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Tumor Board Tuesday

@tumorboardtuesday.bsky.social

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Online Tumor Board with a molecular angle ~ Join us every Tuesday 8pm ET for discussions, polls, & mini tweetorials Created by @mpishvaian.bsky.social • @MPishvaian • FREE CME

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Tumor Board Tuesday @tumorboardtuesday.bsky.social · Feb 3

#TumorBoardTuesday
🤔Can Claudin 18.2 be used for treatment💊outside of upper GI cancers❓

📢Join us Tuesday, 02-04-25 at 8PM ET as @ndevitomd.bsky.social & @katherinezhoumd.bsky.social from @dukemedschool.bsky.social 🗣️Claudin 18.2 as a🎯in #pancreaticcancer

RT and bring others into the discussion‼️

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Tumor Board Tuesday @tumorboardtuesday.bsky.social · Feb 5

#TumorBoardTuesday

BOOKMARK THIS DISCUSSION‼️

Thank you so much @ndevitomd.bsky.social &
@katherinezhoumd.bsky.social 🙏

That was an amazing summary of what we know to date about targeting Claudin 18.2 in #PancreaticCancer

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

24/31 #TumorBoardTuesday
🏫Mini Tutorial 21🏫
Pooled analysis of CT041 in met panc (NCT03874897, NCT04581473)
24 pts with advanced panc
ORR 16.7%, DCR 70.8%
mPFS 3.3 mos, mOS 10 mos
mDOR 9.5 mos, DOR 50% at 12 mos
AEs: CRS, GI
doi.org/10.1200/JCO.23.02314

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

25/31 #TumorBoardTuesday
🏫Mini Tutorial 22🏫
2) Phase 1b/2, CT041 in CLDN18.2+ adv gastric or panc (ELIMYN18.2, NCT04404595)
19 patients: 7 gastric/GEJ cancer, 12 pancreatic cancer
doi.org/10.1200/JCO.2024.42.3_suppl.356

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

26/31 #TumorBoardTuesday
🏫Mini Tutorial 23🏫
58% panc pts had ≥3 prior lines
PC: ORR 16.7%, mDOR 3.4 mos, CBR 33.3%
At dose level 3, 2/5 PR in panc pts
CRS mostly grade 1-2, 2 cases grade 3
ICANS grade 1 in 2 pts

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

27/31 #TumorBoardTuesday
Back to our case🔎
Enrolled in CD3 x CLDN18.2 BiTE trial
At 1 month, SD by CT but rising CA19-9 (206 -> 791)

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

28/31 #TumorBoardTuesday
🏫Mini Tutorial 24🏫
How about CLDN18.2 BiTE+X combos?
1) BiTE+chemo
Chemo increases immunogenicity, depletes immunosuppressive Tregs (CD3-targeting BiTEs recruit polyclonal T cells, including Tregs)
NCT05365581: ASP2138 (CD3 x CLDN18.2) ± chemo

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

29/31 #TumorBoardTuesday
🏫Mini Tutorial 25🏫
2) BiTE+ICI
BiTEs -> inhibitory checkpoints upregulated
KPC orthotopic model:
CLDN18.2 x CD3 BiTE + αPD1 -> decreased tumor growth compared to BiTE or αPD1 alone
doi.org/10.1053/j.gastro.2023.06.037

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

30/31 #TumorBoardTuesday
🏫Mini Tutorial 26🏫
3) BiTE+OV
Oncolytic virus -> tumor lysis -> T cell response
SQ model of KPC w/ human CLDN18.2 in CD3ε humanized mice:
OV-BiTE improved tumor control and survival compared to OV-GFP or PBS ctrl
doi.org/10.1016/j.omto.2023.08.011

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

31/31 #TumorBoardTuesday
🏫Mini Tutorial 27🏫
Choice of CLDN18.2 BiTE vs CAR-T?
BiTE: off the shelf, continuous therapy
CAR-T: autologous (takes time), one infusion
doi.org/10.1186/s13045-021-01067-5

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

23/31 #TumorBoardTuesday
🏫Mini Tutorial 20🏫
96.9% CRS, all grade 1-2
8% gastric mucosal injury, 1 pt w/ grade 3
No DLTs, treatment related deaths, ICANS

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

22/31 #TumorBoardTuesday
🏫Mini Tutorial 19🏫
ORR 38.8%, DCR 91.8%, mDOR 6.4 mos
Among 10 pts with PDAC: 2 PR, 7 SD, 1 PD
doi.org/10.1038/s41591-024-03037-z

Waterfall plot for CT041 (CLDN18.2 CAR-T)

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

19/31 #TumorBoardTuesday
Mini Tutorial 16
4) Phase 1/2, PM1032 (CLDN18.2 x 41BB bispecific) in adv solid tumors (NCT05839106)
Activates T and NK cells
30 patients, no DLTs, 66.7% CLDN18.2+
14 gastric/GEJ, 10 panc, 5 other GI
17 CLDN18.2+ pts at ≥5 mg/kg: 2 PR, 7 SD

PM1032 (bispecific targeting CLDN18.2 and 41BB) in advanced solid tumors

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

18/31 #TumorBoardTuesday
🏫Mini Tutorial 15🏫
Efficacy for 600 µg/kg in CLDN18.2 IHC 2+/3+ ≥10%:
27 pts, 8 PRs, 11 SDs, ORR 39.6%, DCR 70.4%
DOR and PFS not reached

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

15/31 #TumorBoardTuesday
🏫Mini Tutorial 12🏫
CLDN18.2 bispecific trials:
1) Phase 1, Q-1802 (PD-L1 x CLDN18.2) (NCT04856150)
17 pts w/ adv gastric, PC, or BTC, mostly ≥3 prior lines
2/9 PRs, 4/9 SDs
AEs: n/v, abd pain, GERD
24.1% G3 TRAEs
doi.org/10.1200/JCO.2023.41.4_suppl.382

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

16/31 #TumorBoardTuesday
🏫Mini Tutorial 13🏫
2) Phase 1, ASP2138 (CD3 x CLDN18.2 BiTE) ± chemo in CLDN18.2+ adv gastric/GEJ or PC (NCT05365581)
2+1: 2 CLDN18.2 binding sites, 1 CD3 binding site

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

17/31 #TumorBoardTuesday
🏫Mini Tutorial 14🏫
3) Phase 1, IBI389 (CLDN18.2 x CD3) in adv PDAC (NCT05164458)
64 patients, median 2 prior lines
54.7% G3+ TRAEs: GGT increased, lymphs decreased, nausea
51.6% CRS, no grade 3+
TEAEs -> dose interruption 37.5%, discontinuation 4.7%

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Mike Pishvaian @mpishvaian.bsky.social · Feb 5

#TumorBoardTuesday

Wow - that was worth the anticipation

This is as a single agent (ADC)❓

This is as promising as all the (well deserved) hype with KRAS⛔

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

14/31 #TumorBoardTuesday
🏫Mini Tutorial 11🏫
CLDN18.2 IHC 1+/2+/3+ ≥40%: ORR 28% (all PRs: 5 PDAC, 2 BTC), DCR 80%
CLDN18.2 ≥60%: ORR 38.5% (all PRs: 4 PDAC, 1 BTC), DCR 84.6%
25.7% G3+ TRAEs: anemia, neutropenia, elevated AST
Dose interruption 20%, discontinuation 2.9%

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

13/31 #TumorBoardTuesday
🏫Mini Tutorial 10🏫
2) Phase 1, IBI343 (CLDN18.2 ADC w/ exatecan) in PDAC or BTC (NCT05458219)
35 patients enrolled: 28 PDAC, 7 BTC (all pretreated)
Dose expansion: CLDN18.2 IHC 1+/2+/3+ ≥40%
doi.org/10.1200/JCO.2024.42.16_suppl.3037

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

12/31 #TumorBoardTuesday
Mini Tutorial 9
Trials of CLDN18.2 ADCs:
1) Phase 1, SYSA1802/EO3021 (CLDN18.2 ADC w/ MMAE) in adv solid tumors (NCT05980416)
Promising results in gastric/GEJ, panc results pending
TEAEs: nausea, anorexia, fatigue, diarrhea

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Mike Pishvaian @mpishvaian.bsky.social · Feb 5

#TumorBoardTuesday

So - it seems like there is higher Claudin 18.2 expression in more advanced #PancreaticCancer - but interesting that its expression is not associated with survival🤔

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

11/31 #TumorBoardTuesday
🏫Mini Tutorial 8🏫
2) Phase 1b, 1L FG-M108 + gem/abraxane for advPC w/ CLDN18.2 IHC 1+/2+/3+ ≥10% (NCT04894825)
FG-M108: afucosylated human CLDN18.2 mAb w/ enhanced ADCC
ORR 50%, DCR 100% among 14 pts
SEs: nausea, emesis, neutropenia, anemia

FG-M108 plus nab-paclitaxel and gemcitabine 1L for CLDN18.2+ locally advanced unresectable or metastatic pancreatic cancer

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

10/31 #TumorBoardTuesday
🏫Mini Tutorial 7🏫
Trials of CLDN18.2 antibodies:
1) Phase 2, mPC w/ mod-strong CLDN18.2 IHC >75% randomized to 1L gem/abraxane ± zolbetuximab (NCT03816163) - results pending (rb.gy/yhczya)

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

9/31 #TumorBoardTuesday
🏫Mini Tutorial 6🏫
CLDN18.1 isoform is expressed in lung
CLDN18.2 is dominant in gastric/pancreatic cancer (rb.gy/uwykch)
% CLDN18.2+ seems to matter more than staining intensity (unlike HER2)

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Katherine Zhou @katherinezhoumd.bsky.social · Feb 5

8/31 #TumorBoardTuesday
🏫Mini Tutorial 5🏫
Ventana CLDN18 43-14A RxDx assay
FDA approved for zolbetuximab in gastric/GEJ adeno
43-14A binds intracellular domain, does not distinguish CLDN18.2 vs CLDN18.1
doi.org/10.1038/s41571-024-00874-2

Binding sites of anti-CLDN18.2 antibodies

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