Abstract PL04-01: Improving patient outcomes in lung cancer by targeting different driver mutations
Authors: Johnson Bruce E. 
Published: July 2012

Multiple groups reported in 2004 on the association between clinical response to treatment with gefitinib and erlotinib and somatic mutations of the epidermal growth factor receptor (EGFR) in patients with lung cancer. Subsequent research showed these somatic sensitizing mutations of EGFR are also driver mutations. Somatic mutations of EGFR are predictive markers for higher response rates, prolonged time to progression, and a trend towards longer survival in patients with non-small cell lung cancer (NSCLC) treated with gefitinib or erlotinib rather than combination chemotherapy. The prospective clinical trials have led to approval of gefitinib for as initial treatment for patients with sensitizing mutations of EGFR or following relapse after conventional chemotherapy in Europe. Erlotinib is recommended as initial therapy for patients with sensitizing mutations of EGFR in the National Comprehensive Cancer Network (NCCN) guidelines.

However, only 10% to 30% of patients with lung cancer have activating mutations of EGFR. Ongoing research is attempting to identify additional driver mutations in patients with lung cancer and other malignancies that can be targeted with existing or novel compounds. The activating mutations in both adenocarcinomas and squamous cell carcinomas of the lung are being systemically characterized through the Tumor Sequencing Project, The Cancer Genome Atlas projects (http://cancergenome.nih.gov/wwd/program), and other programs around the world. These projects have identified the most frequently mutated and/or activated genes in both lung adenocarcinoma and in squamous cell carcinoma of the lung.

In addition to EGFR mutations, other driver mutations that can be effectively treated with existing targeted agents have been identified including EML4-ALK intrachromosomal rearrangements and BRAF mutations. Investigators from Japan discovered a gene that arose from a intrachromosomal rearrangement in adenocarcinomas of the lung which could transform NIH 3T3 cells. The transforming gene is a fusion of the ALK gene with echinoderm microtubule-associated protein-like 4 (EML4). The chromosomal rearrangement gives rise to a fusion gene in which the ALK tyrosine kinase is constitutively activated. Further studies have shown the EML4-ALK rearrangements are present in NSCLC arising in patients from the United States and Europe. The translocated gene can now be detected by using fluorescence in situ hybridization (FISH) in histological sections of the tumor. There are drugs that are directed against the ALK tyrosine kinase including PF2341066 or crizotinib. Crizotinib has been tested in patients with EML4-ALK intrachromosomal rearrangements in an expansion cohort of the phase I trials. Crizotinib has shown evidence of antitumor activity with response rates of approximately 57% and progression-free survival in excess of 6 months in patients with this rearrangement. Crizotinib is being tested in patients with relapsed NSCLC and EML4-ALK translocations randomized to either conventional therapy with pemetrexed or docetaxel versus crizotinib (ClinicalTrials.gov NCT01000025).

Other potential therapeutic targets in patients with NSCLC include activating mutations in BRAF, present in 2% of patients with NSCLC. BRAF has been shown to be a driver mutations in melanoma and successfully targeted with PLX4032 {Bollag, #4046; Flaherty, #4045}. One thousand adenocarcinomas of the lung are now being characterized for 10 different mutations, gene amplification, and chromosomal rearrangements through the 14 institutions participating in the Lung Cancer Mutation Consortium (http://www.golcmc.com/). The Clinical Trials Committee within the Lung Cancer Mutation Consortium has established trials with drugs specifically directed at these driver mutations in different subsets of patients with lung cancer. The goal is to continue to expand the number of patients who can be treated with effective targeted therapy against these driver mutations.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr PL04-01. doi:10.1158/1538-7445.AM2011-PL04-01