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
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".