Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC).
Bibliographic record
Abstract
6000 Background: KEYNOTE-048 is a phase 3 study of P or P + chemo (C) vs EXTREME (E) as 1L therapy for R/M HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. We present the protocol-specified final results. Methods: 882 pts with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumor sample for PD-L1 testing were randomized to P 200 mg Q3W for 24 mo (n = 301), P for 24 mo + 6 cycles of C (cisplatin 100 mg/m 2 or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m 2 /d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m 2 loading/250 mg/m 2 QW + 6 cycles of chemo) (n = 300). OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 mo after last pt randomized). Results: P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 mo) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P < .0001; median 13.6 vs 10.4 mo) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 mo and 6.7 vs 4.3 mo, respectively. P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 mo). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 mo. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E. Conclusion: Overall, KEYNOTE-048 showed that compared with E, P+C had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, noninferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC. Clinical trial information: NCT02358031.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".