Thread by @DocCatenacci, Ok...Honeymoon is over & now time to dissect the exciting new data [...]

Ok...Honeymoon is over & now time to dissect the exciting new data presented @ #ESMO2020 for #GEC #KN590 #CM649 #ATTRCN4 #CM577
1st, thank you to all the pts who participated!
& 2nd, congrats to all the investigators involved!
It& #39;s fantastic to have +ve studies! Lets dive deep:

*Caution
I think the facts are accurate - please correct if not. (seeking the truth here)
My opinions are my opinions.
~15 min read (it& #39;s complicated)
No CME offered unfortunately

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Enjoy...

Background:
IO monotx effective in a subgroup of GEC pts in 1L+:
1. MSI-H
2. High PDL1 (cut-off at least CPS 10 22C3)
3. low tumor burden
4. PS0
5. Asian > Western pts
6. SCC > AC
7. GC > EGJ
Outside of above, most pts are better-served w chemo based on crossing #yinyang curves

Some studies that provided this background:
#GEA
KN12 ATTRCN2 KN59
CM32 KN61 KN62
JAVLN300&100
#EsoSCCAC
KN28 KN180 KN181
#EsoSCC
ATTRCN3, ONO-4538-07
#AST
MSI-H (bunch of KN study subsets pooled)

#yinyang:

These led to
1) nivo 3L+ approval #GEA (Asia)
2) pembro 3L+ approval PDL1 CPS>1 22C3 #GEA (US)
3) pembro MSI-H 2L+ any solid tumor #GEC
4) pembro 2L+ CPS>10 22C3 #EsoSCC
5) nivo 2L+ approval #EsoSCC
These are the approvals as of & #39;the glorious day& #39; (TGD) 9/21/20 @ #ESMO2020

For the KN181 study, although the ITT, the all SCC (including <CPS10) & the all CPS>10 (including AC) demonstrated improved OS when lumped with SCC>10, Forrest plot clearly shows lack of benefit for AC, and PDL1<1. FDA approved only #SCC CPS >10. See #Cresendo plots later@ #KN62.

ATTRCN3 #SCC 2L study - akin to KN181
1) mini #yinyang curve
2) there were 18 non-Asian pts. Check out KN181 Forrest plot

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👆" title="Rückhand Zeigefinger nach oben" aria-label="Emoji: Rückhand Zeigefinger nach oben"> re Asian vs ex-Asian
3) TPS 28-8 PDL1 & #39;did not predict outcome& #39; but trend to more benefit with higher level:

ATTRCN3 #SCC 2L study - akin to KN1811) mini #yinyang curve2) there were 18 non-Asian pts. Check out KN181 Forrest plot https://abs.twimg.com/emoji/v2/... draggable=

re Asian vs ex-Asian3) TPS 28-8 PDL1 & #39;did not predict outcome& #39; but trend to more benefit with higher level:" title="ATTRCN3 #SCC 2L study - akin to KN1811) mini #yinyang curve2) there were 18 non-Asian pts. Check out KN181 Forrest plot https://abs.twimg.com/emoji/v2/... draggable="false" alt="👆" title="Rückhand Zeigefinger nach oben" aria-label="Emoji: Rückhand Zeigefinger nach oben"> re Asian vs ex-Asian3) TPS 28-8 PDL1 & #39;did not predict outcome& #39; but trend to more benefit with higher level:">

Specifically for 1L, no approvals to date. The only phase 3 1L study before TGD: KN062 N=750 1:1:1. Pertinents:
1. 3-arm R placbo contrlld study CPS >1 22C3 only
open labl pembro monotx
& cis/FP+pembro/placbo
2. monotx arm - #yinyang even CPS>10 N~100 per arm #donoharm plz!

3. Chemo arms: -ve for superiority (HR0.85, p=0.05 #alphasplittinggalore)
4. Chemo arms: #Crescendo

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🎼" title="Partitur" aria-label="Emoji: Partitur">curves suggesting magnitude of benefit by

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">ing gradient (higher PDL1 level?)
5. This was the 1st/only Phase3 data of chemo+IO in 1L #GEC before TGD.
Remember only CPS>1 22C3 pts!

3. Chemo arms: -ve for superiority (HR0.85, p=0.05 #alphasplittinggalore)4. Chemo arms: #Crescendohttps://abs.twimg.com/emoji/v2/... draggable=

curves suggesting magnitude of benefit byhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">ing gradient (higher PDL1 level?)5. This was the 1st/only Phase3 data of chemo+IO in 1L #GEC before TGD. Remember only CPS>1 22C3 pts!" title="3. Chemo arms: -ve for superiority (HR0.85, p=0.05 #alphasplittinggalore)4. Chemo arms: #Crescendohttps://abs.twimg.com/emoji/v2/... draggable="false" alt="🎼" title="Partitur" aria-label="Emoji: Partitur">curves suggesting magnitude of benefit byhttps://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">ing gradient (higher PDL1 level?)5. This was the 1st/only Phase3 data of chemo+IO in 1L #GEC before TGD. Remember only CPS>1 22C3 pts!">

Last background- Biomarker assays to date:
pembro 22C3 CPS>1 ~60%, >10 ~15-25%
nivo 28-8 TPS>1 ~15-30%
Avelu 73-10 TPS>1 ~10-26.8%

Notice, nivo not previously been evaluated by CPS
Diff diagnostic Abs=diff +ve rate =diff predictive performance

Which will you do?

Enter TGD:
Let& #39;s start with #KN590 #EsoSCCAC
N=749 pts 1:1 Cis/FP +pembro/placebo
CPS>10 ~50% & Asian 50%, SCC 73% (!) of pts
Results great!
But VERY similar to KN181 (

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👆" title="Rückhand Zeigefinger nach oben" aria-label="Emoji: Rückhand Zeigefinger nach oben">). More #crescendo plots.
Q: The CPS >10 curve is shown, what& #39;s the CPS <10 look like by SCC and AC?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">

Enter TGD:Let& #39;s start with #KN590 #EsoSCCACN=749 pts 1:1 Cis/FP +pembro/placeboCPS>10 ~50% & Asian 50%, SCC 73% (!) of ptsResults great!But VERY similar to KN181 (https://abs.twimg.com/emoji/v2/... draggable=

). More #crescendo plots.Q: The CPS >10 curve is shown, what& #39;s the CPS <10 look like by SCC and AC? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">" title="Enter TGD:Let& #39;s start with #KN590 #EsoSCCACN=749 pts 1:1 Cis/FP +pembro/placeboCPS>10 ~50% & Asian 50%, SCC 73% (!) of ptsResults great!But VERY similar to KN181 (https://abs.twimg.com/emoji/v2/... draggable="false" alt="👆" title="Rückhand Zeigefinger nach oben" aria-label="Emoji: Rückhand Zeigefinger nach oben">). More #crescendo plots.Q: The CPS >10 curve is shown, what& #39;s the CPS <10 look like by SCC and AC? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">">

So #KN590, even though the ITT & all #SCC appear to benefit, those #crescendo plots get less pronounced, due to many pts added that don& #39;t benefit, compared to the #SCC CPS >10 & all CPS >10 plots.
HRs of 0.57 & 0.62 went to 0.72 & 0.73 - what must the isolated HR AC/CPS<10 be?

Q: What is the % of Adeno in #KN590 that are CPS>10? This is important when comparing to other studies, and is not reported in the Forrest plot

Q: Will the FDA see past this #KN590 illusion, as it did with KN181, or no?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">
#KN590 My Thoughts:
Practice change for 1L CPS >10 (for sure #EsoSCC, but probably also #EsoAC)
I need to see #EsoSCC CPS <10 & <1 isolated to really comment if it is yay or nay. Hopefully yay, but

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤷‍♂️" title="Achselzuckender Mann" aria-label="Emoji: Achselzuckender Mann">

P.S. EsoAC = GEJAC = Cardia in my book.
P.P.S. Can we stop doing studies lumping SCC&AC so tweetorials don& #39;t have to be so long to explain?
P.P.P.S. For now ok to lump GC&EGJAC #GEA

Next up, #CM649
N=originally 1266 1:1 (633 each) all comers (Primary endpt >1% TPS (28-8 Ab))
FOLFOX/CapeOx nivo/ipi
**Nivo/Ipi terminated early - no public info o/w

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">
Major Amendments @ dif times: Added 3rd arm FOLFOX-nivo, CPS>5, &

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">& #39;d size of chemo arms: to ~1600 (~800 each)

Next up, #CM649N=originally 1266 1:1 (633 each) all comers (Primary endpt >1% TPS (28-8 Ab))FOLFOX/CapeOx nivo/ipi**Nivo/Ipi terminated early - no public info o/w https://abs.twimg.com/emoji/v2/... draggable=

Major Amendments @ dif times: Added 3rd arm FOLFOX-nivo, CPS>5, & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">& #39;d size of chemo arms: to ~1600 (~800 each)" title="Next up, #CM649N=originally 1266 1:1 (633 each) all comers (Primary endpt >1% TPS (28-8 Ab))FOLFOX/CapeOx nivo/ipi**Nivo/Ipi terminated early - no public info o/w https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">Major Amendments @ dif times: Added 3rd arm FOLFOX-nivo, CPS>5, & https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">& #39;d size of chemo arms: to ~1600 (~800 each)">

Amending trial structure & primary endpoints mid-trial - yikes! FOLFOX-nivo arm was not in the original design!

**Nivo/Ipi #CM649 will likely be a #YinYang plot in all-comers, the original endpoint of TPS >1% & likely even the CPS >5. Will be interesting to see this soon plz.

Biomarker contrasts of chemo arms:
CM649 N=1581 any PDL1 28-8 Ab
CPS>1 n=1296 (82%)
CPS>5 n= 955 (60%)

KN062 N=500 only CPS>1 22C3Ab
CPS>1 N=500 Usually ~60% of all pts tested are +ve
CPS>10 n=200 (~20%) (~40% of the CPS>1 pts)
CPS>5 (~35%ish)

Summary: 28-8 calls >pts +ve.

So...nice result for CPS >5 28-8, the amended primary endpt. Why different than Chemo comparison of #KN062 for both CPS>1 & CPS>10 22C3?? (and subject of the pre-test poll) See later

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇" title="Rückhand Zeigefinger nach unten" aria-label="Emoji: Rückhand Zeigefinger nach unten">
#Crescendo

So...nice result for CPS >5 28-8, the amended primary endpt. Why different than Chemo comparison of #KN062 for both CPS>1 & CPS>10 22C3?? (and subject of the pre-test poll) See later https://abs.twimg.com/emoji/v2/... draggable=

#Crescendo" title="So...nice result for CPS >5 28-8, the amended primary endpt. Why different than Chemo comparison of #KN062 for both CPS>1 & CPS>10 22C3?? (and subject of the pre-test poll) See later https://abs.twimg.com/emoji/v2/... draggable="false" alt="👇" title="Rückhand Zeigefinger nach unten" aria-label="Emoji: Rückhand Zeigefinger nach unten"> #Crescendo" class="img-responsive" style="max-width:100%;"/>

1. CPS>1? Let& #39;s add ~150 pts to the nivo arm (+ the 473 CPS>5)
2. All comers? Let& #39;s add ~150pts more (+ the 150pts CPS1-4 and 473 CPS>5)
dampened #crescendo plots
What do the CPS <1 and CPS <5 and CPS 1-4 look like?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">& Forest plot did not include these subgroups - why not?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">

1. CPS>1? Let& #39;s add ~150 pts to the nivo arm (+ the 473 CPS>5) 2. All comers? Let& #39;s add ~150pts more (+ the 150pts CPS1-4 and 473 CPS>5)dampened #crescendo plotsWhat do the CPS <1 and CPS <5 and CPS 1-4 look like? https://abs.twimg.com/emoji/v2/... draggable=

& Forest plot did not include these subgroups - why not?https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">" title="1. CPS>1? Let& #39;s add ~150 pts to the nivo arm (+ the 473 CPS>5) 2. All comers? Let& #39;s add ~150pts more (+ the 150pts CPS1-4 and 473 CPS>5)dampened #crescendo plotsWhat do the CPS <1 and CPS <5 and CPS 1-4 look like? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">& Forest plot did not include these subgroups - why not?https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">">

PS @pashtoonkasi MSI-H incidence exactly where it should be for #CM649: 3-4% in the metatastic setting. #KN062 is inflated because >90% of MSI-H tumors are CPS>1, while MSS are only ~50-60% CPS >1, so nearly double the expected rate there.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👀" title="Augen" aria-label="Emoji: Augen"> the MSI-H HR with nivo? 0.33! #CM649

Sidestep to #ATTRCN04
N=724 1:1 All Asian, All comers, any PDL1
SOX/CapeOx +nivo/placebo
PFS endpt met, BUT OS endpt not met (mos ~17m! HR0.9)

Why neg compared to #CM649? More cross-over, more later line therapies in Asia? Maybe But also:

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

To the pre-test:
Q: What are the differences b/w #KN062 #CM649 & #ATTRCN4 that led to only #CM649 positive for OS?
1. Oxaliplatin #CM649 & #ATTRCN4 vs Cisplatin #KN062?
2. Double/Triple sample size to have more power?
3. Open label vs Blinded
4. Amended primary endpoint mid-trial

1. Oxali vs Cis. Least likely of all.
Oxali better synergy? but Cis was +ve in #KN590 (and other tumor types+IO). ATTRCN4 had oxali but neg OS.
2/4.

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

https://abs.twimg.com/emoji/v2/... draggable="false" alt="⬆️" title="Pfeil nach oben" aria-label="Emoji: Pfeil nach oben">er sample size & CPS>5 more

https://abs.twimg.com/emoji/v2/... draggable="false" alt="👊" title="Fisted hand" aria-label="Emoji: Fisted hand">?Yep
3.

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🐘" title="Elefant" aria-label="Emoji: Elefant">in the Zoom: CM649 the only open label trial. Do we need to Rehash need for placebos?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤷‍♂️" title="Achselzuckender Mann" aria-label="Emoji: Achselzuckender Mann">

Q: What will the FDA do with the #CM649 study? Approve only by the amended primary endpt CPS>5? Or also >1, or all comers?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">
#CM646 My Thoughts:
Obvious approval of CPS>5. (MSI-H included in here)
I will not treat my pts with this until I see the isolated results CPS<1& CPS1-4

#CM577
N=794
R 2:1 nivo vs placebo in high risk ypT+N+ #EsoSCCAC
70% AC, 30% SCC
Primary endpt DFS
Fantastic result - I agree w @DrRonanKelly, 10% absolute DFS here will likely translate to OS benefit.
The sobering part: ~40% recur by 1yr, ~50% by 2yr, ~60% by 3yr. Plateau!(?)

However, bit of a #tuningfork curve here suggesting some patients not benefitting. Who are they?

As expected Forest plot shows the benefit from SCC >> AC.
Q: What do the DFS curves look like for AC?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">(Probably a more pronounced tuning fork)
Q: What do the DFS curves look like for AC CPS <1 vs 1-4 vs >5?

https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht"> (maybe even more pronounced tuning forks for CPS<5)
Let& #39;s see soon?

As expected Forest plot shows the benefit from SCC >> AC. Q: What do the DFS curves look like for AC? https://abs.twimg.com/emoji/v2/... draggable=

(Probably a more pronounced tuning fork)Q: What do the DFS curves look like for AC CPS <1 vs 1-4 vs >5? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht"> (maybe even more pronounced tuning forks for CPS<5)Let& #39;s see soon?" title="As expected Forest plot shows the benefit from SCC >> AC. Q: What do the DFS curves look like for AC? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht">(Probably a more pronounced tuning fork)Q: What do the DFS curves look like for AC CPS <1 vs 1-4 vs >5? https://abs.twimg.com/emoji/v2/... draggable="false" alt="🤔" title="Denkendes Gesicht" aria-label="Emoji: Denkendes Gesicht"> (maybe even more pronounced tuning forks for CPS<5)Let& #39;s see soon?" class="img-responsive" style="max-width:100%;"/>

I will leave the Triplet chemo vs CRT for another day, but #KN585 periop doublet chemo +pembro/placebo results will be interesting here for the Adeno comparison with #CM577 adeno component

So will the FDA approve adjuvant nivo by these DFS data alone (the primary endpoint), or require OS as well (secondary endpoint)?

The results are exciting & it& #39;s great to have better outcomes for pts w #GEC
I make the points above b/c it is our responsibility to identify who is & isn& #39;t deriving benefit from IO, so we get it to those who do, but with intentions to figure out why it isn& #39;t working in others.

"Targeted therapies for targeted populations."
Immune checkpoint inhibitors are targeted therapies, and they are not immune to this concept.

Cheers

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