Emerging Mechanism of Action

Key Mechanisms of Action Emerging for Lung Cancer Treatment

Recent PubMed publications highlight several emerging mechanisms of action for lung cancer treatment:

Immune Checkpoint Inhibitors (ICIs)

PD-1/PD-L1 inhibitors have become a cornerstone in non-small cell lung cancer (NSCLC) treatment, significantly improving overall survival (HR 0.71), progression-free survival (HR 0.88), and objective response rate (HR 2.03) compared to chemotherapy. Pembrolizumab and atezolizumab are now approved for first-line treatment of advanced NSCLC. The efficacy of ICIs is influenced by single gene mutation status, with TP53, EGFR, and KRAS mutations affecting survival benefits differently.

Targeted Molecular Therapies

Tyrosine kinase inhibitors (TKIs) targeting specific mutations show promising results: - ALK inhibitors have evolved through three generations, with lorlatinib showing the best progression-free survival and alectinib demonstrating the best overall survival and safety profile - MET inhibitors like capmatinib received FDA approval for NSCLC with MET exon 14 skipping mutations - EGFR mutations remain predictive of benefit from TKIs

Combination Approaches

Novel combination strategies demonstrate enhanced efficacy: - PD-1/PD-L1 inhibitors combined with radiotherapy improve survival outcomes in NSCLC - Anti-angiogenesis agents with immunotherapy show satisfactory antitumor activity with acceptable toxicity - PD-1/L1 inhibitors plus anti-VEGF agents demonstrate superior clinical benefit compared to PD-1/L1 inhibitors plus CTLA-4 inhibitors - Adjuvant PD-1/PD-L1 inhibitors reduce relapse risk (HR 0.72)

Antibody-Drug Conjugates (ADCs)

ADCs combine targeted therapy precision with cytotoxic effects of chemotherapy: - Trastuzumab Deruxtecan and Patritumab Deruxtecan show promise in HER2-positive and EGFR-mutant NSCLC - TROP-2 directed ADCs (Sacituzumab Govitecan and Datopotamab Deruxtecan) yield promising activity with manageable safety profiles

Biomarkers for Treatment Selection

Inflammatory biomarkers including NLR, ALI, PLR, CRP, and mGPS demonstrate independent prognostic value in patients receiving immunotherapy. Platelet to lymphocyte ratio (PLR) is associated with poorer overall survival (HR=2.24) and progression-free survival (HR=1.66).

Complementary Approaches

• eHealth programs promote physical activity among thoracic malignancy survivors as a therapeutic strategy
• Cordyceps sinensis as an adjuvant treatment improves tumor response rate, quality of life, and immune function by increasing CD4, CD8, NK cells, and immunoglobulin levels

Despite these advances, challenges remain, including resistance mechanisms to targeted therapies and the need for higher quality trials investigating combinations of histopathological type and genotyping to better guide treatment decisions. Gene sequencing during clinical treatment is increasingly important to determine mutations and predict treatment efficacy.

Emerging End Points

Recent Studies

Recent Lung Cancer Studies: Interventions and Outcomes

GBP1 in NSCLC (2021)

Intervention: GBP1 knockdown using shRNA in NSCLC cells

Efficacy Outcomes: - GBP1 knockdown significantly inhibited proliferation of NSCLC cells - Cell apoptosis was promoted after GBP1 knockdown - Resistance to paclitaxel was reversed after GBP1 knockdown in paclitaxel-resistant cells - Wnt/β-catenin signaling pathway was repressed via knockdown of GBP1 - GBP1 was identified as a novel oncogene in NSCLC

Circ-MYBL2 in NSCLC (2022)

Intervention: Study of circ-MYBL2 and its interaction with miR-28

Efficacy Outcomes: - Circ-MYBL2 suppressed the effects of miR-28 on cell proliferation and apoptosis - Circ-MYBL2 sponges oncogenic miR-28 to suppress cancer cell proliferation and promote cell apoptosis - Close correlations between circ-MYBL2 and miR-28 and patients' survival were observed

UCHL1 in Lung Adenocarcinoma (2022)

Intervention: UCHL1 silencing in lung adenocarcinoma cells

Efficacy Outcomes: - Silencing of UCHL1 significantly inhibited migration and invasion of lung adenocarcinoma cells - Lung adenocarcinoma cells with silenced UCHL1 showed a higher probability of apoptosis - UCHL1 could improve the detection rate of clinical lung adenocarcinoma and affect drug sensitivity

Immune Checkpoint Inhibitors in NSCLC (2022)

Intervention: Systematic review of 17 treatment regimens including various immune checkpoint inhibitors

Efficacy Outcomes: - For all-comers population, pembrolizumab/chemotherapy (CT) and cemiplimab were most likely the best treatments - For PD-L1 <1%, nivolumab/ipilimumab with/without CT ranked first for overall survival (OS) - For PD-L1 >1% and 1%-49%, pembrolizumab/CT ranked first for OS - For PD-L1 >50%, cemiplimab ranked first for OS - Atezolizumab/CT/bevacizumab ranked first in most subgroups for progression-free survival (PFS)

FLAURA Study with Osimertinib

Intervention: Osimertinib (third-generation EGFR-TKI)

Efficacy Outcomes: - Extended median overall survival by 6.8 months compared with standard EGFR-TKIs (38.6 vs. 31.8 months) - 20% reduction in mortality risk (hazard ratio 0.80) - Statistically significant reduction in the risk of central nervous system disease progression (HR, 0.48) - 28% of patients remained on osimertinib treatment for 3 years - Duration of first subsequent treatment with osimertinib was 25.5 months compared with 13.7 months with standard EGFR-TKIs

Pembrolizumab Study (2023)

Intervention: First-line pembrolizumab for advanced NSCLC

Efficacy Outcomes: - Median progression-free survival was 8.2 months - Overall survival was 22 months

Safety Outcomes: - Factors associated with shorter survival: never-smoker status, adenocarcinoma histology, poor performance status, and elevated neutrophil/lymphocyte ratio