Real-world survival and responses to HER2 directed treatment in gastrointestinal cancers based on HER2 non-amplified mutation and HER2 amplification/overexpression status.

307 Background: Human epidermal growth factor receptor 2 (HER2) plays a vital role in cell proliferation, apoptosis, and ultimately tumorigenesis. HER2 targeted treatment (HER2 tx) has improved survival for patients with HER2 amplified tumors; however, its role in HER2 nonamplified mutated GI cancers is not well established. The objective of this study is to determine trends in survival and response to HER2 tx for GI cancers based on tumor location and non-amplified HER2 mutation and HER2 amplification/overexpression status. Methods: The retrospective, multicenter analysis used the Flatiron Health Research Database, a deidentified electronic health record-derived database of real world (rw) patients with advanced GI cancers who received HER2 tx. Patients were categorized as HER2mut+ or HER2mut- based on the presence or absence of a definitely pathogenic or likely pathogenic HER2 non-amplification mutation. HER2Amp+ or HER2Amp- was defined by the presence or absence of HER2 amplification/overexpression (either HER2 gene amplification or 3+ by IHC and 2+/FISH+). Index date was defined by the start of HER2 tx. The cox proportion hazards models were used to compare rw overall survival (OS) and progression-free survival (PFS) across subgroups. Results: A total of 858 patients who received HER2 tx were included [esophagogastric (EGC) n=709 and non-EGC (colorectal, pancreatic, and HCC) n=149]. In HER2mut+ EGC, OS was longer among those with HER2Amp+ compared to HER2Amp-, with an OS of 17 and 7.1 months, respectively. Among HER2Amp+ EGC, there was no statistically significant difference in OS between HER2mut+ and HER2mut-. Similarly, there was no difference in PFS for HER2mut+/HER2Amp+ and HER2mut-/HER2Amp+ (7.4 vs. 7.4 mo). In the non-EGC cohort, there was a non-statistically significant trend towards worse OS and PFS with HER2mut+/HER2Amp+ compared to HER2mut-/HER2Amp+ (OS 5 vs. 16 mo; PFS 2.2 vs. 4.6 mo). Conclusions: Our study identifies a lack of benefit with HER2 tx in HER2mut+ EGC in the absence of HER2 amplification/overexpression. This highlights the importance of HER2 amplification rather than presence of a HER2 non-amplifying mutation for EGC. In EGC, coexisting HER2 mutation does not have a negative effect on HER2 tx efficacy in the setting of HER2 amplification; however, there may be a negative impact with coexisting HER2 mutations in the setting of HER2 amplified non-EGC. Further investigation is needed to determine if specific HER2 mutations alone can be targeted to induce a treatment response.