The concept of using information from a patient's tumor to make therapeutic and treatment decisions has revolutionized the landscape for cancer care and research. This concept is called personalized medicine.
Genomic analyses have identified key driver mutations for lung cancer. Targeting the most important mutations in lung cancer and developing drug discovery platforms will enable fast and efficient development of new drugs for the new discovered drug targets. This approach holds the most promise to successfully find curative therapies for lung cancer.
The FDA has recently approved several immunotherapy drugs for lung cancers that over-express PD-L1. For example, patients who received pembrolizumab had longer median 10.3 months progression-free survival than 6.0 months progression-free survival in patients who received chemotherapy.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are widely used as first-line therapy in patients with non-small cell lung cancer (NSCLC), but the EGFR T790M point mutation leads to resistance to TKI. In the AURA3 trial osimertinib could improve survival for patients with NSCLC. The median progression-free survival was 10.1 months with osimertinib vs 4.4 months with standard platinum/pemetrexed treatment.
Approximately one-fifth of patients with small cell lung cancer (SCLC) are MYC positive. MYC positive cancer is more aggressive: growing and spreading faster, and they tend to quickly develop resistance to chemotherapy. Drug screening revealed that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition. Aurora in combination with chemotherapy, strongly suppresses tumor progression and increases survival.
Development status: phase 3, by Eli Lilly
MOA: CD4/6 dual inhibitor
LY2835219 is a cell cycle inhibitor, designed to block the
growth of cancer cells by specifically inhibiting CDK 4 and 6. Although abemaciclib inhibits both CDK 4 and CDK 6, the results from the cell-free enzymatic assays have shown that it was most active against Cyclin D 1 and CDK 4. Results
from preclinical and early-stage clinical studies support the further evaluation of abemaciclib for the treatment of human cancers - including breast cancer and lung cancer - in which aberrant CDK 4 and 6 pathways enhance cancer cell
growth. Abemaciclib has now entered into Phase III
development with two trials in HR+ breast cancer patients, as well as a Phase III trial in lung cancer.
In the Phase I study, 57 patients with advanced NSCLC who progressed or relapsed after standard treatments were enrolled. Patients received abemaciclib twice daily during the study.
Development status: phase 2 ongoing, by Vernalis
MOA: HSP90 inhibitor
AUY922 is an HSP90 inhibitor that causes degradation of HSP chaperones and their client proteins, including epidermal growth factor receptor. We conducted a phase I/II trial to evaluate AUY922 and erlotinib for patients with EGFR-mutant lung cancer and disease progression during erlotinib treatment. In phase I, 18 patients were treated with AUY922 intravenously once per week and erlotinib once per day in 28-day cycles using a 3 + 3 dose-escalation design. In phase II, 19 additional patients were treated at the maximum-tolerated dose. The primary end point of the phase II trial was complete plus partial response rate. The partial response rate was 16% (four of 25 patients; 95% CI, 5% to 36%) and was independent of tumor T790M status. Common drug-related adverse events were diarrhea, skin rash, hyperglycemia, and night blindness.
Development status: phase 2
ongoing, by Eisai Co.
MOA: multitargeted tyrosine kinase inhibitor
E7080 is an orally active multi-targeted kinase inhibitor whose targets include vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptors (PDGFR). It has been shown to inhibit NSCLC tumor angiogenesis by targeting endothelial cells. E7080 had little effect on tumor cell proliferation. 135 pts enrolled in the study. Per protocol, the study was unblinded and analyzed after 90 deaths. 76% received ≥ 3 prior anti-cancer regimens and 85% received prior erlotinib or gefitinib (similar rates in each arm). A summary of efficacy and safety is presented by study arm.