Two investigational immunotherapies show promise in advanced melanoma

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

[email protected]

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

[email protected]

SAN DIEGO – DEDN6526A, a new anti–endothelin B receptor antibody-drug conjugate, demonstrated safety, tolerability, and hints of clinical efficacy against different types of metastatic or unresectable melanoma, results from a phase I trial showed.

During a press briefing at the annual meeting of the American Association for Cancer Research, Dr. Jeffrey R. Infante said that anti–endothelin B receptor (ETBR), a G-protein–coupled receptor that can activate RAF/MEK signaling, is overexpressed in metastatic melanoma, compared with normal skin. Developed by Genentech using Seattle Genetics antibody-drug conjugate (ADC) technology, DEDN6526A is an ADC with the anti-mitotic agent monomethyl auristatin E (MMAE) linked to the humanized IgG1 anti-ETBR antibody and represents a targeted chemotherapy to melanoma. ETBR "regulates migration and proliferation of melanocyte precursors from the neural crest during embryonic development," explained Dr. Infante, director of the drug development program at Sarah Cannon Research Institute in Nashville, Tenn. "It is associated with malignant transformation of melanocytes and with potentiation of metastatic spread."

©2014 AACR/Todd Buchanan

A prototype ETBR assay is being developed as a potential comparison diagnostic in melanoma. The assay is used on formalin-fixed, paraffin-embedded melanoma.

In an effort to determine the maximum tolerated dose of DEDN6526A, 28 patients with metastatic or unresectable cutaneous, mucosal, or ocular melanoma received the intravenous agent every 3 weeks. The researchers collected pharmacokinetic samples and assessed tumor tissue for ETBR expression by immunohistochemistry. Clinical activity was evaluated per RECIST v1.1. (Response Evaluation Criteria in Solid Tumors version 1.1).

Dr. Infante reported that more than half of study participants had more than three prior therapies and 70% had two or more prior therapies. Eight of the patients had ocular melanoma and three of them had mucosal melanoma. Dose escalation started at 0.3 mg/kg and patients received a median of six doses of the agent. The maximum tolerated dose was determined to be 2.4 mg/kg, which is currently being tested in the expansion phase of the trial.

The most common adverse event of any grade was fatigue (57%), followed by chills (39%), alopecia (32%), diarrhea (32%), nausea (29%), decreased appetite (25%), headache (25%), and infusion-related reaction (25%). Neutropenia was the most frequent grade 3 or 4 event. "It often did not require a dose reduction, so it was manageable," Dr. Infante said.

Complete radiographic data were available on 24 patients. Among these, clinical benefit was observed in 12 of the 19 patients who were assigned to a dosing regimen of 1.8 g/kg of DEDN6526A or more. Four of the 12 patients achieved complete response (two were cases of cutaneous melanoma and two were cases of mucosal melanoma). "It did not seem to depend on whether they had a BRAF mutation or had prior treatment with ipilimumab," Dr. Infante said. The other eight patients had stable disease for at least 6 months. "If you can stay on drug for 6 months, that’s probably meaningful benefit in an early phase I trial," he commented.

Dr. Thomas Lynch, director of the Yale Cancer Center and physician-in-chief of Smilow Cancer Hospital at Yale University, New Haven, Conn., who moderated the press briefing, noted that while antibody-drug conjugates such as DEDN6526A "look very promising," the biomarker used in the trial is not fully developed yet. "It may well be that with a mature biomarker, it turns out to have good predictive value," he said.

In an unrelated presentation at the meeting, Dr. Mark Middleton presented findings from a phase I trial of IMCgp100, an investigational agent being developed by Immunocore that is comprised of an affinity-enhanced T-cell receptor specific for the HLA-A2 restricted melanoma gp100 peptide fused to an anti-CD3 antibody fragment. "What’s important about this method of targeting is that it’s very different from a lot of immunotherapies that have been reported," said Dr. Middleton, the study’s principal investigator who is professor of experimental cancer medicine at the University of Oxford (England). "Rather than targeting cell surface proteins, this is targeting the peptide HLA complex, and therefore brings in intracellular protein targets. The premise is that high affinity binding of the T-cell receptor portions of the cancer cell then leads to recruitment of T cells, formation of an immune synapse, and the release of lytic granules leading to apoptotic cell death of the cancer cell."

He and his associates conducted a phase I dose-escalation study using a standard 3+3 cohort design in melanoma patients who had disease in a variety of sites, including the lung, liver, lymphatic system, and various soft tissues. All patients received a single, 5 ng/kg dose of IMCgp100 followed by 30 days of observation. After this 30-day observation period patients could go on to have six weekly infusions followed by 4 weeks of rest if they continued to derive clinical benefit. "On establishment of the maximum tolerated dose, we specified that we would conduct an expansion cohort to explore pharmacodynamics, clinical efficacy, and safety in more detail," Dr. Middleton said, noting that a total of eight cohorts were studied. Patients had to have stage 4 or unresectable stage 3 melanoma, had to be HLA-A2 positive and have an Eastern Cooperative Oncology Group Performance Status of 0 or 1.

The researchers administered IMCgp100 as a 4-hour infusion followed by 48 hours of in-patient observation. Over that 48-hour period they conducted extensive safety evaluations and pharmacokinetic and pharmacodynamic analysis, including detailed audiometric and ophthalmic review. "Because we started with such a low dose we said that we would triple the dose in the absence of toxicity, moving to smaller increments according to safety and pharmacokinetic profile," he said.

Dose-limiting toxicities were defined as drug-related toxicities that occurred within 8 days of drug administration. Anything grade 3 or higher would be deemed as a dose-limiting toxicity.

Among the 40 patients in the trial, the mean age was 59 years and 23 were male. The researchers started to see toxicity at a dose of 45 ng/kg, "which would manifest as a rash that would endure for a few hours, perhaps into the next day," Dr. Middleton said. "At a dose of 135 ng/kg this became more widespread, albeit transient, and we therefore slowed the rate of increase between cohorts." One patient in the 405 ng/kg cohort and two patients in the 900 ng/kg cohort developed grade 3 hypotension 10-12 hours after drug administration. This in part led the researchers to declare a nontolerated dose of 900 ng/kg and a maximum tolerated dose of 600 ng/kg.

Among the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg, the most common adverse event was an itchy rash, "which is often widespread, and associated with edema, which can be periorbital and more widespread," Dr. Middleton said. "This is transient; it usually settles down within 48-72 hours and is not as severe with subsequent administration of the drug." One case of hypotension occurred. The patient recovered after intensive supportive care. Evaluation of pharmacokinetics showed evidence of lymphocyte trafficking, neutrophilia, and a rise in C-reactive protein.

Efficacy results from 10 of the first 15 patients to be treated with the maximum tolerated dose of 600 ng/kg showed evidence of "significant and durable clinical responses, particularly in two patients who were treated in the dose escalation phase," he said. Those two patients met the RECIST criteria for response.

Dr. Middleton and his associates are continuing study expansion at the current dose level, with mandated tumor biopsies before treatment, and testing a weekly dosing arm. The goal is to identify the optimal dosing regimen for IMCgp100. The trial is expected to be complete in 2015.

The study was funded by Immunocore. Dr. Middleton disclosed that he is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, Eisai, GSK, Millenium, and Roche.

The study of DEDN6526A was funded by Genentech. Dr. Infante said that he had no relevant financial conflicts to disclose.

Dr. Lynch disclosed that he is on the board of directors for Bristol Myers Squibb and Infinity Pharmaceuticals, and that he receives honoraria and stock from both companies. He is also on the scientific advisory board for Arvinas, and he receives honoraria and stock from that company. In addition, Dr. Lynch is a patent holder with Partners Healthcare for an EGFR mutation–testing patent and receives royalties.

[email protected]