Abstract CT001: Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial
Bibliographic record
Abstract
Abstract Background: The checkpoint inhibitors ipilimumab and nivolumab are approved by FDA as adjuvant therapy for patients with resected high-risk stage III melanoma. We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients with resected high-risk stage III melanoma. Methods: Eligible patients included those ≥18 years of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as stage IIIA (excluding lymph node metastasis ≤1 mm), IIIB or IIIC (excluding those with in-transit metastasis). A total of 1019 patients were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. In the absence of brain metastases, patients with recurrence were eligible for cross-over or re-challenge (those who received pembrolizumab and recurred more than 6 months after completing 1 year of therapy). The 2 co-primary endpoints were recurrence-free survival (RFS) in the intention-to-treat overall population and in patients with PD-L1-positive tumors. A total of 409 RFS events were needed to provide 92% power to detect a hazard ratio (HR) for recurrence or death of 0.70 (1-sided alpha=1.4%). The interim analysis was performed at 1-sided alpha=0.8% (O'Brien-Fleming alpha error spending function) in the overall patient population, and at 2.5% in the PD-L1 positive population. Results: Overall, 15%/46.5%/37.5% of patients had stage IIIA/IIIB/IIIC. At 1.25 yr median follow-up, pembrolizumab (135 events) compared with placebo (216 events) significantly prolonged RFS in the overall population (12-month RFS rate: 75.4% vs 61.0%; HR 0.57, 98.4% CI 0.43-0.74; P<0.0001). Same was true in those with a PD-L1-positive tumor (N=852; HR 0.54, 95% CI 0.42-0.69; P<0.0001) or a PD-L1-negative tumor (N=116; HR 0.47, 95% CI 0.47 (0.26, 0.85); P=0.01). RFS was consistently prolonged across subgroups. Drug-related grade 3 to 5 adverse events were reported in 14.7% (N=75) in the pembrolizumab group and 3.4% (N=17) in the placebo group. There was only one pembrolizumab-related death due to myositis. The highest incidence of immune-related adverse events (irAEs), mostly grade 1 to 2, observed in the pembrolizumab vs placebo group were endocrine disorders (23.4% versus 5.0%) [hypothyroidism (14.3% vs 2.8%), hyperthyroidism (10.4% vs 1.2%), thyroiditis (3.1%) vs 0.2%)]. The incidence of grade 3-4 irAEs was 7.1% vs 0.6%: colitis (2.0% vs 0.2%), pneumonitis (0.8% vs 0%), hepatitis (1.4% vs 0.2%), all others had incidences < 1%. Conclusions: As adjuvant therapy for resected high-risk stage III melanoma pembrolizumab 200 mg every 3 weeks, for up to 1 year, resulted in significantly prolonged RFS with a favorable benefit-risk profile. Citation Format: Alexander M. Eggermont, Christian U. Blank, Mario Mandala, Georgina V. Long, Victoria Atkinson, Stéphane Dalle, Andrew Haydon, Mikhail Lichinitser, Adnan Khattak, Matteo S. Carlino, Shahneen Sandhu, James Larkin, Susana Puig, Paolo A. Ascierto, Piotr Rutkowski, Dirk Schadendorf, Rutger Koornstra, Leonel Hernandez-Aya, Michele Maio, Alfonsus J. van den Eertwegh, Jean-Jacques Grob, Ralf Gutzmer, Rahima Jamal, Veronica Rivas, Nageatte Ibrahim, Sandrine Marreaud, Sven Janssen, Alexander van Akkooi, Stefan Suciu, Caroline Robert. Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: Efficacy and safety results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT001.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| 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) | 0.009 | 0.002 |
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".