FDAがTMB 10mut/Mb以上にペムブロリズマブを承認したことに関するTwitterでの議論のまとめ

FDAがTMB 10mut/Mb以上にペムブロリズマブを承認したことに関するTwitterでの議論のまとめ
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Amit Kulkarni @AmitKulkarniMD

#FDA recently approved #pembrolizumab- a tissue agnostic indication in metastatic tumors with high #TMB (>10 mut/MB) using Foundation One Dx companion diagnostic test. I want to share a tweetorial on why this indication could be problematic and hope to share some nuances on #TMB

2020-06-19 15:12:07
Amit Kulkarni @AmitKulkarniMD

Dad, Husband, Assistant Professor, Thoracic Oncologist, University of Minnesota | Masonic Cancer Center

Amit Kulkarni @AmitKulkarniMD

I hope to cover the following ➡️What is TMB ? ➡️Why is it important? ➡️ Controversy regarding appropriate cut-offs for TMB ➡️Finally KN-158-study based on which the approval was gained

2020-06-19 15:12:08
Amit Kulkarni @AmitKulkarniMD

➡️Tumor mutational burden (#TMB) most ideal definition -total number of somatic mutations (only in tumor), including base substitutions, insertions/deletions per coding area of tumor genome

2020-06-19 15:12:08
Amit Kulkarni @AmitKulkarniMD

👉One of the first two papers highlighting the mutational heterogeneity in cancers bit.ly/2BgbYSt (Lawrence et al) bit.ly/2YfWRS5 (Alexandrov et al)

2020-06-19 15:12:08
Amit Kulkarni @AmitKulkarniMD

Lawrence et al had 👉3,083 tumor/normal pairs across 27 tumors, 2,957 whole-exome and 126 whole-genome pic.twitter.com/O8eKpPKzFi

2020-06-19 15:12:09
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Amit Kulkarni @AmitKulkarniMD

Alexandrov et al had 👉7,042 samples of 30 tumor types (507 whole genome and 6,535 exomes) 👉Both showed tumors towards the right not only had higher mutation burden-but also had the most success with immunotherapy initially 👉BTW both papers are one of the most highly cited

2020-06-19 15:12:10
Amit Kulkarni @AmitKulkarniMD

Tumor mutations creates targets for T-cell recognition= 🌟neoantigens🌟 👉TMB was thought to be a surrogate marker for neoantigen burden➡️immunogenecity➡️susceptibility to checkpoint blockade Random slide on tumor mutations pic.twitter.com/EU2pWPAIjM

2020-06-19 15:12:11
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Amit Kulkarni @AmitKulkarniMD

First two papers to validate this: 👉Snyder et al in melanoma with CTLA-4 blockade bit.ly/3fPDup5 👉Rizvi et al in NSCLC with PD-L1 blockade bit.ly/2AOYPzW 👉 #TMB determined by whole exome sequencing (protein coding regions of 20,000 genes or~1% whole genome) pic.twitter.com/x9ykGxtlTj

2020-06-19 15:12:12
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Amit Kulkarni @AmitKulkarniMD

👉Rizvi et al showed that higher somatic non-synonymous mutation burden was associated with clinical efficacy of pembrolizumab (synonymous mutations not analyzed) 👉High #TMB defined as > 209 non-synonymous mutations/exome (come back to this later) pic.twitter.com/M3zvq0L1kU

2020-06-19 15:12:13
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Amit Kulkarni @AmitKulkarniMD

Next comes our friendly assay #FoundationOne ➡️~300+ gene panel (only a subset of entire exome/20,000 genes) ➡️ Only mutations in tumor specimens (no germline comparison)-bioinformatically filter out potential germline variants (not perfect) ➡️ Both synonymous & non-synonymous

2020-06-19 15:12:13
Amit Kulkarni @AmitKulkarniMD

First they showed a good concordance between #TMB determined by whole-exome approach and the #FoundationOne panel (bit.ly/3eiJHcs) pic.twitter.com/FQpXqkiCPe

2020-06-19 15:12:14
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Amit Kulkarni @AmitKulkarniMD

Next they showed that Higher #TMB by #FoundationOne was a/w betters outcome with single agent anti-PD1 (RR, PFS and OS) compared to low or intermediate #TMB by @PatelOncology @Dr_R_Kurzrock bit.ly/2AS7nG9 👉Interestingly, this finding was not true with nivo+ipi combo

2020-06-19 15:12:15
Amit Kulkarni @AmitKulkarniMD

👉Important to note that in this paper #FoundationOne own definition was: (this info was previously present but now retracted from website) High #TMB >20 mut/MB (roughly 270 mut/exome) Intermediate #TMB 6-19 mut/MB Low #TMB 1-5 mut/MB

2020-06-19 15:12:15
Amit Kulkarni @AmitKulkarniMD

Clever paper by @MarkYarchoan from @hopkinskimmel showed correlation between response-rate and #TMB as continuous variable (no cut-off) bit.ly/3dejQ4m pic.twitter.com/QBmKbXfLiF

2020-06-19 15:12:16
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Amit Kulkarni @AmitKulkarniMD

Why did #FoundationOne 's definition of High TMB change over time from 20 mut/MB to 10 mut/MB , what was the justification? This was the best I could find. pic.twitter.com/pvcsJkpdit

2020-06-19 15:12:17
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Amit Kulkarni @AmitKulkarniMD

Based off-retrospective studies of CM-026, 012 and 568, where in ROC curve of #TMB by ORR, beyond 10 mut/Mb the ORR plateaued. Basis of CM-227, the first prospective clinical trial using #TMB >10 mut/MB in NSCLC which was also predictive of PFS benefit bit.ly/2zKz3wh

2020-06-19 15:12:17
Amit Kulkarni @AmitKulkarniMD

Lastly, KN-158 study- prospectively-planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in a multicenter, non-randomized, open-label trial receiving pembrolizumab, ORR as primary endpoint

2020-06-19 15:12:18
Amit Kulkarni @AmitKulkarniMD

This is the most important table: Thanks to @agrothey for providing this. The approval was based off of these 100 patients in 10 tumor types pic.twitter.com/dr2mb4d9qV

2020-06-19 15:12:19
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Amit Kulkarni @AmitKulkarniMD

👉About 1/3 rd of the patients were SCLC- current SOC in first line is chemo-immunotherapy based on IMPOWER-133 and CASPIAN 👉 It would not make sense to use single agent pembro following progression on chemo-immunotherapy even with high TMB

2020-06-19 15:12:19
Amit Kulkarni @AmitKulkarniMD

👉Pembro is already approved for recurrent cervical ca in 2nd line- ORR of 15% in all comers (PD-L1+) 👉Pembro is also approved for endometrial ca in 2nd line with lenvatinib based on KN-146 👉All other types of cancers were each n=15 or less; not enough to change practice IMO

2020-06-19 15:12:20
Amit Kulkarni @AmitKulkarniMD

👉The broad approval in all tumors #TMB >10mut/MB just based on ORR 24% irrespective of tumor is baffling 👉My worry is that patients might get pembro based on #TMB>10 mut/MB, when other effective therapies with proven survival benefit already exist in the 2nd line setting

2020-06-19 15:12:20
Amit Kulkarni @AmitKulkarniMD

👉Cut-off of 10 Mut/MB seems arbitary 👉I wont even comment on the PFS and OS of a single arm trial 👉 Please don’t get me wrong, I am all for personalized medicine and precision oncology where it makes sense

2020-06-19 15:12:20
Amit Kulkarni @AmitKulkarniMD

👉Lastly, IMO every tumor type has its own cut-off or threshold for High #TMB to be able to elicit response and improve survival with immunotherapy -shown in this elegant paper bit.ly/2YPRw2N 👉For some cancers, no matter what your #TMB -you wont do well on ICI pic.twitter.com/HtI3GwNMoS

2020-06-19 15:12:21
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