Mobocertinib, a novel EGFR tyrosine kinase inhibitor (TKI), demonstrated clinically meaningful benefit in platinum-pretreated patients with EGFR exon 20 insertion mutant (EGFRex20ins+) non-small cell lung cancer (NSCLC) in an open-label, multicenter clinical trial. This study describes an indirect comparison of clinical outcomes for platinum-pretreated patients with EGFRex20ins+ NSCLC treated with mobocertinib in a clinical trial vs. standard of care (SoC) from real-world data (RWD). Clinical outcomes were compared for platinum-pretreated patients with EGFRex20ins+ NSCLC treated with mobocertinib 160 mg QD in a phase I/II trial (NCT02716116; cutoff 1 Nov 2020) vs. SoC in the post-platinum second or later line (≥2L) setting from the Flatiron electronic health record database (RWD; cutoff 29 Feb 2020). The analysis was conducted in an unadjusted data set and using propensity score modeling with inverse probability of treatment weighting (IPTW) to adjust for group differences in key baseline characteristics. Confirmed overall response rate (cORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. This study included 164 platinum-pretreated patients (n=114 mobocertinib/n=50 RWD; mean age 60/64 years; female, 66%/68%; smoking history 29%/42%; with baseline brain metastasis, 35%/34%). In the RWD, ≥2L SoC treatment consisted of 20% EGFR TKI, 40% immunotherapy alone, and 40% chemotherapy ± immunotherapy or monoclonal antibody. Baseline characteristics were balanced after weighting. In the weighted cohort, cORR for mobocertinib vs. RWD was 35 % vs. 12%, median PFS was 7.3 vs. 3.3 mo, and median OS was 24.0 vs. 12.4 mo, respectively (Table).Table: 1211PMobocertinib (n=114)aRWD Post-platinum ≥2L bUnweighted (n=50)Weighted (n=109)cORR % (95% CI)35 (26, 45)14 (6, 27)12 (6, 18)Rate difference % (95% CI)21 (8, 34)23 (12, 34)Odds ratio (95% CI)cP-value3.32 (1.68, 6.58) 0.00063.75 (2.05, 6.89) <0.001Median PFS, mo (95% CI)7.3 (5.6, 8.8)3.3 (2.3, 5.9)3.3 (2.2, 7.3)HR (95% CI)dP-value0.57 (0.36, 0.89) 0.01490.57 (0.36, 0.90) 0.0153Median OS, mo (95% CI)24.0 (14.6, 28.8)11.5 (7.9, 16.6)12.4 (7.1, 16.6)HR (95% CI)dP-value0.54 (0.34, 0.84) 0.00680.53 (0.33, 0.83) 0.0056acORR and PFS: per investigator using RECIST 1.1 bcORR: confirmed real-world response by radiologic imaging cLogistic model dCox model CI, confidence interval; HR, hazard ratio Open table in a new tab acORR and PFS: per investigator using RECIST 1.1 bcORR: confirmed real-world response by radiologic imaging cLogistic model dCox model CI, confidence interval; HR, hazard ratio Mobocertinib was associated with significant improvements in cORR, PFS, and OS compared to SoC used in the in platinum-pretreated patients with EGFRex20ins+ NSCLC.