Early mortality with immune checkpoint inhibitors (IOs) in solid tumors: An inconvenient truth?
Bibliographic record
Abstract
12121 Background: Overall survival (OS) benefit with IOs has been demonstrated in several solid tumor types leading to their rapid adoption and use in practice. We noticed IO randomized controlled trials (RCTs) with early crossover of OS Kaplan-Meier (KM) curves favoring control therapy but with overall benefit favoring IO therapy. This suggests a subpopulation of patients at a higher risk of death on IO therapy compared to control therapy early in treatment. We performed a systematic review to examine the frequency and characteristics of IO RCTs showing this negative discordant crossover (NDC). Methods: RCTs studying IOs and non-IOs in solid tumors with published OS KM curves were identified by electronic database search and FDA approvals 2015-17. Early OS divergence was identified by blinded reviewers. NDC of OS KM curves was defined as early divergence discordant with an overall beneficial survival trend. RCT characteristics were compared using Fisher’s exact test. Results: 29 IO RCTs providing 33 comparisons and 24 non-IO RCTs providing 25 comparisons were identified. Nine IO RCTs (27%) and 1 non-IO RCT (4%) demonstrated NDC (p = 0.03). NDC occurred in NSCLC (3/9), urothelial cancer (2/2), melanoma (2/9), SCLC (1/2) and CRPC (1/2) RCTs. RCTs with NDC trended to less often study melanoma (22% v 46%) and squamous cancer (0% v 13%), and less often report OS benefit (22% v 71%). They trended to more often study urothelial cancer (22% v 0%) and 2nd-line treatment (56% v 38%), and more often have active treatment control arms (89% v 75%). Conclusions: Early NDC of overall survival curves occurs commonly in IO RCTs. This suggests a subpopulation of patients at higher risk of early death with IO therapy. Causes of this mortality are unclear but could include toxicity of IO therapy, superior antitumor effects of control therapy, and/or tumor growth promoting effects of IO therapy. We are quantitating this risk. Such crossover complicates proportional hazards modeling. Further research to identify the causes of and patients at risk for early mortality with IO therapy should be a priority and patients should be informed of this potential risk.
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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 | 0.151 | 0.441 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.005 | 0.007 |
| Bibliometrics | 0.004 | 0.006 |
| Science and technology studies | 0.001 | 0.003 |
| Scholarly communication | 0.005 | 0.007 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.003 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 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".