Pembrolizumab-induced immune related adverse events and survival outcomes in advanced melanoma.
Bibliographic record
Abstract
e21577 Background: Anti-PD-1 checkpoint immunotherapies have distinct toxicity profiles that include immune-related adverse events (irAE). Objective response rates (ORR) appear to be higher in patients who develop irAE, but whether survival is impacted is not clear. Methods: Patients with unresectable stage III or stage IV melanoma treated with pembrolizumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAE that occurred while on pembrolizumab. Primary objective was to compare overall survival (OS) with patients who developed any irAE versus those who did not. Secondary outcomes included ORR and progression free survival (PFS). Results: Among 144 patients, any grade and grade ≥ 3 irAE occurred in 38% and 14% of patients, respectively; one patient died of pneumonitis. Patients who developed any irAE were more likely to have better performance status (P = .011), normal lactate dehydrogenase (LDH) levels (P = .037), and receive more cycles (median 11 v 4, P < .001). ORR was 35% and higher in patients who developed any irAE, 67% v 16% (P < .001). Development of any irAE was also associated with longer median PFS, 24.6 v 2.5 months (P < .001), and OS, 39.6 v 4.6 months (hazard ratio [HR], 0.19, P < .001). A landmark analysis excluding patients who died within 12 weeks still demonstrated a median OS of 39.6 v 10.2 months (HR, 0.23, P < .001) for any irAE and no irAE, respectively. In multivariate analysis, elevated LDH (HR, 2.15, P = .003), each additional cycle received (HR, 0.89, P < .001) and the development of any irAE (HR, 0.24, P < .001) were significantly associated with longer OS. Conclusions: Pembrolizumab-associated irAE in advanced melanoma patients is associated with better patient outcomes, including survival. Table 1. Subgroup median OS Characteristic mOS Months (95% CI) HR (95% CI) P LDH Normal 21.6 (10.6 - 32.5) 2.90 (1.86 - 4.52) < .001 Elevated 4.4 (1.2 - 7.7) M stage 0/1a Not reached 1 .007 1b 16.1 (6.2 - 25.9) 2.54 (1.10 - 5.83) 1c 12.2 (2.6 - 21.9) 3.26 (1.46 - 7.29) 1d 6.4 (3.0 - 9.8) 3.81 (1.76 - 8.22) Any irAE No 4.6 (2.5 - 6.7) .19 (.11 - .34) < .001 Yes 39.6 (20.3 - 58.9) Grade ≥ 3 irAE No 8.5 (3.3 - 13.7) .27 (.11 - .68) .005 Yes Not reached
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".