2951 - Impact of clonality and DNA repair mutations on plasma tumor mutation burden (pTMB) and immunotherapy efficacy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC) in CCTG CO.26

Background

We previously showed pTMB selects patients (pts) deriving benefit from PD-L1 and CTLA-4 inhibition with durvalumab and tremelimumab (D+T) compared to best supportive care (BSC) in refractory mCRC in CCTG CO.26.

Methods

We investigated somatic variants contributing to pTMB in MSS pts using cell-free DNA (cfDNA) analysis performed with the GuardantOMNI^TMassay (2.1Mb) on 166 pts from CO.26.

Results

Median pTMB was 16.3 mutations/megabase (mts/Mb). Using a minimum p-value approach, pts with pTMB>28 mts/Mb (21% of MSS pts) had the greatest overall survival (OS) benefit for D + T (HR 0.34, 90% CI 0.18-0.63, p-interaction=0.070) and worse OS in the BSC arm (HR 2.59, 90% CI 1.46-4.62). Of 4044 mts detected, 2718 (67.2%) were subclonal (<10% of max detected mutant allele frequency [MAF]). Anti-EGFR exposure associated with more mts per pt (median 28.5 vs 15.5, P < 0.0001), higher proportion of subclonal mts (78.3% vs 53.7%, P < 0.0001) and higher median pTMB compared to RAS mt pts with no prior anti-EGFR (24.9 vs 13.4 mts/Mb, P < 0.0001). After removing subclonal mts from pTMB calculation, median pTMB decreased to 5.8 mts/Mb. This clonal pTMB remained predictive of D+T improving OS (HR 0.19, 90% CI 0.08-0.45, p-interaction=0.039) when pTMB>10.6 mts/Mb (14.1% pts). Similarly, pTMB calculated using only subclonal mts associated with D+T OS benefit (HR 0.32, 90% CI 0.16-0.67, p-interaction=0.057). Though many genes were associated with pTMB and improved efficacy (see Table), only BRCA1 mts predicted treatment effect (p-interaction=0.035). Most DNA repair mts were subclonal and not associated with increased clonal pTMB.Table:

528PD

Conclusions

Both clonal and subclonal mts causing an elevated pTMB associated with benefit from D+T and mts in select DNA repair genes may correlate with benefit. cfDNA provides an opportunity to evaluate tumor evolution potentially missed in archival tissue.

Clinical trial identification

NCT02870920.

Editorial acknowledgement

Legal entity responsible for the study

Canadian Cancer Trials Group.

Funding

Canadian Cancer Society.

Disclosure

P.Z. Brohawn: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. K. Banks: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. K. Quinn: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Guardant Health. All other authors have declared no conflicts of interest.