigned to BSC and 44 assigned to BSC plus weekly intramuscular injections of ADI-PEG 20 36.8 mg/m². Median follow-up was 25.3 months.

No complete or partial responses were seen on computed tomography scan, but 58% of patients had stable disease at 6 months with ADI-PEG 20 versus none given BSC alone, Dr. Szlosarek said.

Among 39 patients with ASS1-low mesothelioma, 46% had a partial response and 31% had stable disease on positron emission tomography/CT.

A post hoc analysis suggested a much greater benefit with ADI-PEG 20 in patients with an ASS1 loss of more than 75% (HR, 0.27), compared with those with an ASS1 loss of 50-75% (HR, 0.60).

The data support use of a cutoff of at least 50% ASS1 activity to select patients with mesothelioma for ADI-PEG 20 therapy, he said. Notably, this is lower than the cut point of at least 95% ASS1-negative cells used in previous trials in melanoma and small-cell lung cancer.

"Some patients with ASS1 low 50%-75% tumors still benefitted from the drug since the hazard ratio of 0.60 was met and was the target HR for the study," Dr. Szlosarek explained in an interview. "Indeed, the remaining nonprogressing patient, for 18 months so far, was in the 50%-75% group."

Invited discussant Dr. Lee M. Krug, a thoracic oncologist at Memorial Sloan-Kettering Cancer Center, New York, commended the investigators for using "a completely novel strategy in this disease," but said it was unclear whether the 1.3-month gain in progression-free survival was clinically meaningful. It might be interesting to consider combinations with chemotherapy and better selection of patients with the more stringent (ASS1 75%-100%) biomarker, Dr. Krug said.

He described this as an exciting time in mesothelioma, with new insights into the genomics of the disease and more randomized trials than ever before, including a pilot study showing dramatic responses in several patients with the immunoconjugate SS1P in combination with pentostatin and cyclophosphamide.

ADI-PEG 20 monotherapy trials are currently under discussion for patients with ASS1 75%-100% tumors. To improve disease control in the ASS1 low 50%-75% tumors, the investigators plan to move forward with the TRAP (Tumors Requiring Arginine to Assess ADI-PEG 20 with Pemetrexed and Cisplatin) trial due to open in July in the United Kingdom, Dr. Szlosarek said.

Further study is also needed to tackle drug resistance, a known challenge with arginine depletors, he added.

"Several of the patients who had early partial metabolic responses at 3 weeks by PET imaging progressed very quickly at 8 weeks by CT (modified RECIST) criteria, indicating onset of early resistance," Dr. Szlosarek said in the interview. "We are currently exploring a novel mechanism of resistance and will submit a paper later this year addressing this question."

The most common grade 3/4 adverse events with ADI-PEG 20 were neutropenia (11%), fatigue (7%), anaphylactoid/anaphylaxis (7%), rash (2%), and serum sickness (2%).

ADAM was funded by Cancer Research UK. Polaris Pharmaceuticals provided the study drug. Dr. Szlosarek disclosed ties with Roche and BMS. A coauthor reported ties with Polaris Group.

[email protected]