Impact of clonality and DNA repair mutations on plasma tumor mutation burden (pTMB) and immunotherapy efficacy in microsatellite stable (MSS) metas...

Date 29 September 2019
Event ESMO 2019 Congress
Session Poster Discussion – Gastrointestinal tumours, colorectal
Presenter Jonathan Loree
Citation Annals of Oncology (2019) 30 (suppl_5): v198-v252. 10.1093/annonc/mdz246
Authors J.M. Loree1, D.J. Jonker2, H. Feilotter3, H.F. Kennecke4, P.Z. Brohawn5, K. Banks6, K. Quinn7, D. Tu8, C. O'Callaghan8, E.X. Chen9
  • 1Medical Oncology, BC Cancer, V5Z 4E6 - Vancouver/CA
  • 2Department Of Medicine, Division Of Medical Oncology, Ottawa Hospital Research Institute, University of Ottawa, K1H8L6 - Ottawa/CA
  • 3Pathology And Molecular Medicine, Queen's University, K7L 3N6 - Kingston/CA
  • 4Hematology-oncology, Virginia Mason Medical Center, 98101 - Seattle/US
  • 5Research & Development, MedImmune, 20878 - Gaithersburg/US
  • 6Medical Affairs, Guardant Health, 94063 - Redwood City/US
  • 7Bioinformatics, Guardant Health, 94063 - Redwood City/US
  • 8Cctg Trials Unit, Queen's University, K7L 3N6 - Kingston/CA
  • 9Medical Oncology, University Health Network, M5G 2C1 - Toronto/CA

Abstract

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 GuardantOMNITMassay (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

Gene MutationMedian pTMB MT vs WTMedian Clonal pTMB MT vs WTHR (90% CI, p) Among Pts with Selected MT
MSS Study Population (n = 166)16.3 (95% CI: 14.4-20.1)5.8 (95% CI: 4.8-5.8)0.66 (0.49-0.89, 0.024)
BRCA1 (n = 21)23.0 vs 15.3 (P = 0.0006)5.8 vs 5.8 (P = 0.64)0.20 (0.07-0.58, 0.013)
BRCA2 (n = 29)28.9 vs 14.6 (P < 0.0001)5.8 vs 5.8 (P = 0.52)0.39 (0.18-0.85, 0.047)
ATM (n = 31)31.6 vs 13.9 (P < 0.0001)6.7 vs 4.8 (P = 0.023)0.66 (0.37-1.18, 0.24)
Polymerase E/D1/Q/H (n = 20)36.4 vs 14.7 (P < 0.0001)5.3 vs 5.8 (P = 0.57)0.95 (0.44-2.05, 0.91)
TP53 (n = 126)17.2 vs 13.1 (P = 0.024)4.8 vs 6.7 (P = 0.017)0.63 (0.45-0.88, 0.024)
MMR Gene without MSI (n = 31)24.9 vs 14.6 (P < 0.0001)5.8 vs 5.8 (P = 0.85)0.38 (0.17-0.85, 0.050)

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.