1. Simoneaux, Richard

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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.

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Recently, at the 2018 AACR Annual Meeting, Naing presented safety results from ECHO-203, which is an ongoing, phase I/II study assessing the safety, tolerability, and efficacy of epacadostat in combination with durvalumab against multiple tumor types.


"Prior preclinical work suggested that dual inhibition of both indoleamine 2,3-dioxygenase (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.


"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."



Epacadostat, which is an IDO1 inhibitor, is thought to exert its effect by diminishing the activity of immunosuppressive regulatory T cells (Treg) by decreasing their proliferation and differentiation. This compound is also thought to enhance the activity of effector T cells (Teff) and natural killer cells by increasing their proliferation and activation and decreasing their depletion by reducing apoptosis. Exposure of dendritic cells to epacadostat also stimulates the proliferation of neighboring Teff as well as the lysis of tumor cells, providing more material for antigen presentation.


"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," noted Naing. "Ongoing clinical studies are evaluating epacadostat in combination with PD-1 and PD-L1 inhibitors, including pembrolizumab, nivolumab, and durvalumab."


Study Methodology

Among the inclusion/exclusion criteria were the following: age of 18 years or more; cytologically or histologically confirmed diagnosis of pancreatic cancer, melanoma, squamous cell carcinoma of the head and neck (SCCHN), or non-small cell lung cancer (NSCLC); failed one or more previous therapy regimen for locally advanced or metastatic disease, or was treatment-intolerant; no prior IDO inhibitor or checkpoint inhibitor therapy (for unapproved indications); life expectancy of more than 12 weeks; an ECOG performance status of 0 or 1; availability of fresh baseline tumor tissue samples; and presence of laboratory samples within standard protocol levels.


The objectives of this study included the following: assess the safety and tolerability of epacadostat in combination with durvalumab, as well as the maximum tolerated dose (MTD) or a pharmacologically active dose (PAD) in patients with selected advanced solid tumors in phase I of the study; asses the efficacy of the combination in patients with pancreatic cancer; and determine the pharmacokinetics of epacadostat plus durvalumab.


The study included a phase I and a phase II portion. The phase I portion consisted of a 3+3 dosing schedule with the following regimens: epacadostat 25 mg BID + durvalumab 3 mg/kg Q2W; epacadostat 25 mg BID + durvalumab 10 mg/kg Q2W; epacadostat 50 mg BID + durvalumab 10 mg/kg Q2W; epacadostat 75 mg BID + durvalumab 10 mg/kg Q2W; epacadostat 100 mg BID + durvalumab 10 mg/kg Q2W; epacadostat 300 mg BID + durvalumab 10 mg/kg Q2W. The tested combination therapy was planned for 12 months, and for patients completing that regimen, there was an optional period of epacadostat monotherapy.


The phase II portion of the study will be an open-label cohort expansion where the MTD or PAD determined in phase I of the study is utilized in treatment of patient cohorts having the following malignancies: melanoma, NSCLC, SCCHN, triple-negative breast cancer, gastric or gastroesophageal junction cancer, or urothelial carcinoma.


In this trial, dose-limiting toxicities were assessed over a 42-day period. "Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse Events v4.0; AEs of particular interest were assessed based on a predefined list of those associated with durvalumab monotherapy," Naing stated. Participants were deemed safety evaluable if they had one or more dose of study treatment as of data cutoff date of Oct. 29, 2017.


In order to assess efficacy, patient responses were measured every 8 weeks for the first year and then every 12 weeks thereafter beginning in week 56 using a modified RECIST v1.1. Patients were efficacy evaluable if they had one or more post-baseline scan, discontinuation, or died as of the data cutoff date.


Samples for assessing pharmacokinetic parameters were collected on cycle 1, day 8 and/or cycle 2, day 1.


ECHO-203 Results

Clinical investigators tested the combination therapy in 34 patients having a variety of malignancies. The breakdown of patients by disease type was as follows: pancreatic cancer-15 (44%); NSCLC-10 (29%); SCCHN-8 (24%); melanoma-1 (3%). In terms of prior treatments, 22 of the patients enrolled (65%) had received two or more previous therapies for advanced or metastatic disease. The median age for participants in this study was 68 years, while the range was from 46 to 84 years.


Frequently encountered AEs included fatigue (32%), pruritus (15%), diarrhea, nausea, and rash (12% each). As a result of treatment-related AEs, five patients had to discontinue treatment and seven patients required dose interruptions. "There was one DLT during the 42-day observation period," Naing stated. "This was a grade 3 rash requiring systemic steroids; at the time the patient was receiving epacadostat 300 mg BID plus durvalumab 10 mg/kg Q2W.


"Importantly, there were no treatment-related adverse events leading to death," Naing added. Consequently, the maximum tolerated dose of epacadostat was not determined in this study.


Five patients were able to receive 12 months of the combination treatment, and of these, all received epacadostat monotherapy and three were still receiving that treatment as of the cutoff date. One patient withdrew after 6 months as a result of physician decision while another did so after 7 months due to an AE. The remaining 29 patients discontinued therapy for a variety of reasons, including disease progression (24), physician decision (2), AEs (2), and death (1).


The malignancy shared by the largest number of participants was pancreatic cancer (n=15). As of the data cutoff date, all of these patients had discontinued their participation in this trial, with 13 being due to disease progression and one each due to death and physician decision. Five pancreatic cancer patients received epacadostat 300 mg BID + durvalumab 10 mg/kg Q2W, while four were dosed at epacadostat 100 mg BID + durvalumab 10 mg/kg Q2W.


No partial or complete responses were noted in the 15 pancreatic cancer patients; however, five did show stable disease (SD), affording a disease control rate (DCR) of 33 percent. For these five patients, the median duration of disease control was 22 weeks (95% CI: 13-31 weeks). Additionally, three of these five patients discontinued therapy because of disease progression. When asked if further details were available for these patients, Naing replied, "Additional details regarding these pancreatic cancer patients that displayed SD will discussed in upcoming presentations."


Generally, the pharmacokinetic parameters obtained in this study were similar to those obtained in previous investigations utilizing epacadostat. The peak exposures (Cmax) for epacadostat at the 100 mg BID and 300 mg BID dosages were 596 +/- 297 nM and 2210 +/- 1310 nM, respectively. Additionally, the area under the curve (AUC) were 3650 +/- 2900 h*nM and 12,200 +/- 7870 h*nM, for the 100 mg BID and 300 mg BID doses, respectively. Similar half-lives were noted for the 100 mg BID and 300 mg BID doses (4.35 h +/- 3.54 h and 5.25 h +/- 3.63 h); these values were also in agreement with historical data.



"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.


"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."


When discussing the phase II portion of ECHO-203, Naing noted, "Phase II expansions are currently evaluating epacadostat at the 100 mg BID and 300 mg BID levels in combination with 10mg/kg of durvalumab 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."


Richard Simoneaux is a contributing writer.