Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study

Abstract

Background: Advanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial.

Methods: KEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019.

Results: Between December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%-49%) for pembrolizumab plus epacadostat, 21% (6%-46%) for pembrolizumab monotherapy, and 34% (19%-52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3-4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects.

Conclusions: Pembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC.

Trial registration: NCT03358472. Date of trial registration: November 30, 2017.

Keywords: Cetuximab; EXTREME; Head and neck squamous cell carcinoma; Immunotherapy; PD-1; Pembrolizumab.

Fig. 1

Patient disposition. ^a1 patient was randomly assigned to the pembrolizumab plus epacadostat arm on May 2, 2018, but did not receive treatment because the strategic decision was made to stop patient enrollment on the same day. ^b1 patient was randomly assigned to the EXTREME arm but did not receive EXTREME treatment because the patient withdrew consent to participate in the trial

Fig. 2

Circulating kynurenine levels^a,b in patients receiving pembrolizumab + epacadostat, pembrolizumab monotherapy, or EXTREME. Kynurenine levels at cycle 1, day 1, and cycle 2, day 1, were compared using a paired Student’s t test within each treatment arm. ns not significant. ^aBlood samples were drawn before administration of any study drug on day 1 of cycle 1 and day 1 of cycle 2. ^bDotted line at 1.5 µM represents the median circulating kynurenine level in healthy subjects [12]