Thread by @AmitKulkarniMD, #FDA recently approved #pembrolizumab- a tissue agnostic indication in metastatic tumors with [...]

#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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">What is TMB ?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">Why is it important?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> Controversy regarding appropriate cut-offs for TMB

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">Finally KN-158-study based on which the approval was gained

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">One of the first two papers highlighting the mutational heterogeneity in cancers
https://bit.ly/2BgbYSt ">https://bit.ly/2BgbYSt&q... (Lawrence et al)
https://bit.ly/2YfWRS5 ">https://bit.ly/2YfWRS5&q... (Alexandrov et al)

Lawrence et al had

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">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" title="Lawrence et al had https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">3,083 tumor/normal pairs across 27 tumors, 2,957 whole-exome and 126 whole-genome" class="img-responsive" style="max-width:100%;"/>

Alexandrov et al had

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">7,042 samples of 30 tumor types (507 whole genome and 6,535 exomes)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Both showed tumors towards the right not only had higher mutation burden-but also had the most success with immunotherapy initially

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">BTW both papers are one of the most highly cited

Tumor mutations creates targets for T-cell recognition=

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🌟" title="Leuchtender Stern" aria-label="Emoji: Leuchtender Stern">neoantigens

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🌟" title="Leuchtender Stern" aria-label="Emoji: Leuchtender Stern">

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">TMB was thought to be a surrogate marker for neoantigen burden

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">immunogenecity

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">susceptibility to checkpoint blockade
Random slide on tumor mutations

Tumor mutations creates targets for T-cell recognition= https://abs.twimg.com/emoji/v2/... draggable=

First two papers to validate this:

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Snyder et al in melanoma with CTLA-4 blockade https://bit.ly/3fPDup5
https://bit.ly/3fPDup5&q... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Rizvi et al in NSCLC with PD-L1 blockade https://bit.ly/2AOYPzW
https://bit.ly/2AOYPzW&q... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts"> #TMB determined by whole exome sequencing (protein coding regions of 20,000 genes or~1% whole genome)

First two papers to validate this: https://abs.twimg.com/emoji/v2/... draggable=

Snyder et al in melanoma with CTLA-4 blockade https://bit.ly/3fPDup5&q... class="Emoji" style="height:16px;" src=" " title="First two papers to validate this: https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Snyder et al in melanoma with CTLA-4 blockade https://bit.ly/3fPDup5&q... class="Emoji" style="height:16px;" src=" " class="img-responsive" style="max-width:100%;"/>

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Rizvi et al showed that higher somatic non-synonymous mutation burden was associated with clinical efficacy of pembrolizumab (synonymous mutations not analyzed)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">High #TMB defined as > 209 non-synonymous mutations/exome (come back to this later)

Rizvi et al showed that higher somatic non-synonymous mutation burden was associated with clinical efficacy of pembrolizumab (synonymous mutations not analyzed)https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">High #TMB defined as > 209 non-synonymous mutations/exome (come back to this later)" title="https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Rizvi et al showed that higher somatic non-synonymous mutation burden was associated with clinical efficacy of pembrolizumab (synonymous mutations not analyzed)https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">High #TMB defined as > 209 non-synonymous mutations/exome (come back to this later)" class="img-responsive" style="max-width:100%;"/>

Next comes our friendly assay #FoundationOne

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts">~300+ gene panel (only a subset of entire exome/20,000 genes)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> Only mutations in tumor specimens (no germline comparison)-bioinformatically filter out potential germline variants (not perfect)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="➡️" title="Pfeil nach rechts" aria-label="Emoji: Pfeil nach rechts"> 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 )">https://bit.ly/3eiJHcs&q...

First they showed a good concordance between #TMB determined by whole-exome approach and the #FoundationOne panel ( https://bit.ly/3eiJHcs&q...

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
https://bit.ly/2AS7nG9&q... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Interestingly, this finding was not true with nivo+ipi combo

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">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 ">https://bit.ly/3dejQ4m&q...

Why did #FoundationOne & #39;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.

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 ">https://bit.ly/2zKz3wh&q...

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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">About 1/3 rd of the patients were SCLC- current SOC in first line is chemo-immunotherapy based on IMPOWER-133 and CASPIAN

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts"> It would not make sense to use single agent pembro following progression on chemo-immunotherapy even with high TMB

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Pembro is already approved for recurrent cervical ca in 2nd line- ORR of 15% in all comers (PD-L1+)

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Pembro is also approved for endometrial ca in 2nd line with lenvatinib based on KN-146

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">All other types of cancers were each n=15 or less; not enough to change practice IMO

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">The broad approval in all tumors #TMB >10mut/MB just based on ORR 24% irrespective of tumor is baffling

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">Cut-off of 10 Mut/MB seems arbitary

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">I wont even comment on the PFS and OS of a single arm trial

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts"> Please don’t get me wrong, I am all for personalized medicine and precision oncology where it makes sense

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">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
https://bit.ly/2YPRw2N&q... class="Emoji" style="height:16px;" src=" https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">For some cancers, no matter what your #TMB -you wont do well on ICI

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&q... class="Emoji" style="height:16px;" src=" " title="https://abs.twimg.com/emoji/v2/... draggable="false" alt="👉" title="Rückhand Zeigefinger nach rechts" aria-label="Emoji: Rückhand Zeigefinger nach rechts">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&q... class="Emoji" style="height:16px;" src=" " class="img-responsive" style="max-width:100%;"/>

Curious to hear thoughts from the experts @VivekSubbiah @Dr_R_Kurzrock @StephenVLiu @n8pennell @VPrasadMDMPH @oncology_bg @Alfdoc2 @PatelOncology @JackWestMD @FAndreMD @DSolit @CharuAggarwalMD

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