Early results favorable for combo TLR9 agonist + pembro in advanced melanoma

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.