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Simple Summary: The tyrosine kinase inhibitor alectinib is currently the first-line treatment for advanced ALK-positive non-small cell lung cancer. The aim of this commentary is to highlight data from clinical trials, case reports, and case series evaluating alectinib in patients with early-stage ALK-positive non-small cell lung cancer in the adjuvant and perioperative setting. The results of the commentary suggest that alectinib could be the new adjuvant option for stage IB-IIIA ALK-positive NSCLC based on the phase III ALINA trial and, in the near future, the results of the phase II ALNEO and NAUTIKA1 trials, evaluating alectinib in the neoadjuvant/perioperative setting, which could further modify the current therapeutic strategy. Background: Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease. Results: The ALINA trial evaluated the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging. Conclusion: In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we strive to identify clinically relevant image feature (IF) changes during chemoradiation in patients with non-small-cell lung cancer (NSCLC) to be able to predict tumor responses in an early stage of treatment. All patients underwent static (3D) and respiratory-gated 4D PET/CT scans before treatment and a 3D scan during or after treatment. Our proposed method rejects IF changes due to intrinsic variability such as noise, resolution and movement through breathing. The IF variability observed across 4D PET is employed as a patient individualized normalization factor to emphasize statistically relevant IF changes during treatment. The aim of this study is to identify clinically relevant image feature (IF) changes during chemoradiation and evaluate their efficacy in predicting treatment response. Patients with non-small-cell lung cancer (NSCLC) were enrolled in two prospective trials (STRIPE, PET-Plan). We evaluated 48 patients who underwent static (3D) and retrospectively-respiratory-gated 4D PET/CT scans before treatment and a 3D scan during or after treatment. Our proposed method rejects IF changes due to intrinsic variability. The IF variability observed across 4D PET is employed as a patient individualized normalization factor to emphasize statistically relevant IF changes during treatment. Predictions of overall survival (OS), local recurrence (LR) and distant metastasis (DM) were evaluated. From 135 IFs, only 17 satisfied the required criteria of being normally distributed across 4D PET and robust between 3D and 4D images. Changes during treatment in the area-under-the-curve of the cumulative standard-uptake-value histogram (δAUCCSH) within primary tumor discriminated (AUC = 0.87, Specificity = 0.78) patients with and without LR. The resulted prognostic model was validated with a different segmentation method (AUC = 0.83) and in a different patient cohort (AUC = 0.63). The quantification of tumor FDG heterogeneity by δAUCCSH during chemoradiation correlated with the incidence of local recurrence and might be recommended for monitoring treatment response in patients with NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Osimertinib, a third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has shown marked clinical benefit for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, resistance to osimertinib inevitably develops and heterogeneous mechanisms of acquired resistance have been documented. Therefore, new strategies to bypass resistance are urgently needed. In this study, we investigated the potential activity of abemaciclib as second-line therapeutic approach after osimertinib progression and the effect of combining abemaciclib with osimertinib on the appearance of resistance in osimertinib-sensitive models. Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment. [ABSTRACT FROM AUTHOR]

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4–3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6–5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing. [ABSTRACT FROM AUTHOR]