222-N Analysis of pathologic features and efficacy outcomes with neoadjuvant nivolumab plus platinum-doublet chemotherapy for resectable non-small cell lung cancer in CheckMate 816
Bibliographic record
Abstract
Background Pathologic response assessment after neoadjuvant treatment is the potential analog to radiographic response for advanced disease, with regard to study design, clinical care, and accelerated regulatory approvals. A standardized system for assessing degree of pathologic response in the primary tumor (PT) and lymph nodes (LNs) as a survival surrogate is an unmet need. It is also a prerequisite for determining whether patients with versus without LN involvement benefit from neoadjuvant therapy. Here, in a pre-specified exploratory analysis from CheckMate 816, we report the first in-depth assessment of the full spectrum of percent residual viable tumor (RVT; beyond pathologic complete response) in both the PT and LNs and its association with event-free survival (EFS). This study represents the first prospective use of such a pan-tumor scoring system in a phase 3 registrational trial.Methods Pathologic response was prospectively assessed in the randomized phase 3 study of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with resectable non-small cell lung carcinoma. Percentages of RVT, regression, and necrosis were quantified (0%-100%) in the PT and LNs using pan-tumor immune-related pathologic response criteria (irPRC). Pathologic features scored using this system were tested for association with EFS. An exploratory comparison between pathologic response, radiographic response, and circulating tumor DNA (ctDNA) clearance was performed.Results In both treatment arms and regardless of pathologic evidence of LN involvement, EFS was improved in patients with 0% versus >0% RVT-PT (HR=0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (AUC=0.74); 2-year EFS rates were 90%, 60%, 57%, and 39% for patients with 0%-5%, >5%-30%, >30%-80%, and >80% RVT, respectively. Each 1% increase in RVT associated with a 0.017 increase in HR for EFS. Combining pathologic response from PT+LNs helped differentiate outcomes. An increase in%necrosis was not observed in paired pre- and on-treatment specimens in either treatment arm. Further, necrosis within the on-treatment specimens was associated with lower EFS rates, arguing against necrosis as a histologic feature of treatment effect. When pathologic response was compared to radiographic response and ctDNA clearance, pathologic response best approximated EFS.Conclusions Percent RVT associates with improved EFS, supporting pathologic response as an emerging survival surrogate. Given the prognostic value of%RVT, its assessment using routine surgical pathology workflows, and a scoring system generalizable to any solid tumor type, it is also anticipated to become a biomarker for guiding subsequent adjuvant therapy. Further assessment of clinically-relevant%RVT cutoffs in PT+LN is warranted.Acknowledgements Funding for this study was provided by Bristol Myers Squibb and Ono Pharmaceutical Company Ltd.Trial Registration NCT02998528Ethics Approval This study was approved by the Johns Hopkins University Institutional Review Board.
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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 | 0.001 |
| 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) | 0.002 | 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".