Abstract 3041
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.
Resources from the same session
4370 - Continental differences in pathologic response with neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO) in patients with macroscopic stage III melanoma in the phase 2 OpACIN-neo trial.
Presenter: Irene Reijers
Session: Poster Display session 3
Resources:
Abstract
3230 - Comparable responses of melanoma at primary site and synchronous lymph node metastases upon neoadjuvant ipilimumab (IPI) and nivolumab (NIVO)
Presenter: Judith Versluis
Session: Poster Display session 3
Resources:
Abstract
3171 - Adjuvant Therapies for Stage III Melanoma: Benchmarks for Bringing Clinical Trials to Clinical Practice
Presenter: Tina HIEKEN
Session: Poster Display session 3
Resources:
Abstract
3493 - Mixture-cure modeling for resected stage III/IV melanoma in the phase 3 CheckMate 238 trial
Presenter: Jeffrey Weber
Session: Poster Display session 3
Resources:
Abstract
3036 - An open-label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib for patients with unresectable advanced BRAFV600-mutant melanoma: a subgroup analysis of patients with brain metastasis
Presenter: Caroline Dutriaux
Session: Poster Display session 3
Resources:
Abstract
2233 - Adverse event (AE) kinetics in patients (pts) treated with dabrafenib + trametinib (D + T) in the metastatic and adjuvant setting
Presenter: Jean Jacques Grob
Session: Poster Display session 3
Resources:
Abstract
2435 - A Single Arm, Open Label, Phase II, Multicenter Study to Assess the Detection of the BRAF V600 Mutation on cfDNA from Plasma in Patients with Advanced Melanoma
Presenter: Piotr Rutkowski
Session: Poster Display session 3
Resources:
Abstract
1766 - Efficacy and Safety of Dabrafenib and Trametinib in Patients with Metastatic BRAFV600 Mutation-positive Melanoma in the Real-World Setting – Interim results of the non-interventional COMBI-r study
Presenter: Carola Berking
Session: Poster Display session 3
Resources:
Abstract
2131 - Trial update: A randomized Phase Ib/II study of the selective small molecule Axl inhibitor Bemcentinib (BGB324) in combination with either dabrafenib/trametinib (D/T) or pembrolizumab in patients with metastatic melanoma
Presenter: Oddbjørn Straume
Session: Poster Display session 3
Resources:
Abstract
4074 - Analysis of pyrexia in patients (pts) treated with dabrafenib (D) and/or trametinib (T) across clinical trials
Presenter: Caroline Robert
Session: Poster Display session 3
Resources:
Abstract