Background: Despite an initial good response to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), resistance to treatment eventually develops. Although several resistance mechanisms have been discovered, little data exist regarding Asian patient populations. Methods: Among patients at a tertiary referral hospital in Korea who initially responded well to gefitinib and later acquired resistance to treatment, we selected those with enough tissues obtained before EGFR-TKI treatment and after the onset of resistance to examine mutations by mass spectrometric genotyping technology (Asan-Panel), MET amplification by fluorescence in situ hybridization (FISH), and analysis of AXL status, epithelial-to-mesenchymal transition (EMT) and neuroendocrine markers by immunohistochemistry. Results: Twenty-six patients were enrolled, all of whom were diagnosed with adenocarcinoma with EGFR mutations (19del: 16, L858R: 10) except one (squamous cell carcinoma with 19del). Secondary T790M mutation was detected in 11 subjects (42.3%) and four of these patients had other co-existing resistance mechanisms; increased AXL expression was observed in 5/26 patients (19.2%), MET gene amplification was noted in 3/26 (11.5%), and one patient acquired a mutation in the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA) gene. None of the patients exhibited EMT; however, increased CD56 expression suggesting neuroendocrine differentiation was observed in two patients. Interestingly, conversion from L858R-mutant to wild-type EGFR occurred in one patient. Seven patients (26.9%) did not exhibit any known resistance mechanisms. Patients with a T790M mutation showed a more favorable prognosis. Conclusion: The mechanisms and frequency of acquired EGFR-TKI resistance in Koreans are comparable to those observed in Western populations; however, more data regarding the mechanisms that drive EGFR-TKI resistance are necessary.

Trastuzumab deruxtecan (T-DXd) demonstrated strong and durable responses in patients with previously treated human epidermal growth factor receptor 2 (HER2;ERBB2)-mutant (HER2m) metastatic non-small cell lung cancer (mNSCLC) in the DESTINY-Lung02 primary analysis (December 23, 2022, data cutoff). This final analysis evaluated T-DXd efficacy and safety after 8 additional months of follow-up, including clinically relevant subgroups and patient-reported outcomes. DESTINY-Lung02 was a randomized, dose-blinded, multicenter, phase 2 trial. Patients with previously treated HER2m mNSCLC were randomized 2:1 to receive T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review. As of August 25, 2023, 102 and 50 patients had received T-DXd 5.4 or 6.4 mg/kg, respectively. Median follow-up (Q1-Q3) was 15.8 months (8.2-20.7) and 16.5 months (9.4-20.8). cORR (95% CI) was 50.0% (51/102; 39.9%-60.1%) and 56.0% (28/50; 41.3%-70.0%). Safety profile was acceptable and generally manageable. Median treatment duration (Q1-Q3) was 7.7 months (3.7-14.4) and 8.3 months (2.8-13.1); drug-related grade ≥3 treatment-emergent adverse events occurred in 39.6% (40/101) and 60.0% (30/50), with nausea most common (67.3% [68/101], 82.0% [41/50]). Adjudicated drug-related interstitial lung disease (ILD) occurred in 14.9% (15/101) and 32.0% (16/50), mostly grade 1/2; one grade 5 in each arm. Health-related quality of life (HRQoL) was preserved for the duration of T-DXd treatment while sample size was sufficient for analysis, with no adverse effects on HRQoL observed at either dose. T-DXd showed strong and durable responses at both doses, with no clinically significant changes in toxicity. The approved 5.4-mg/kg dose showed a more favorable benefit-risk profile, including lower adjudicated drug-related ILD incidence.

To investigate the efficacy and safety of nivolumab in Korean patients with stage IIIB/IV or recurrent non-small-cell lung cancer (NSCLC) who failed platinum-based chemotherapy. In this multicenter, open-label, Phase II study, 100 patients with stage IIIB or IV squamous (n = 44) or non-squamous (n = 56) NSCLC received nivolumab 3 mg/kg every 2 weeks for 6 weeks per treatment cycle. Patients continued treatment until disease progression or intolerable adverse events (AEs), and then entered a follow-up phase. The primary efficacy endpoint was the centrally assessed objective response rate (ORR). The ORR was 20.0% (95% confidence interval [CI]: 13.3-28.9%) in the total population, 15.9% (7/44 patients; 95% CI: 7.9-29.4%) in patients with squamous NSCLC, and 23.2% (13/56 patients; 95% CI: 14.1-35.8%) in patients with non-squamous NSCLC. Median overall survival was 13.9 (95% CI: 10.8-18.5) months in the total population, 12.3 (95% CI: 8.2-18.5) months in squamous NSCLC, and 16.3 (95% CI: 10.8, -) months in non-squamous NSCLC. Median progression-free survival was 2.8 (95% CI: 1.4-5.7), 2.6 (95% CI: 1.3-5.7), and 5.3 (95% CI: 1.4-7.1) months in the total, squamous, and non-squamous NSCLC populations, respectively. The median duration of response was 11.7 (95% CI: 5.6, -), 12.0 (95% CI: 4.8, -), and 12.1 (95% CI: 3.0, -) months in the total, squamous, and non-squamous NSCLC populations, respectively. The most frequent AEs were decreased appetite, dyspnea, and cough in 43 (43.0%), 32 (32.0%), and 29 (29.0%) patients, respectively. The most common Grade ≥3 AE was pneumonia, occurring in 7.0% of patients. Common treatment-related AEs included decreased appetite (14.0%) and pruritus (6.0%), neither of which was Grade ≥3. The efficacy and safety of nivolumab in Korean patients with advanced or recurrent squamous or non-squamous NSCLC are consistent with previous reports.