Impact of consensus molecular subtyping (CMS) on survival in the CO.26 trial of durvalumab plus tremelimumab versus best supportive care (BSC) in metastatic colorectal cancer (mCRC).
Bibliographic record
Abstract
3551 Background: CO.26 was a phase 2 trial (2-sided α=0.1 and 80% power) that randomized 180 patients with refractory mCRC 2:1 to durvalumab + tremelimumab vs BSC with improved overall survival (OS) (HR 0.73, 90%CI 0.55-0.97, P=0.07). A Nanostring assay validated for use with FFPE was used to determine CMS for correlation with outcome. Methods: Archival FFPE from 163/180 (91%) of patients (pts) underwent RNA extraction and CMS subtyping. Cox proportional hazard models evaluated the prognostic and predictive impact of CMS on overall survival. Results: CMS distribution was skewed towards CMS4 (76%), with lower prevalence of CMS1 (2%), CMS2 (16%) and CMS3 (2%). There were 7/163 cases of indeterminate CMS (4%). Subgroup analysis was restricted to CMS2 and CMS4 based on sample size. With BSC alone, CMS2 showed trends to worse OS compared to all other patients pooled (HR 1.93, 90% CI 1.03-3.61, P=0.085), while CMS4 did not (HR 0.86, 90% CI 0.50-1.48, P=0.64). OS but not progression free survival (PFS) was improved with durvalumab + tremelimumab in the overall population. OS was improved with durvalumab + tremelimumab among patients with CMS2 tumors (HR 0.39, 90% CI 0.19-0.82, P=0.035) but not in patients with CMS4 tumors (HR 0.73, 90% CI 0.52-1.02, P=0.12) compared to BSC. Neither CMS2 (P-interaction=0.37) nor CMS4 (P-interaction=0.91) were predictive of OS benefit from durvalumab + tremelimumab compared to BSC. Disease control rate (DCR) trended to being better among CMS4 (24/85) than CMS2 cancers (1/15, OR 5.51, 90% CI 1.10-29.88, P=0.11) or CMS4 vs all non CMS4 cancers (1/21, OR 7.87, 90% CI 1.65-41.98, P=0.023) for patients on durvalumab + tremelimumab. PFS was not improved with durvalumab + tremelimumab in CMS2 (P=0.19) or CMS4 (P=0.29) cancers relative to BSC. Conclusions: In this trial of refractory colorectal cancer, we saw a shift in CMS subtype with more CMS4 than expected. Compared to CMS4, CMS2 showed stronger signals towards improved OS with durvalumab + tremelimumab but had a lower disease control rate. Differences in immune signaling by CMS may be important determinants of which component of immune regulation needs to be targeted in mCRC to improve outcomes. Clinical trial information: NCT02870920. [Table: see text]
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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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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, 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".