3041 - Blood-based TMB (bTMB) correlates with tissue-based TMB (tTMB) in a multi-cancer Phase I IO Cohort

Background

High tissue-tumor mutation burden (tTMB) is a predictor of response to immunotherapy (IO). Tissue availability and tumor heterogeneity are barriers to tTMB use in clinical practice. Plasma-based blood TMB (bTMB) is a convenient alternative that strongly correlates with tTMB in non-small cell lung cancer. Whether this correlation holds true in other cancers is unknown. Here, we examined the correlation between bTMB and tTMB as well as the clinical utility of TMB as a predictive marker of response in a heterogeneous Phase I IO cohort.

Methods

Advanced cancer patients (pts) treated with mono- or combination IO therapy at the Princess Margaret phase I unit were enrolled. Pre-treatment plasma ctDNA and matched normal blood controls were collected via an institutional liquid biopsy program (LIBERATE, NCT03702309). Available archival tissue FFPE samples were analyzed. The GeneseeqPrime 425 gene panel was used to sequence both ctDNA and FFPE samples.

Results

From December 2017 to July 2018, 39 pts with 19 tumor types were accrued from 25 different trials, 87% of which involved a PD-1/PD-L1 inhibitor. The median age was 59y (21 – 77) and 52% were female. The most frequent cancers were colorectal, head and neck and breast, each with 5 cases. Thirty-one patients (79%) had detectable mutations in plasma ctDNA. The median bTMB was 5 (1 - 53) mut/Mb. Twenty-one pts had available FFPE samples. Of those, mutations were detected in 20 (95%) samples. The median tTMB was 6 (2 - 124) mut/Mb. Among the 16 pts with detectable mutations in both FFPE and plasma samples, a significant correlation between bTMB and tTMB was observed (r = +0.67; p < 0.01). For survival analysis, 1 pt was excluded due to screen failure. The median PFS and OS for the entire cohort were 1.84m and 8.47m, respectively, with 3 (8%) partial response (PR), 11 (29%) stable disease (SD), and 24 (63%) progressive disease (PD). There was no association between bTMB or tTMB with survival; however, 2 of 3 PRs (anal and MSI-H endometrial cancer) exhibited a high bTMB of 53 and 46, respectively.

Conclusions

In a typical heterogeneous phase I IO cohort, bTMB was correlated with tTMB. In this small series, neither bTMB nor tTMB were associated with survival. However, 2/3 PRs had high bTMB. Further studies in larger cohorts are warranted.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Lillian Siu.

Funding

Princess Margaret Cancer Centre; BMO Chair in Precision Genomics; Geneseeq Technology Inc.

Disclosure

A. Wang: Full / Part-time employment: Geneseeq Technology Inc. J. Huang: Full / Part-time employment: Geneseeq Technology Inc. A. Spreafico: Advisory / Consultancy, Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Oncorus; Travel / Accommodation / Expenses: Idera; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Symphogen; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Surface Oncology; Research grant / Funding (self): Jansseen Oncology; Research grant / Funding (self): Northern Biologics. A.R. Hansen: Advisory / Consultancy: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Boston Biomedical; Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Pfizer; Research grant / Funding (institution): Karyopharm Therapeutics. A.A. Razak: Advisory / Consultancy, Research grant / Funding (self): Lilly; Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): CASI Pharmaceuticals; Research grant / Funding (self): Novartis; Research grant / Funding (self): Deciphera; Research grant / Funding (self): Karyopharm Therapeutics; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Roche/Genentech; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Blueprint Medicines; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Adaptimmune. P. Bedard: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Servir; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): SignalChem; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Lilly. H. Bao: Full / Part-time employment: Geneseeq Technology Inc. X. Wu: Leadership role, Full / Part-time employment: Geneseeq Technology Inc. T.J. Pugh: Advisory / Consultancy: DynaCare; Licensing / Royalties: Hybrid-capture sequencing for determining immune cell clonality; Licensing / Royalties: Combined hybrid-capture DNA sequencing for disease detection; Honoraria (self): Merck; Honoraria (self): Prosigna; Honoraria (self): Chrysalis Biomedical Advisors; Research grant / Funding (institution): Boehringer Ingelheim. L.L. Siu: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy: MorphoSys; Advisory / Consultancy, Research grant / Funding (institution): Symphony Evolution; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Loxo; Shareholder / Stockholder / Stock options, Spouse / Financial dependant, Immediate Family Member - Leadership and Stock/Owenership: Angios; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma. All other authors have declared no conflicts of interest.