Abstract 1053P
Background
TMB is an emerging biomarker of IO response, however in the setting of a wide variation in median TMB values between cancer subtypes, histology specific thresholds predicting response remain unclear. The TruSight Oncology 500® (TSO 500) is a comprehensive 523 gene NGS assay and is highly concordant with whole exome sequencing in TMB assessment. Thresholds predicting meaningful response to IO such as CR in metastatic melanoma using this panel are needed.
Methods
Consenting cutaneous melanoma patients treated with IO with radiographic or metabolic CR of at least 6 months duration, and patients with early progression (EP) (confirmed disease progression within 6 months, including stage III patients on adjuvant IO) had IO-naïve tissue sequenced with the TSO 500. TMB values in mutations per megabase (mut/Mb) were calculated and compared with the Mann–Whitney U test. TMB thresholds predicting CR vs EP were assessed using area under the receiver operator curve (AUC) regression analysis, after adjustment for covariates including age, stage, BRAF status & IO type.
Results
18 EP samples and 34 CR tumours have been sequenced with adequate quality control. 31/34 CRs are ongoing. 50% of EP and 56% of CR patients had received anti-PD1 monotherapy with remainder having received combination therapy. TMB correlated strongly with CR (p<0.001) with a median TMB of 13.3 (EP) vs 53.2 (CR). The AUC for TMB by responder group (95%CI) was 0.843 (0.724-0.962) (p<0.001). Thresholds predicting CR vs EP are shown in the table. TMB as a continuous variable correlated strongly with CR (OR of 1.03 for every 1 mut/Mb TMB increase), both in univariate and multivariate modelling (p=0.014). Table: 1053P
TMB thresholds predicting CR after IO based on AUC regression
| TMB threshold | Sensitivity (%) | Specificity (%) | OR (95% CI) |
| TMB>10* | 100 | 44.4 | Not calculable |
| TMB>16 | 91.2 | 61.1 | 16.24 (3.56-74.05) P<0.001 |
| TMB>23** | 76.5 | 77.8 | 11.38 (2.91-44.53) p<0.001 |
*Maximum sensitivity cutoff, **Optimal sensitivity & specificity cutoff using Youden Index
Conclusions
Overall, TMB measured using the TSO 500 is a strong predictor of CR. Ongoing validation in a cohort of 40 patients will be presented.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Western Australian Health Translation Network, WA Cancer and Palliative Care Network.
Disclosure
T. Meniawy: Financial Interests, Personal, Funding: Bristol-Myers Squibb. M. Millward: Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Funding: AstraZeneca; Financial Interests, Personal, Funding: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.