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#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
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
What is TMB ?Why is it important? Controversy regarding appropriate cut-offs for TMBFinally KN-158-study based on which the approval was gained
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
One of the first two papers highlighting the mutational heterogeneity in cancershttps://bit.ly/2BgbYSt (Lawrence et al)
https://bit.ly/2YfWRS5 (Alexandrov et al)
Lawrence et al had 3,083 tumor/normal pairs across 27 tumors, 2,957 whole-exome and 126 whole-genome
3,083 tumor/normal pairs across 27 tumors, 2,957 whole-exome and 126 whole-genome
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
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 initiallyBTW both papers are one of the most highly cited
Tumor mutations creates targets for T-cell recognition= 
neoantigens
TMB was thought to be a surrogate marker for neoantigen burdenimmunogenecitysusceptibility to checkpoint blockade
Random slide on tumor mutations
neoantigensTMB was thought to be a surrogate marker for neoantigen burdenimmunogenecitysusceptibility to checkpoint blockadeRandom slide on tumor mutations
First two papers to validate this:
Snyder et al in melanoma with CTLA-4 blockade https://bit.ly/3fPDup5
Rizvi et al in NSCLC with PD-L1 blockade https://bit.ly/2AOYPzW
#TMB determined by whole exome sequencing (protein coding regions of 20,000 genes or~1% whole genome)
Snyder et al in melanoma with CTLA-4 blockade https://bit.ly/3fPDup5 Rizvi et al in NSCLC with PD-L1 blockade https://bit.ly/2AOYPzW #TMB determined by whole exome sequencing (protein coding regions of 20,000 genes or~1% whole genome)
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)
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
~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
First they showed a good concordance between #TMB determined by whole-exome approach and the #FoundationOne panel ( https://bit.ly/3eiJHcs )
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
https://bit.ly/2AS7nG9
Interestingly, this finding was not true with nivo+ipi combo
https://bit.ly/2AS7nG9
Interestingly, this finding was not true with nivo+ipi combo
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
Clever paper by @MarkYarchoan from @hopkinskimmel showed correlation between response-rate and #TMB as continuous variable (no cut-off) https://bit.ly/3dejQ4m
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.
This was the best I could find.
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 https://bit.ly/2zKz3wh
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
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
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
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-146All other types of cancers were each n=15 or less; not enough to change practice IMO
The broad approval in all tumors #TMB >10mut/MB just based on ORR 24% irrespective of tumor is bafflingMy 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
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
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 https://bit.ly/2YPRw2N For some cancers, no matter what your #TMB -you wont do well on ICI
Curious to hear thoughts from the experts @VivekSubbiah @Dr_R_Kurzrock @StephenVLiu @n8pennell @VPrasadMDMPH @oncology_bg @Alfdoc2 @PatelOncology @JackWestMD @FAndreMD @DSolit @CharuAggarwalMD
