Effect of bone metastasis on outcomes in the CCTG BR.34 phase II randomized trial of dual immune checkpoint inhibitor (ICI) treatment with or without chemotherapy in high-risk, stage IVA/B NSCLC.
Bibliographic record
Abstract
9067 Background: Bone metastasis (BM) occurs in about 40% of patients with metastatic lung cancer. Recently, BM was associated with decreased OS to nivolumab in previously-treated NSCLC (Landi L et al, P1.01.53, 19th WCLC, 2018). CCTG BR.34 (NCT03057106) was an open-label, randomized phase II clinical trial that randomized 301 patients with treatment-naïve, high-risk, stage IVA/B NSCLC without sensitizing EGFR or ALK alterations (1:1) to durvalumab plus tremelimumab with or without platinum doublet chemotherapy. First, 109 patients accrued with stage IVB, or selected IVA disease. Then 192 patients accrued with any stage IVA/B disease. In CCTG BR.34, median OS was not significantly different: 16.6 mo in the chemotherapy plus immunotherapy (C+IO) arm, vs 14.1 mo in the IO alone arm (HR 0.88, p = 0.46) (Leighl NB et al, J Thor Oncol, 2021). However, in BR.34 PFS was significantly longer in the C+IO arm (7.7 mo) compared to the IO alone arm (3.2 mo) (HR 0.67, 95% CI, 0.52 0.88). Here we analyzed the effect of BM on outcomes in BR.34. Methods: The 301 patients in the trial were characterized by the presence of BM at study entry (129-yes, 172-no). BM effect was evaluated on trial outcomes (OS, PFS, and ORR) using Cox/logistic regression analysis. Multivariable analysis was performed adjusting for the clinical and molecular covariates available. Results: In univariate analysis of the entire study population, median OS was significantly shorter for patients with BM vs those without BM (10. 9 vs 18.7 mos, HR 1.68, p = 0.001), as was median PFS (3.4 vs 7.2 mos, HR 1.82, p < 0.0001), and lower ORR (29.5% vs 45.9%, OR 0.52, p = 0.003), respectively. There was no evidence of differential association of BM with treatment arms for OS (p = 0.23), PFS (p = 0.84), and ORR (p = 0.25, Breslow-Day test). In multivariate analysis (MVA), BM remained significantly associated with worse OS (HR 1.44, p = 0.026), PFS (HR 1.69, p < 0.0001), and ORR (OR 0.52, p = 0.01). In MVA for OS: TMB, histology type, race, and ECOG were also significant; but age, smoking history, and PD-L1 IHC status were not significant. Conclusions: In CCTG BR.34 the presence of BM at trial entry was associated with significantly shorter OS, PFS, and lower ORR. BM is therefore a significant adverse prognostic factor in high-risk, stage IVA/B NSCLC treated with durvalumab and tremilimumab (with or without platinum doublet chemotherapy). If confirmed in a larger phase III trial, BM should be considered as an important new stratification factor in all clinical trials of immune checkpoint inhibitor (ICI) therapy. We and others have reported that molecules arising in the bone microenvironment (e.g: IL-8, PTHrP, TGF-b, sclerostin, and activin A) cause immunosuppression in cancer, and future trials should evaluate the addition of targeted therapies against these factors in combination with the ICIs in patients with BM.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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".