Background: Targeted therapies (tx) have had limited benefit in advanced (aGEA) due to baseline spatial (primary vs metastatic tumor PT/MT) & temporal molecular heterogeneity (BMH/TMH). We previously reported PANGEA methods & results: 35% BMH rate & 1⁰ OS results achieving 1yr OS of 66% & mOS of 16.4 months (m) using the personalized tx strategy (Catenacci et al. GI ASCO 2020 Abstr356). Here we will report the TMH rates at progressive disease points (PD1 & PD2), ORR/PFS/DCR in each of 3 tx lines, time to strategy failure (TTF), & updated OS/safety. Methods: PANGEA enrolled newly diagnosed aGEA pts who then received up to 3 cytotoxic (cx) tx lines (L). Baseline tissue biomarker profiling (BP) was mandated on PT/MT & PD1/PD2, & ctDNA analysis throughout. After initiating 1L cx & upon learning MT BP results, antibody (AN) was added by a predefined prioritized tx algorithm incorporating tissue & blood BP (Table). At PD1, pts went to 2L cx + initial AN. Upon results of PD1 BP, pts changed AN only if BP evolved per tx algorithm. The same was done at PD2. The 1⁰ endpoint was 1yr OS; enrolling 68 pts provided 80% power to detect a 63% 1yr OS compared to historical 50% 1yr OS (HR 0.67), using a 1-sided test (0.10 alpha). Results: 80 pts were enrolled, & 68 tx’d per protocol. At data cut-off 2/1/20, 15 pts were still on trial with only 2 of these pts on tx <12m (8 pts in 1L, 5 in 2L, 2 in 3L). All 68 pts had at least 1 dose of 1L tx, 87% 2L tx, & 36% 3L tx. AN assigned by the tx algorithm at 1L, OS, TTF, & ORR₁/PFS₁/DCR₁ of 1L tx are shown in Table; 2L & 3L ORR/DCR outcomes will be shown. The 3yr & 4yr OS rates were 12% & 8%. TMH leading to molecular subgroup change by tx algorithm was 51% after 1L & 36% after 2L; details & results by subgroup will be provided. Any grade >3 non-heme tox thru all 3 tx lines was seen in 25% of pts. Conclusions: PANGEA showed superior 1⁰& 2⁰ endpoint efficacy, even when excluding HER2- pts, compared to historical outcomes. Clinical trial information: NCT02213289.

1 MT priority over PT 2 priority over HER2 only 2L+ 3 priority to highest gene copy 4 not in ITT