1502 - An exploratory analysis of on-treatment ctDNA measurement as a potential surrogate for overall survival for atezolizumab benefit in the OAK Study

Background

Overall survival (OS) is the most relevant endpoint for evaluation of checkpoint inhibitors (CPI). Identification of early surrogates of OS is important to inform early clinical efficacy signals and treatment decisions. Here, we evaluated multiple metrics of circulating tumor DNA (ctDNA) for association with OS in the Ph3 OAK study, which demonstrated clinically significant OS benefit in ≥ 2L NSCLC patients treated with atezolizumab vs docetaxel.

Methods

Plasma from 94 patients taken at baseline and at subsequent cycles of therapy every three weeks (C2D1, C3D1, and C4D1) were analyzed retrospectively for ctDNA with the AVENIO ctDNA Surveillance Kit* (Jiang et al., 2018). Mutations detected in matched PBMC DNA were excluded in correlation analyses with clinical outcomes (Yaung et al., 2019). ctDNA was measured by allele frequency (AF) or mutant molecules per milliliter (MMPM), and summarized across multiple mutations within a sample by median, mean or maximum. Concordance between these per-sample metrics and PFS/OS were assessed using C index, which is equivalent to AUC under a Receiver Operating Characteristic (ROC) curve. *For Research Use Only; Not for use in diagnostic procedures.

Results

Using absolute and relative change from baseline of these metrics showed various levels of association with OS for both treatment arms (atezolizumab arm C index average 0.63, range 0.47 -0.76 and docetaxel arm C index average 0.50, range 0.39 - 0.61). As noted, maximal MMPM at C3D1 or 6 weeks had comparable association with OS in both treatment arms (atezolizumab arm C index = 0.74 and docetaxel arm C index = 0.73). Dichotomized at a median of 8.75 maximal MMPM, KM curves showed the 1-year survival rate in the atezolizumab arm among MMPM low vs high patients was 0.81 vs 0.43; and in the docetaxel arm was 0.7 vs 0.07. Associations with PFS tended to be weaker than those for OS.

Conclusions

Overall ctDNA levels were associated with OS in 2L+ NSCLC. ctDNA may be a promising non-invasive blood based biomarker in the metastatic setting of NSCLC and warrants further studies to demonstrate its utility in clinical development.

Clinical trial identification

OAK (NCT02008227).

Editorial acknowledgement

Legal entity responsible for the study

Roche.

Funding

Roche.

Disclosure

D.R. Gandara: Advisory / Consultancy: AstraZeneca, Celgene, CellMax Life, FujiFilm, Roche-Genentech, Guardant Health, Inviata, IO Biotech, Lilly, Liquid Genomics, Merck, Samsung Bioepis, Pfizer; Research grant / Funding (institution), Research grants : Bristol-Myers Squib, Roche-Genentech, Novartis, Merck. W. Zou: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. J. Jiang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. S. Yaung: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. F. Fuhlbrück: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. J. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. M. Peterson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. J. Palma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. M. Ballinger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. E. Peters: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. D. Shames: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. N. Patil: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche.