Background: Amivantamab is an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune cell-directing activity. Amivantamab has demonstrated efficacy and safety in patients (pts) with EGFR exon 20 insertion (Exon20ins) in the ongoing CHRYSALIS phase 1 study in advanced non-small cell lung cancer (aNSCLC). Because CHRYSALIS is a non-randomized, single arm study, external controls (EC) can add valuable context in interpreting amivantamab’s efficacy and appreciating the unmet needs given real-world therapies. A protocol-driven treatment comparison was conducted of amivantamab vs real-world therapies in pts with Exon20ins aNSCLC who progressed after platinum chemotherapy. Methods: Custom curated, real-world data abstracting clinically relevant measures that are not typically available from off-the-shelf datasets were obtained from 3 US-based companies: Flatiron, COTA, and ConcertAI. Datasets were de-duplicated via a tokenization procedure, analyzed separately and as a single pooled database. Key eligibility for the EC included: Exon20ins aNSCLC, prior platinum chemotherapy, ≥1 line after platinum therapy, and ECOG PS 0 or 1. Propensity score weighting (average treatment effects on the treated) was used to adjust for differences in age, brain metastases, ECOG PS, and number of prior lines of therapy (LOT). Results: The amivantamab-treated population (N = 81) included post-platinum pts with EGFR Exon20ins aNSCLC treated at the recommended phase 2 dose (Sabari WCLC 2020 Abs #3031). After de-duplication of the custom real-world datasets, 126 unique pts formed the EC. Most frequent treatments after platinum doublet chemotherapy in the EC group were checkpoint inhibitors (CPI; 25%), single-agent, non-platinum chemotherapies (25%), and EGFR tyrosine-kinase inhibitors (TKIs; 16%). Baseline demographics were generally similar between amivantamab and the EC pts; notable differences included a higher percentage of Asian pts (56% vs 9%) and more prior LOT (median 2 vs 1) among the amivantamab compared to the EC pts. Median overall survival (OS) among amivantamab pts was 22.8 months and EC pts was 13.1 months (HR = 0.53 [95% CI, 0.33, 0.86]). Similarly, amivantamab pts had longer progression-free survival (8.3 vs 2.9 months; HR = 0.46 [95% CI, 0.33, 0.63]) and time to next treatment (14.8 vs 4.8 months; HR = 0.42 [95% CI, 0.29, 0.6]) compared to the EC pts. Confirmed overall response rate was 40% among amivantamab pts and 10% for the EC pts (odds ratio = 4.44 [95% CI 2.42, 8.14]). Conclusions: Amivantamab demonstrated a 10-month higher OS than real-world therapies in the post-platinum setting. The poor performance of the EC, frequently treated with CPI, single chemotherapies, and EGFR TKI, highlights the ineffectiveness of these agents and the urgent need to find more alteration-specific treatments in aNSCLC.