Division of Oncology, Department of Medicine, University of Washington, Seattle, WA
Dimitra Rafailia Bakaloudi , Rafee Talukder , Dimitrios Makrakis , Leonidas Nikolaos Diamantopoulos , Ubenthira Patgunarajah , Vinay Mathew Thomas , Tanya Jindal , Jason R Brown , Marija Miletic , Jeffrey Johnson , Gavin Hui , Lucia Alonso Buznego , Rafael Morales-Barrera , David Humberto Marmolejo Castañeda , Charles B Nguyen , Pedro C. Barata , Tyler F. Stewart , Shilpa Gupta , Petros Grivas , Ali Raza Khaki
Background: MSI and TMB correlate with ICI efficacy. We assessed the association between TMB and MSI with outcomes in pts with aUC treated with anti-PD1/L1 in a ‘real-world’ cohort. We hypothesize that pts with high TMB and MSI-high (H) have better outcomes with ICI. Methods: In this retrospective study we included pts from 13 sites treated with ICI for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using KM method from ICI start. TMB and MSI were assessed by NGS. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. The analysis was stratified by therapy line (1L/upfront, 2+L). Multivariable models were adjusted by Khaki factors for 1L/upfront and Bellmunt factors for 2+L. We separately analyzed pts on maintenance avelumab (mAV). MSI is reported with descriptive statistics only. Results: 342 pts were treated with ICI 1L/upfront or 2+L (69% pure UC, median age at ICI start 69, 77% men, 90% White, 16% upper tract primary, 12% liver metastases [mets], 78% ECOG PS 0-1). Median f/u from ICI start was 34 months (mo). ORR was 36% (95%CI 26-46%) in pts with TMB≥10 vs 30% (95%CI 23-36%) with TMB<10 (OR=1.4 [95%CI 0.8-2.5] p=0.3). ORR was 75% (6/8) in pts with MSI-H and 30% (60/200) with MSI stable (MSI-S). mPFS was similar between TMB≥10 and <10 groups (6 vs 4 mo; HR=0.88 [95%CI 0.61-1.26] p=0.48) and between MSI-H and MSI-S (5 mo). mOS was numerically longer (not significant) in pts with TMB≥10 vs TMB<10: 25 vs 21 mo; (HR=0.7 [95%CI 0.50-1.09] p=0.12) and with MSI-H and MSI-S (NR and 20 mo). A significant association was found between TMB (continuous variable) and OS (HR=0.97 [95%CI 0.95-0.99] p=0.01). TMB analyses by therapy line are shown in Table. In the 1L/upfront setting (N=144), ORR 71% (5/7) vs 33% (45/135), mPFS 5 and 4 mo, mOS NR and 22 mo for MSI-H and MSI-S, respectively. Pts on mAV (n=77) were 77% men, 92% White, 16% upper primary, 13% liver mets, 84% ECOG PS 0-1 with median f/u 15 mo from avelumab start; mOS was NR for MSI-H and 24 mo for MSI-S; mPFS was 4 mo for both groups. Of 3 pts on mAV with MSI-H: 1 CR, 2 SD; of 58 pts with MSI-S: 4CR, 4PR, 24 SD, 21 PD, 5 unknown. Conclusions: MSI-H had numerically higher ORR and higher TMB was associated with longer OS with ICI, but further validation is needed. Limitations: retrospective design, small sample size for MSI-H cases, lack of randomization and central scan review, selection/confounding.
N | ORR N (%) | OR (95%CI) | N | mPFS mo (95%CI) | HR (95%CI) | N | mOS mo (95%CI) | HR (95%CI) | ||
---|---|---|---|---|---|---|---|---|---|---|
1L | ||||||||||
TMB<10 | 123 | 44 (36%) | Ref | 88 | 4 | Ref | 123 | 25 (17-34) | Ref | |
TMB≥10 | 64 | 23 (36%) | 0.9 (0.4-1.9) | 39 | 7 | 0.7 (0.4-1.0) | 65 | 35 (12-57) | 0.7 (0.4-1.2) | |
2+L | ||||||||||
TMB<10 | 59 | 11 (19%) | Ref | 49 | 4 | Ref | 60 | 16 (12-20) | Ref | |
TMB≥10 | 23 | 4 (17%) | 0.6 (0.1-2.5) | 17 | 4 | 1.5 (0.8-2.8) | 23 | 20 (12-28) | 1.3 (0.7-2.5) | |
mAV | ||||||||||
TMB<10 | 40 | 4 CR, 4 PR, 14 SD, 17 PD, 1 unknown | 27 | 3 | Ref | 39 | 24.2 | Ref | ||
TMB≥10 | 28 | 4 CR, 1 PR, 13 SD, 6 PD, 4 unknown | 19 | 4 | 0.7 (0.3-1.5) | 27 | NR | 0.5 (0.1-2.7) |
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