Lee, Chee KhoonChee KhoonLeeBIN-CHI LIAOSubramaniam, ShaliniShaliniSubramaniamChiu, Chao-HuaChao-HuaChiuMersiades, Antony JAntony JMersiadesCHAO-CHI HOBrown, ChrisChrisBrownLai, Chun-LiangChun-LiangLaiHughes, Brett G MBrett G MHughesYang, Tsung-YingTsung-YingYangO'Byrne, KenKenO'ByrneLuo, Yung-HungYung-HungLuoYip, SoniaSoniaYipHo, Ching-LiangChing-LiangHoBray, VictoriaVictoriaBraySu, Wu-ChouWu-ChouSuMoore, MelissaMelissaMooreFeng, Wei-LienWei-LienFengBai, Ya-YingYa-YingBaiFord, KateKateFordCummins, Michelle MMichelle MCumminsStockler, Martin RMartin RStocklerSolomon, Benjamin JBenjamin JSolomonJohn, ThomasThomasJohnChih-Hsin Yang, JamesJamesChih-Hsin Yang2025-02-172025-02-172025-02https://scholars.lib.ntu.edu.tw/handle/123456789/725278Introduction: EGFR-mutant NSCLC is associated with low mutation burden and low levels of PD-L1 expression. We conducted a phase 2 trial to determine the efficacy of durvalumab, tremelimumab, and platinum-pemetrexed in EGFR-mutant NSCLC after progression with EGFR tyrosine kinase inhibitors (TKIs). Methods: Participants were treated with induction durvalumab, tremelimumab, and platinum-pemetrexed, followed by durvalumab-pemetrexed maintenance. Participants were divided into two cohorts: (1) EGFR exon 20 T790M negative (T790M−, progressing on either first-line osimertinib, or on a single line of first/second generation TKI), and (2) T790M positive (T790M+, progressing on greater than or equal to 1 lines of TKI, including osimertinib). The primary endpoint was the confirmed objective response rate (ORR) assessed by the investigators. Progression-free survival and safety were secondary outcomes. Results: One hundred participants from Australia and Taiwan were enrolled. Median follow-up was 26 months with 88% and 96% experiencing progression events for T790M− and T790M+, respectively. The ORR for T790M− was 31% (95% confidence interval: 20–45), including two complete responses. The ORR for T790M+ was 21% (95% confidence interval: 12–34). Median durations of response were 9.5 months and 6.3 months for T790M− and T790M+, respectively; median progression-free survival rates were 6.5 months and 4.9 months, respectively. For T790M−, ORR was 27% for 50% or higher PD-L1 (n = 22) and 0% for less than 50% PD-L1 (n = 10), respectively. For T790M+, ORR was 17% for 50% or higher PD-L1 (n = 24). The safety profile was consistent with previous reports. Conclusions: Durvalumab, tremelimumab, and platinum-pemetrexed had modest anti-tumor activity in EGFR-mutant NSCLC after progression on TKI. The T790M− cohort had higher ORR and a longer duration of response. Immune adverse events were not increased with tremelimumab. The clinical registration number of this trial is NCT03994393.enCheckpoint inhibitorsChemotherapyEGFR mutationNon-small cell lung cancer[SDGs]SDG3journal article10.1016/j.jtocrr.2024.10077139877028