Characterization of cytokine release syndrome (CRS) following treatment with tebentafusp in patients (pts) with previously treated (2L+) metastatic uveal melanoma (mUM).
Bibliographic record
Abstract
9531 Background: Cytokine-mediated adverse events (AEs) are commonly reported in pts treated with T cell engaging therapies. Tebentafusp (tebe), a bispecific consisting of an affinity-enhanced T cell receptor fused to an anti-CD3 effector that can redirect T cells to target gp100+ cells, has shown an overall survival benefit for pts with untreated mUM in a Ph3 trial (NCT03070392). Here we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-102 trial of 2L+ pts with mUM (NCT02570308). Methods: 127 HLA-A*02:01+ 2L+ mUM pts were treated with tebe at the RP2D of 68mcg following intra-patient dose escalation of 20 mcg dose 1 and 30 mcg dose 2. Pts were monitored overnight to allow management of hypotension and other cytokine-related AEs. Because the rate of severe CRS was low in Ph1, prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria [1]. Circulating cytokines in serum were measured before and at 8hr and 12-24hr after dosing for the 1st, 3rd and 4th doses (n=105). This analysis was conducted on the primary analysis snapshot dated 04Jun20. Results: The most frequent treatment-related AEs that were likely cytokine-mediated included fever (80%), chills (64%), nausea (59%), hypotension (41%) and hypoxia (4%). In a post-hoc review using ASTCT criteria, 86% of pts (n=109) had any grade CRS. The majority of these 109 pts had either grade (G) 1 (n=42; 33%) or G2 (n=62; 49%), with few G3 (n=4; 3.1%), one G4 (0.8%), and no deaths. Onset of CRS began within 24 hours of administration and G≥2 hypotension or hypoxia typically resolved within 2 days of onset. Most CRS events occurred after the first 3 doses with a marked reduction in the frequency and severity of CRS thereafter; G3-4 CRS was limited to first two doses. Only 2 pts discontinued tebe due to CRS (1 G3 and 1 G4). Treatment of G≥2 CRS included iv fluids (n=45), iv steroids (n=18), oxygen (n=8), and vasopressor use (n=2). No pts received tocilizumab. Tebe induced a transient increase in peripheral cytokines, including IFNγ, IL-10, IL-6 and TNFα, within hours of tebe dosing, which were several fold higher in pts with CRS compared to pts without CRS. Higher levels of TNFα trended with severity of CRS. Conclusions: CRS, a common AE observed with all T cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity even without the use of prophylactic premedications, were reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation. Pts with CRS tended to have greater increases in serum cytokines, consistent with tebe’s proposed mechanism of action. [1] Lee, DW et al. Biol Blood Marrow Transplant 2019. Clinical trial information: NCT02570308.
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How this classification was reachedexpand
Direct model labels (unvalidated)
Per-model category and study-design labels from the labeling rounds. They are machine output, unvalidated, and the disagreement between models ships as data. No study design here is MEDLINE-validated yet.
| Model arm | Categories | Study design | Confidence |
|---|---|---|---|
| gemma | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Not applicable | low |
| gpt | no category Domain: not available · Genre: Empirical About the Canadian research system: no · About a Canadian topic: no | Observational | low |
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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.001 | 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, unvalidatedLabeled directly by 2 models reading the full record.
The models disagree on parts of this classification; every voice is preserved in the section at the end of the page.
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".