#ESMO26 #GIST: three nice abstracts tackling the same problem (polyclonal resistance) from different angles. Resistance after imatinib is a mosaic of secondary KIT mutations and no approved KIT inhibitor addresses them all. Kudos to Dr. @RobinL_Jones, Dr Bauer, Dr Chi and Dr @dileo_palma for an excellent session. Great discussion by Dr. Dileo. 🔹 PEAK crossover bezuclastinib + sunitinib (SUT) after PD on 2L SUT: • ORR 29.7% (56% if best response to SUT was PD); • mPFS 7.4; • Gr≥3 TRAEs 39%, discontinuation 2.3% Caveat: non-randomized, benefit drops from the historical 16.5 mo upfront to 7.4 mo after SUT failure. 🔹 NB003 - final analysis of ph1 (n=158): • ORR 46.7% in 3L and 45.7% in 4L, 12.5% in ≥5L • mPFS 13.8 mo (3L), 11.0 mo (4L), 3.9 mo (≥5L) • Responses across a variety of secondary mutations in ABP and AL. Caveat: predominant Asian representation (67%), Gr≥3 anemia 55%, CPK rise 49%. Phase 3 GISTAR-1 (vs. Rego) will provide more definitive efficacy data in the 3rd-line setting, but will only accrue in Asia. 🔹 StrateGIST-1 —> longitudinal ctDNA analysis: • Detectable baseline ctDNA: PFS 7.3 vs 16.6 mo (HR 0.39) • Clearance (>99% drop in maxVAF) at wk 2/4/8: HR 0.51/0.65/0.57 • Mutation-agnostic maxVAF outperformed mean VAF and Guardant360 score Caveat: exploratory, landmark bias, not shown independent of imaging or tumour burden. Hypothesis-generating. 💡 Take-Home: 1. Broader KIT coverage is the shared goal, and treating earlier is likely better. 2. Combination vs single broad-spectrum agent is unresolved, with different toxicity trade-offs (and access/costs, once these drugs start getting approved). 3. ctDNA could serve all three strategies, as an early efficacy readout, for response-adapted treatment and for trial enrichment, but needs prospective validation. #ESMO2026 #ESMOAmbassadors @myESMO #GIST