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

Abstract

4515 Background: Epacadostat (E) is a potent oral inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression. Preclinical and clinical data suggest that epacadostat has antitumor activity when combined with checkpoint inhibitors, including the PD-1 inhibitor pembrolizumab (P). ECHO-202/KEYNOTE-037 is an ongoing open-label, phase 1/2 (P1/2) study evaluating E + P in multiple tumor types. We report preliminary P1/2 efficacy and safety data for the advanced renal cell carcinoma (RCC) cohort as of a 29OCT2016 data cutoff. Methods: Eligible patients (pts) had advanced clear-cell RCC, prior antiangiogenic therapy (tx), and no prior checkpoint inhibitor tx. 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. Safety/tolerability was assessed in pts receiving ≥1 E + P dose. Results: 33 pts (P1, n = 11; P2, n = 22) were enrolled (median age, 63 years; 70% men; 97% white; MSKCC criteria of favorable, intermediate, and poor in 6%, 64%, and 12% of pts, respectively). Of 30 efficacy-evaluable pts, 63% (n = 19) had 0–1 prior tx and 37% (n = 11) had ≥2 prior tx for advanced disease. ORR (CR+PR) and DCR (CR+PR+SD) for pts with 0–1 prior tx was 47% (9/19; 1 CR, 8 PR) and 58% (11/19; 1 CR, 8 PR, 2 SD), respectively; for pts with ≥2 prior tx, ORR and DCR were 0% and 36% (4/11; all SD). At data cutoff, 9/9 responses were ongoing (range, 1+ to 372+ days). PFS and biomarker analyses are ongoing. TRAEs occurring in ≥10% of the 33 pts included fatigue and rash (36% each); and arthralgia, diarrhea, pruritus, and pyrexia (12% each). Grade ≥3 TRAEs occurred in 15% of pts (none in > 1 pt). Two pts discontinued due to TRAEs (grade 3 autoimmune hepatitis, n = 1; grade 3 aseptic meningitis/headache/nausea/vomiting/anxiety, n = 1). Conclusions: E + P was generally well tolerated and associated with encouraging response outcomes in advanced RCC pts with 0–1 prior line of tx. E + P represents a novel immunotherapeutic strategy. A phase 3 RCC study is planned. Clinical trial information: NCT02178722.

High IDO‐1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma

“…For example, the phase 1/2 ECHO‐202/KEYNOTE‐037 study evaluates the efficacy, tolerability and safety of combining the IDO inhibitor epacadostat plus pembrolizumab in patients with various tumor entities such as advanced RCC, urothelial carcinoma, triple‐negative breast and ovarian cancer, head and neck tumors and non‐small cell lung cancer (NCT02178722). Regarding advanced RCC, preliminary results demonstrated an ORR in patients with 0‐1 prior lines of treatment of 47% (CR in 5%) and a disease control rate (DCR) of 58%, confirming responses regardless of PD‐L1 expression …”

Phase I Study of the Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitor Navoximod (GDC-0919) Administered with PD-L1 Inhibitor (Atezolizumab) in Advanced Solid Tumors

“…In the clinic, IDO1 inhibition alone has little anticancer effect in a majority of patients (6,7). However, early-phase studies demonstrating encouraging response rates and durability of responses suggested that the addition of IDO1 inhibitors to programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibition may enhance the efficacy of checkpoint blockade alone (8)(9)(10)(11).…”

Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma

“…• Epacodostat/pembrolizumab, solid tumors including RCC • Phase 1/2 (ECHO-202/KEYNOTE-037/NCT02178722) [99] • ORR in 19 RCC pts with 0-1 prior tx: 47% (1 CR, 8 PR)…”

“…Ongoing trials are also combining checkpoint inhibitors with novel/ investigational immunotherapies. These include: NKTR 214 (pegylated IL-2), an agonist of CD-122 that stimulates CD-8+ and NK cells [96]; pegilodecakin, a pegylated human IL-10, as IL-10 receptors are expressed on activated CD8+ cells [97]; CPI-444, an oral adenosine A2a receptor antagonist [98]; and epacadostat, an inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophan-catabolizing enzyme that induces immune tolerance by T-cell suppression [99]. Preliminary results from a phase 1/2 study for epacadostat combined with pembrolizumab in advanced RCC reported an ORR of 47% [99]; however, a recent phase 3 trial of this combination in patients with melanoma failed to meet its primary endpoint of improved PFS relative to pembrolizumab monotherapy [100].…”