#tumorboardtuesday 🤔Hmmm....much more rapid disease progression on the CDK4/6🚫+AI - does this portend for a worse prognosis in subsequent lines of therapy❓

#tumorboardtuesday Any subtle differences in outcomes based on the specific mutation identified AKT vs. PTEN vs. PIK3CA❓

#TumorBoardTuesday 📢Join us Tuesday, 10-21-25 at 8PM ET as @drgattimays.bsky.social & @KennaKoehler 🗣️ Tx options after CDK4/6⛔️: What to consider in the 2nd line for HR+/HER2– mBC❓ RT and bring others into the discussion‼️

Tune in tomorrow 10/21/25 at 8pm EST for discussion about the ever changing landscape of 2L metastatic ER+ breast cancer #TBT #BCSM @tumorboardtuesday.bsky.social @osuwexmed.bsky.social #BreastCancer

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

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

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

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)

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

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

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

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

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

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

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

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

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

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

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%

#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⛔

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%

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

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

#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🤔

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

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)

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)

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

7/31 #TumorBoardTuesday 🏫Mini Tutorial 4🏫 More CLDN18.2+ if N+ (64% vs 40%) or M1 (79% vs 44%) CLDN18.2 not associated w/ survival (doi.org/10.4251/wjgo.v14.i7.1252) LN and liver mets also express CLDN18.2 (>60%) (doi.org/10.1002/ijc.28400)

6/31 #TumorBoardTuesday 🏫Mini Tutorial 3🏫 Transcription regulated by PKC signaling and CpG methylation Higher CLDN18.2 in gastric-type IPMN (vs intestinal-type), well-diff PDAC (vs poor-diff) doi.org/10.1002/jcb.23095

#TumorBoardTeusday I could definitely see trying FOLFIRINOX or some permutation again 🤔Any NGS🧬results❓

🏫Mini Tutorial 1🏫 CLDN18.2 In normal gastric mucosa: part of tight junctions, not accessible In gastric cancer: becomes exposed -> targetable doi.org/10.1038/s41571-024-00874-2

5/31 #TumorBoardTuesday 🏫Mini Tutorial 2🏫 CLDN18.2 ectopically expressed in PanIN (97%), IPMNs (95), MCNs (80%), PDAC (70%), but not normal pancreatic duct (doi.org/10.1369/0022155411420569)

#TumorBoardTuesday Waiting for a RAS⛔trial is definitely the most common answer (and probably the right one) 📣When are we going to get rapid espanded access to these new agents 👉Calling on you @fda.gov

3/31 #TumorBoardTuesday Continued gem/abraxane Waitlisted for RAS inhibitor trials Screened for CLDN18.2 x CD3 bispecific trial

2/31 #TumorBoardTuesday Abd wall met bx: panc adenocarcinoma MSS TMB 8.5 mut/Mb KRAS G12R CDKN2A frameshift mutation TP53 R282W BRCA1/2 wild-type CLDN18.2 1–50% (positive, low)

1/31 #TumorBoardTuesday 73yo M w/ PDAC met to abd wall, R pelvis, and b/l inguinal canals S/p Whipple + 6 mos adj FOLFIRINOX 3 yrs ago for T2N1 disease 1L gem/abraxane -> PD after 4 mos w/ slight growth of abd wall met (2.8 -> 3.2 cm) ECOG PS 1

✅This #TumorBoardTuesday🗣️with @ndevitomd.bsky.social & @katherinezhoumd.bsky.social is provided by @IntegrityCE 👍Supported by ed grants from Astellas, AstraZeneca, Janssen, Lilly, Novartis, Seagen and Taiho Oncology🙏 Info about 🆓 CME: integrityce.com/TBT2024

#PreTest Q1️⃣ #TumorBoardTuesday Free #CME integrityce.com/TBT2024 B4⃣@ndevitomd.bsky.social & @katherinezhoumd.bsky.social🗣️Claudin 18.2 as a🎯in #pancreaticcancer , test your🧠with these 2❓ 🤔What % of pancreatic adenocarcinoma cases typically express Claudin 18.2❓ 1) 30% 2) 50% 3) 70% 4) 90%

#PreTest Q2⃣#TumorBoardTuesday Free #CME integrityce.com/TBT2024 🧐 Which of the following would you select for a 78-year-old man with mPDAC (CLDN18.2, 45%; MSS; gBRCA WT) and disease progression after gemcitabine/nab=pac❓ 1) FOLFIRINOX 2) Regorafenib trial 3) CLDN18.2 BiTe trial 4) Pembrolizumab

#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‼️

18/20 #TumorBoardTuesday @dr-rshatsky.bsky.social Beyond SERDs/SERMs…novel endocrine therapies targeting other mechanisms in pipeline: Proteolysis targeting chimeras (PROTACs), selective ER covalent antagonists, complete ER antagonists just to name a few!🤯

19/20 #TumorBoardTuesday @dr-rshatsky.bsky.social 👉For instance: Feb 2024, ARV-471, an investigational, oral PROTAC studied in the phase 3 VERITAC-2 trial, received FDA fast-track designation. www.pfizer.com/news/announc...

20/20 #TumorBoardTuesday @dr-rshatsky.bsky.social 🔑points 👉Novel ET are changing trt landscape for ER+/HER2- ABC 🤔W/ expanding options, come opportunities and challenges ➡️Many burning questions: Sequencing therapy, new combinations (ie CDK4/6i+SERDs)...

#PostTest Q1️⃣ #TumorBoardTuesday 👉🏽#CME Eval 🔗 integrityce.com/TBTeval24 👉🏽ALL CME🔗 integrityce.com/TBT2024 Per INAVO120 data in ET-refractory, PIK3CA+ HR+ la/mBC, adding inavolisib to palbociclib + fulvestrant improved mPFS to: 9 months 12 months 15 months 18 months

#PostTest Q2️⃣ #TumorBoardTuesday 👉🏽 Free CME 🔗 integrityce.com/TBT2024 Which is likely to be optimal for HR+ mBC that progresses after 1Y of 1L ribociclib + AI and harbors an ESR1 Y537S mutation? Abemaciclib + fulvestrant Imlunestrant + abemaciclib Elacestrant Capivasertib + fulvestrant

I love this so much! I want to be in a place where I have TOO MANY options for my patients and struggle to choose. It’s never been that way and I am really feeling hopeful that we’re getting there. Because #StageIVNeedsMore! #CanSky #OncSky @tumorboardtuesday.bsky.social

11/20 #TumorBoardTuesday @dr-rshatsky.bsky.social 👩‍⚕️Mini Tutorial 2👩‍⚕️ ESR1 mutations are present in: ~4% of 1L setting ~30% in 2L+ setting 👉Not all ESR1 mutations are created the same! -ESR1 Y537S is associated with relative resistance to fulvestrant! pmc.ncbi.nlm.nih.gov/articles/PMC...

12/20 #TumorBoardTuesday @dr-rshatsky.bsky.social 2023, FDA approved elacestrant based on the EMERALD trial Pts: prior 1-2L ET, ≤1 chemo for ABC: R 1:1 ➡️elacestrant vs SoC ➡️ PFS all: HR = 0.70; p = .002 PFS ESR1m: HR = 0.55; p = .0005 Benefit in key subgroups: PIK3CA mut, ESR1 mut, and TP53 mut

13/20 #TumorBoardTuesday @dr-rshatsky.bsky.social 👩‍⚕️Mini Tutorial 4👩‍⚕️ Novel, oral SERDs in development w/ ⬆️efficacy ⬇️toxicities 👉💡imlunestrant, studied in the EMBER-3 trial presented at #SABCS24 🔑Pt features: ~37% with ESR1m, ~40% with PIK3CAm, >50% visceral disease 👉1/3 adj ET, 2/3 prior CDK4/6i