TLR9 Agonist CMP-001-Pembrolizumab Combination Shows Early Efficacy in Patients With Metastatic Melanoma Resistant to Anti-PD-1

CHICAGO—A combination of CMP-001, an intratumoral Toll-like receptor 9 (TLR9) agonist, and pembrolizumab (Keytruda), tested in patients withmetastatic melanoma resistant to PD-1 checkpoint inhibition, was well tolerated and had clinical activity according to preliminary data presented from the ongoing phase Ib clinical trial at the AACR Annual Meeting 2018, April 14-18, in Chicago.

“Checkpoint inhibition is quickly becoming a key tool for oncologists to treat cancer,”said Mohammed Milhem, MBBS, clinical professor of internal medicineat the University of Iowa, Iowa City. “However, there are many patients that either initially respond to checkpoint inhibition and then progress, or never respond to this therapy to begin with. Finding safe and effective therapies for these patients is critical.

”While pembrolizumab is the standard of care for patients with metastatic melanoma, over 50 percent of these patients develop resistance, explained Milhem. In an attempt to address this, Milhem and colleagues combined the TLR9 agonist CMP-001 with checkpoint inhibition.

Previous work has shown that tumors with an increase in interferon (IFN) gene expression are more responsive to PD-1 inhibition, explained Milhem. “The strongest known inducer of IFN production is the TLR9 pathway, so we thought that adding a TLR9 activator to anti-PD-1therapy would elicit a response in patients who stopped or never responded to PD-1 inhibition,” he noted.

In this phase Ib clinical trial, Milhem and colleagues enrolled patients with advanced melanoma who had either not responded to or had progressed during prior anti-PD-1 therapy. As of March 27, 2018, 85 patients have been treated in the trial; 44 patients were enrolled in the dose escalation phase, while 41 patients have been enrolled in the ongoing dose expansion phase.

Throughout the completed dose escalation phase, patients received CMP-001 via direct intratumoral injection at doses ranging from 1to 10mg in combination with pembrolizumab. There were two treatment schedules for the administration of CMP-001: one injection per week for seven weeks followed by every three weeks until discontinuation (weekly treatment); or one injection per week for two weeks followed by every three weeks until discontinuation (q3w treatment). During the dose escalation phase, one dose-limiting toxicity occurred; no maximum tolerated dose (MTD) was identified.

Target lesions (both injected and not injected with CMP-001) were assessed via RECIST v1.1. “To date, across both the dose escalation and expansion cohorts,15 patients have responded,”Milhem said. The objective response rate(ORR) is 22 percent. The ORR is 23 percent and 15 percent for patients on weekly and q3w treatment, respectively.

Among the 15 patients who had responded, 11 remain on study; three of these patients have maintained their response beyond one year. Three additional patients that continued study therapy beyond their initial progression had responded according to iRECIST criteria, Milhem said. The median duration of response has not been reached.

Notably, Milhem and colleagues saw a reduction in non-injected tumors in cutaneous, nodal, hepatic, and splenic metastases.“The abscopal effect observed in these patients is a hallmark of successful intratumoral immunotherapy treatment,” noted Milhem.

“Based on these preliminary findings, the combination of CMP-001 and pembrolizumab appears to have a manageable safety profile and meaningful clinical activity,” said Milhem. “Additional larger studies in this patient population will need to be conducted to further evaluate the clinical benefit, but if the current results are confirmed, it appears that this combination could offer a new treatment option for patients with advanced melanoma who are not responsive to pembrolizumab.

”This study is sponsored and managed by Checkmate Pharmaceuticals. Milhem declares no conflict of interest.

ABSRACT CT144:

M. Milhem, et al. Intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ibtrial in subjects with advanced melanoma

Background: CMP-001 comprises a CpG-A oligodeoxynucleotide packaged within a virus-like particle. It is designed to activate tumor-associated plasmacytoid dendritic cells via TLR9 inducing an interferon-rich tumor microenvironment and anti-tumor CD8+T cell responses.

Materials and Methods: CMP-001-001 is an ongoing phase Ib trial evaluating intratumoral (IT) CMP-001 in combination with pembrolizumab (administered per label) in subjects with advanced melanoma resistant (either did not respond or progressed) on prior anti-PD-1 monotherapy or in combination. During dose escalation, subjects were enrolled to cohorts of ≥ 3 subjects at CMP-001 doses of 1, 3, 5, 7.5, and 10 mg in two dosing schedules (weekly for 7w, followed by q3w; or weekly for 2w, followed by q3w). CMP-001 was administered IT into an accessible lesion(s), and response assessed in all target lesions (injected and non-injected) by RECIST v1.1. Study therapy was continued until progression, toxicity, investigator decision or withdrawal of consent. Baseline and on-therapy serum was collectedfor cytokine analysis. Immunohistochemical and RNA-Seq analysis was performed on available pre-and post-treatment tumor biopsies. 

Results: As of December 31, 2017, 68 subjects have been treated (44 in Escalation and 24 in Expansion). Safety data from 63 subjects demonstrated a manageable acute toxicity profile consisting predominately of fever, N/V, headache, hypotension and rigors. Grade 3/4 related AEs reported in ≥1 subject; hypotension (n=7), anemia (n=2), chills (n=2), hypertension (n=2) and fever (n=2). The Objective Response Rates (ORR) across all dose cohorts on weekly (n=40) and q3week schedules (n=13) were 22.5% (9/40; 95 % CI 11-39%) and 7.7%% (1/13; 95% CI 0-36%) respectively. For subjects dosed weekly at 3 and 5 mg, the ORR was 33.3% (6/18 95% CI 13-59%). Of the 10 responders, 1 progressed (w36), 2 withdrew consent (w13, w25), 7 remain on study with 2 subjects maintaining their response though w72. Regression of non-injected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases. CMP-001 induced TLR9 activation with a median 5.9 fold increase in serum CXCL10 (range of 0.9 -276.3; mean fold increase of 21.8 with SD=48.8; n=39). Immunohistochemical and RNA-Seq analysis of tumor biopsies revealed increases in tumor-infiltrating CD8 T cells (>5 fold), PD-L1 expression (>3 fold increase in H score), and transcriptional signature of inflammation in 2/4 subjects with analyzable pre-and post-treatment samples.

Conclusions: CMP-001 in combination with pembrolizumab resulted in objective, durable tumor responses with tolerable toxicities in subjects with advanced melanoma resistant to prior anti-PD-1 therapy. CMP-001 dosing at 5 mg/weekly has been selected for further evaluation in the ongoing dose expansion phase of this study.

Dual Inhibition of IDO1and PD-L1 Safe in Patients With Advanced Solid Tumors

CHICAGO—An immunotherapy treatment combining the IDO1 inhibitor epacadostat and the PD-L1 inhibitor durvalumab was found to be safe in patients with advanced solid tumors, with safety data similar to treatment with durvalumab alone, according to data presented from the ongoing ECHO-203 clinical trial at the AACR Annual Meeting 2018, April 14-18, in Chicago.

“Immune checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, have provided meaningful clinical benefits for patients with cancer; however, novel immunotherapy combination treatments are needed to improve efficacy with limited additive toxicity,” said Aung Naing, MD, FACP, associate professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston. “This is the first report of IDO1 inhibition in combination with PD-L1 antagonism, and we found that epacadostat plus durvalumab was generally well-tolerated in patients with advanced cancers, with a safety profile consistent with previous reports of durvalumab monotherapy.

”Prior preclinical work suggested that dual inhibition of both IDO1 and the PD-1/PD-L1 axis was more efficacious than targeting either component alone, noted Naing. “These studies laid the foundation for the human trials of agents that target the PD-1/PD-L1 pathway and IDO1,” he explained.

“ECHO-203 is part of the broader ECHO clinical development program investigating efficacy and safety of epacadostat as a core component of combination therapy in a broad range of solid tumor types as well as hematological malignancies,”said Naing. “Ongoing clinical studies are evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors including pembrolizumab, nivolumab, and durvalumab.

”Naing and colleagues tested the combinatorial treatment in 34 patients with advanced pancreatic cancer, melanoma, non-small cell lung cancer (NSCLC), or squamous cell carcinoma of the head and neck (SCCHN). Exclusion criteria included prior checkpoint inhibition therapy for any unapproved indications.

Patients received doses of epacadostat ranging from 25 to 300mg twice daily in combination with 3 or 10mg/kg of durvalumab every two weeks. Safety data were compiled from patients who received at least one treatment dose. One dose-limiting toxicity (DLT) was observed.

Common adverse events (AEs) included fatigue (32 percent), pruritus (severe itching; 15 percent), diarrhea, nausea, and rash (12 percent each); five patients discontinued treatment due to AEs.

As of Oct. 29, 2017, efficacy data for 15 patients with advanced pancreatic cancer treated at various dose levels revealed no responses. Four patients had stable disease, resulting in a disease control rate of 27 percent; one patient discontinued treatment following clinical progression.

“Because pancreatic cancer has an immunosuppressive tumor microenvironment that generally excludes T cells, combinatorial therapies that enhance the immune response will be needed for an effective immunotherapeutic regimen,” explained Naing.

“However, as pancreatic cancer is not generally responsive to immunotherapy, these results were not a complete surprise,” he noted. “We found that epacadostat drug levels were slightly lower in pancreatic cancer patients who had prior pancreatic and duodenal surgeries, which are commonly performed in this patient population.”

Phase II expansions, with epacadostat doses of 100 and 300mg in combination with 10mg/kg of durvalumab, are currently being evaluated in patients with NSCLC, SCCHN, and urothelial carcinoma. “Since these tumor types have demonstrated efficacy with checkpoint inhibition monotherapy, they were considered more likely to potentially benefit from combination immunotherapy,” noted Naing.

This trial is sponsored by Incyte Corporation; Incyte and AstraZeneca provided funding for this study.

Naing has received grants and/or research support from the National Cancer Institute, EMD Serono, MedImmune, Healios Oncology Nutrition, Attercor, Amplimmune, ARMO Biosciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, and Bristol-Myers Squibb. He is an advisory board member for CytomXand Novartis, and he has received travel and accommodation expenses from ARMO Biosciences. 

ABSTRACT CT177:

A. Naing, et al. Epacadostat plus durvalumabin patients with advanced solid tumors: preliminary results of the ongoing, open-label, phase I/II ECHO-203 study

Introduction: Epacadostat, a potent and highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, plus durvalumab, an anti-PD-L1 antibody, is being studied in patients with advanced solid tumors (NCT02318277). Phase 1 preliminary safety data for the overall population and efficacy data for patients with advanced pancreatic cancer (PC) are reported as of 29 Oct 2017 data cutoff.

Methods: Adult patients with PC, melanoma, NSCLC, or SCCHN were enrolled in the 3+3 dose-escalation phase 1. Prior treatment with immune checkpoint inhibitors (in unapproved indications) or IDO inhibitors was not allowed. Patients received epacadostat (25, 50, 75, 100, or 300 mg twice daily [BID]) plus durvalumab (3 or 10 mg/kg every 2 weeks [Q2W]). Safety was assessed in patients receiving ≥1 treatment dose. Response was measured in evaluable patients (≥1 postbaseline scan or discontinued/died before the first scan) per modified RECIST v1.1.

Results: Thirty-four patients were enrolled in phase 1. Median age (range) was 68 (46-84) years; most patients were male (62%) and had an ECOG PS of 1 (82%). There was 1 dose-limiting toxicity (grade 3 rash requiring systemic steroids; epacadostat 300 mg BID plus durvalumab 10 mg/kg Q2W) during the 42-day observation period. The most common (≥10%) treatment-related adverse events (TRAEs) were fatigue (32%), pruritus (15%), diarrhea, nausea, and rash (12% each). Grade ≥3 TRAEs occurring in >1 patient included fatigue and rash (n=3 [9%] each). Five patients (15%) discontinued because of TRAEs (grade 1 pneumonitis, grade 2 diarrhea, grade 2 subarachnoid hemorrhage, grade 2 peripheral edema, and grade 3 dyspnea). Therewere no TRAEs leading to death.

Fifteen patients with PC were enrolled across multiple dose levels. Median age (range) was 66 (46-72) years, 67% had liver metastases, and 87% had an ECOG PS of 1. Fourteen patients had received ≥1 prior therapy. PD-L1 expression test results were available in 7/15 patients: 2 had detectable (≥1%) staining of tumor cells; 5 did not. No responses were observed among patients with PC; the disease control rate was 27% (4 SD) per RECIST v1.1 (1 of 4 patients with SD discontinued treatment because of clinical progression). The median duration of disease control was 156 days (95% CI, 91-219). Epacadostat exposure was consistent with previous reports, except in patients with PC where somewhat lower peak exposures (Cmax) were observed.

Conclusions: Epacadostat plus durvalumab was generally well tolerated in patients with advanced cancers; the safety profile was consistent with previous reports of durvalumab and epacadostat as monotherapies. In unselected patients with PC, no objective responses were observed; a phase 2 expansion for PC was not conducted. Epacadostat 100 and 300 mg BID are being evaluated in the ongoing phase 2 expansions, including patients with NSCLC, SCCHN, and urothelial carcinoma.