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Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.
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Background and Objective: The adoption of targeted therapy and immunotherapy has revolutionised the treatment landscape of non-small cell lung cancer. For early staged disease, incorporation of targeted therapy and immunotherapy has recently been demonstrated to reduce recurrence. Development of targeted therapies in advanced lung cancer is driven by advanced genomic sequencing techniques, better understanding of drug resistance mechanisms, and improved drug designs. The list of targetable molecular alteration is continuously expanding, and next generation molecular therapies have shown promise in circumventing drug resistance. Lung cancer patients may achieve durable disease control with immune checkpoint inhibitors however most patients develop immunotherapy resistance. A wide spectrum of resistance mechanisms, ranging from impaired T-cell activation, presence of coinhibitory immune checkpoints, to immunosuppressive tumour microenvironment, have been proposed. A multitude of novel immunotherapy strategies are under development to target such resistance mechanisms. This review aims to provide a succinct overview in the latest development in targeted therapy and immunotherapy for NSCLC management. Methods: We searched all original papers and reviews on targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) using PubMed in June 2022. Search terms included "non-small cell lung cancer", "targeted therapy", "immunotherapy", "EGFR", "ALK", "ROS1", "BRAF V600E", "MET", "RET", "KRAS", "HER2", "ERBB2", "NRG1", "immune checkpoint", "PD-1", "PD-L1", "CTLA4", "TIGIT", "VEGF", "cancer vaccine", "cellular therapy", "tumour microenvironment", "cytokine", and "gut microbiota". Key Content and Findings: We first discuss the incorporation of targeted therapy and immunotherapy in early staged NSCLC. This includes the latest clinical data that led to the approval of neoadjuvant immunotherapy, adjuvant immunotherapy and adjuvant targeted therapy for early staged NSCLC. The second section focuses on targeted therapy in metastatic NSCLC. The list of targetable alteration now includes but is not limited to EGFR, ALK, ROS1, BRAF V600E, MET exon 14 skipping, RET, KRAS G12C, HER2 and NRG1. Potential drug resistance mechanisms and novel therapeutics under development are also discussed. The third section on immunotherapy in metastatic NSCLC, covers immunotherapy that are currently approved [anti-PD-(L)1 and anti-CTLA4], and agents that are under active research (e.g., anti-TIGIT, cancer vaccine, cellular therapy, cytokine and other TME modulating agents). Conclusions: This review encompasses the latest updates in targeted therapy and immunotherapy in lung cancer management and discusses the future direction in the field.