Epacadostat plus pembrolizumab in patients with SCCHN: Preliminary phase I/II results from ECHO-202/KEYNOTE-037.

Abstract

6010 Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. IDO1 overexpression has been associated with poor survival in SCCHN. Epacadostat (E) is a potent, selective oral IDO1 inhibitor. ECHO-202/KEYNOTE-037 is an open-label, phase I/II (P1/2) study evaluating E plus PD-1 inhibitor pembrolizumab (P) in multiple tumor types. We report preliminary P1/2 efficacy, safety, and tolerability findings in the SCCHN cohort as of a 29OCT2016 data cutoff. Methods: Eligible adult patients (pts) had metastatic SCCHN and received ≥1 prior chemotherapy regimen that included a platinum agent. Prior checkpoint inhibitor therapy (tx) was not permitted, and pts with carcinoma of the nasopharynx or salivary gland were excluded. In P1 dose escalation (3+3+3), pts received E (25, 50, 100, or 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) dosing was selected for P2 cohort expansion. Response was assessed in RECIST 1.1 evaluable pts. Results: A total of38 pts (P1, n = 2; P2, n = 36) were evaluated. Median age was 63 years, 87% of pts were men, 95% were white, and 66% received prior cetuximab. Of 36 efficacy-evaluable pts, 81% (n = 29) received 1–2 prior lines of tx and 19% (n = 7) received ≥3 prior lines of tx. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 1–2 prior tx were 34% (2 CR, 8 PR) and 62% (8 SD), respectively; for pts with ≥3 prior tx, ORR and DCR were 14% (1 PR) and 43% (2 SD). Response was observed regardless of HPV status. At data cutoff, 9/11 responses were ongoing (range, 1+ to 563+ days). PFS and biomarker analyses are ongoing. The most common TRAEs in all 38 pts were fatigue (24%), nausea (11%), and decreased weight (11%). Grade ≥3 TRAEs occurred in 11% of pts; only increased amylase and lipase (both asymptomatic) were grade ≥3 TRAEs that occurred in > 1 pt. TRAEs led to discontinuation in 1 pt (increased amylase and lipase). Conclusions: In pts with advanced SCCHN, E + P was generally well tolerated and associated with encouraging response rates, particularly in pts with 1–2 prior lines of tx. A phase III SCCHN study is planned. Clinical trial information: NCT02178722.

Updates in the Clinical Development of Epacadostat and Other Indoleamine 2,3-Dioxygenase 1 Inhibitors (IDO1) for Human Cancers

“…The efficacy data of other cohorts and AEs are described in Table 1 . The response in different types of cancers, ranged from 33 to 58% and they were higher than historical single agent P studies (16 to 33%) (Table 1 ) ( 37 – 40 ). Safety analysis in 244 patients in the ECHO 202 study is also detailed in Table 1 .…”

Durable intracranial and extracranial response to nivolumab with appearance of secondary resistance in a heavily pretreated patient with head and neck cancer

“…The upregulation of IDO1 is also of importance as this enzyme is expressed in the TME, promoting T effector cell inhibition. Indeed, early clinical trials combining PD‐1 blockade with IDO inhibitors in SCCHN have shown to increase response rates compared to PD‐1 inhibition alone …”

“…Indeed, early clinical trials combining PD-1 blockade with IDO inhibitors in SCCHN have shown to increase response rates compared to PD-1 inhibition alone. 22…”

The evolving immunotherapeutic landscape in advanced oesophagogastric cancer

“… 102 IDO inhibition synergises with ICPIs in preclinical models in their activation of intratumoural CD8+ T cells. 68 Based on the provisional positive results of trials combining nivolumab with the IDO inhibitor epacadostat 103 and pembrolizumab, 104 a further phase I/II study is currently assessing the safety and preliminary efficacy of epacadostat in combination with durvalumab in subjects with selected advanced solid tumours, including gastric cancer [ClinicalTrials.gov identifier: NCT02318277]. Preclinically, A2AR inhibition synergises with ICPIs 105 and recruiting early phase trials in advanced solid tumours include the combination of durvalumab with the A2AR antagonist AZD4635 [ClinicalTrials.gov identifier: NCT02740985].…”