The emerging treatment landscape of targeted therapy in non-small-cell lung cancer

Abstract

Lung cancer is one of the most common cancer in the world. In 2018, there were over 2 million new cases of lung cancer and over 1.7 million deaths were attributed to lung cancer. Targeted therapy has emerged as an important mean of the disease management for patients with non-small-cell lung cancer (NSCLC). Herein, we review and analyze recent literature, discuss the targeting pathways and ongoing clinical trials in lung cancer. Chemotherapy is no longer the best available treatment for all patients. Therapeutic decisions should be guided by an understanding of the molecular features of patient's tumor tissues. The future gains will likely emerge from finding optimal ways of combining targeted therapy, immunotherapy, and chemotherapy.

Keywords: Lung cancer; Target identification.

Fig. 1. Therapies targeting the key oncogenic signaling pathways in lung cancer.

There are several abnormal signaling and cell physiology-related pathways in lung cancer. Drugs targeting these abnormal pathways are depicted schematically. These drugs include agents specifically inhibiting components of the EGFR pathway and other family members and/or members of the VEGFR pathways. Other agents in development include inhibitors of the PI3K/AKT/mTOR pathway, the RAS/BRAF/MAPK pathway, and the JAK–STAT pathway.

Fig. 2. Clonal evaluation of EGFR-mutant lung cancer during therapy.

Visual representation of the minimal residual disease and malignant cell progression after anti-EGFR TKIs demonstrating genomic patterns of selection observed in clinical samples during different lines of therapy.

Fig. 3. A map of the clinical trials of combination immunotherapy in lung cancer.

Combination strategies have shown promise to overcome therapeutic resistance in some clinical trials in lung cancer. Clinical trials studying the combination of immunotherapy with standard therapies (e.g., chemotherapy, radiotherapy, antiangiogenic therapy, and targeted therapy), and combination of checkpoint inhibitors (anti-PD-L1/PD-1 therapies) with other immunotherapy inhibitors are ongoing. In total, 356 studies of combination immunotherapy in lung cancer were found.

Fig. 4. Schematic of the ALCHEMIST trial.

8000 patients are planned to be screened through this trial to facilitate accrual to three substudies: ALCHEMISTEGFR (A081105; NCT02193282), ALCHEMIST-ALK (E4512; NCT02201992), and ALCHEMIST-nivo (EA5142; NCT02595944). In this trial, patients will have first undergone resection and completed standard adjuvant therapy. The patients with EGFR-mutated NSCLC will be randomized 1:1 to either erlotinib or placebo. The patients with ALK-rearranged NSCLC will be randomized 1:1 to crizotinib or placebo. The patients who are negative for EGFR or ALK mutations will be randomized to adjuvant nivolumab or observation for 1 year.