IDO1, PD-L1 inhibition safe for advanced tumours
A dual-inhibition immunotherapeutic regimen consisting of the highly selective IDO1* inhibitor epacadostat and the PD-L1** inhibitor durvalumab was safe for advanced solid tumours, according to findings from the ongoing ECHO-203*** study presented at AACR 2018.
“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,” said Dr Aung Naing from the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, Texas, US.
Naing and colleagues evaluated 34 patients (median age 68 years, 62 percent male, 82 percent with ECOG PS# of 1) with advanced pancreatic cancer, melanoma, non-small-cell lung cancer (NSCLC), or squamous cell carcinoma of the head and neck (SCCHN). Among those with pancreatic cancer, 67 percent had liver metastases, 87 percent had an ECOG PS of 1, and 14 had previously received at least one therapy. Epacadostat was administered twice daily with a starting dose of 25 mg escalating up to 300 mg, while durvalumab 3 or 10 mg/kg was given Q2W. Safety data were obtained from participants who received at least one treatment dose. [AACR 2018, abstract CT177]
One dose-limiting toxicity with epacadostat 300 mg (grade 3 rash which required systemic steroids) was observed during the 42-day observation period.
The most common treatment-related adverse event (TRAEs) was fatigue (32 percent), followed by pruritus (15 percent), diarrhoea, nausea, and rash (12 percent each). Fifteen percent discontinued treatment because of TRAEs (ie, grade 1 pneumonitis; grade 2 diarrhoea, subarachnoid haemorrhage, and peripheral oedema; and grade 3 dyspnoea). No TRAEs led to death.
No response in pancreatic cancer
In the subgroup comprising patients with pancreatic cancer (n=15), disease control rate was 27 percent (median duration, 156 days, 95 percent confidence interval, 91–219) and no objective response was observed.
“[A]s pancreatic cancer is not generally responsive to immunotherapy, these results were not a complete surprise,” said Naing. “[The] 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.”
Considering the immunosuppressive tumour microenvironment in pancreatic cancer which generally excludes T cells, combination therapies that boost the immune response might be necessary for the immunotherapy regimen to be effective, noted Naing.
Essential combo regimen component
Despite the proven benefit of immune checkpoint inhibitors in cancer treatment, new immunotherapeutic combination treatments are warranted to establish alternatives that demonstrate improved efficacy and reduced toxicity, said Naing.
The efficacy of epacadostat 100 and 300 mg combined with durvalumab 10 mg/kg in patients with NSCLC, SCCHN, and urothelial carcinoma is being investigated in the ongoing phase 2 expansion, noted Naing. “Since these tumour types have demonstrated efficacy with checkpoint inhibition monotherapy, they were considered more likely to potentially benefit from combination immunotherapy.”
In line with the ECHO programme’s objective of establishing epacadostat as a core component of combination therapy in a broad range of solid tumours and haematological malignancies, other ongoing trials are investigating the potential of epacadostat in combination with PD-1## and other PD-L1 inhibitors (ie, pembrolizumab and nivolumab), added Naing.