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Cyclin-dependent kinases (CDKs) are key regulators of cell cycle progression in malignant tumor cells and play an important role through complex molecular interactions. Dysregulation of CDK dependent pathways is often found in non-small cell lung cancer, which indicates its vulnerability and can be used in clinical benefit. CDK4/6 inhibitors can prevent tumor cells from entering the G approved 1 and S phases, which have been studied in a series of explorations and brought great clinical effect to patients and encouragement to both physicians and researchers, thereby showing potential as a new therapeutic agent. A series of preclinical and clinical studies have been carried out on CDK4/6 inhibitors in NSCLC, and have been achieved some results, which may become a new potential treatment in the future. This review focuses on the research progress on CDK4/6 inhibitors in NSCLC, particularly the mechanisms of action, drugs, clinical research progress, and future application.

Background: Despite the emergence of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors in the treatment of non-small cell lung cancer (NSCLC) patients with brain metastases (BMs), knowledge gaps remain regarding the impact and timing of cranial radiotherapy for patients receiving anti-PD-1/PD-L1 therapy.Methods: Data were collected from 461 consecutive patients who received anti-PD-1/PD-L1 therapy for metastatic NSCLC at three institutions between June 2017 and September 2020. Intracranial progressive disease (PD) at the original disease sites, new sites, or both sites were classified as original-site PD (OPD), new-site PD (NPD), and original-and-new-site PD (ONPD), respectively. Patients with baseline BMs were categorized based on whether they received upfront cranial radiotherapy (uCRT) at any time point between the introduction of anti-PD-1/PD-L1 therapy and the first subsequent progression.Results: Of the 461 patients enrolled, 110 (23.9%) had BMs at baseline. The presence of BMs did not show independent prognostic value for progression-free survival (PFS) or overall survival (OS). During a median follow-up of 13.2 months, 96 patients with BMs developed PD, of whom 53 (55.2%) experienced intracranial PD. OPD, NPD, and ONPD were observed in 50.9%, 18.9%, and 30.2% of patients, respectively. Patients who received uCRT exhibited a longer median OS than those with BMs who did not receive uCRT (25.4 vs. 14.6 months, HR: 0.52, 95% CI: 0.29-0.91, P=0.041); this survival advantage was more prominent in patients with 1-4 BMs (median OS, 25.4 vs. 17.0 months, HR: 0.42, 95% CI: 0.22-0.81, P=0.024), and uCRT was independently associated with OS among these patients. Conclusions:The presence of BMs at baseline was not associated with poorer OS in patients with metastatic NSCLC treated with anti-PD-1/PD-L1 therapy. Intracranial progression on PD-l/PD-L1 inhibitors predominately occurred at the original BM sites. The use of uCRT may improve OS, especially in NSCLC patients with 1-4 BMs.

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Introduction Considerable differences of treatment response and pattern of failure may exist between definitive chemoradiation (CRT) treated locally advanced non‐small cell lung cancer (LA‐NSCLC) patients. The clinical value of additional tyrosine kinase inhibitors (TKIs) before disease recurrence and salvage local therapy after initial recurrent disease remain controversial. Methods and Materials Consecutive LA‐NSCLC patients receiving definitive CRT and having definite results about driver mutations (EGFR, ALK and ROS1) were retrospectively reviewed. Initial recurrent disease was classified as in‐field recurrence, out‐of‐field recurrence and distant metastasis. Recurrent disease occurred only in the brain or limited to ≤3 extra‐cranial organs and ≤5 extra‐cranial lesions, was defined as oligo‐recurrence. Progression free survival and overall survival (OS) were calculated from diagnosis to disease progression or death, and to death, respectively. OS2 was measured from initial disease recurrence to death among patients who had recurrent disease. Results Of the 153 enrolled patients, 39 had driver mutations and 13 received additional TKI therapy besides definitive CRT. Patients harboring driver mutations but without additional TKI therapy had a similar PFS and significantly longer OS ( p = 0.032) than those without driver mutations. Additional TKI therapy prolonged PFS ( p = 0.021) but not OS among patients with driver mutations. No significant difference of pattern of failure was observed between patient subgroups stratified by the status of driver mutations and the usage of additional TKI therapy. Furthermore, 57 of the 95 patients with initial recurrent disease developed oligo‐recurrence and salvage local therapy significantly improved OS2 ( p = 0.01) among patients with oligo‐recurrence disease. Conclusion LA‐NSCLC patients receiving definitive CRT generally had similar PFS and pattern of treatment failure, regardless of driver mutation status. Additional TKI therapy besides definitive CRT could prolong PFS but not OS. The majority of recurrent disease after definitive CRT belongs to oligo‐recurrence and salvage local therapy may provide survival benefit.