Using Genetic Targeting to Exploit Lung Cancer’s Vulnerabilities

By Nathan Pennell, MD, PhD

Cancer is fundamentally a disease of genes gone awry, diverting normal cellular functions into abnormal growth, invasion and metastasis. Nowhere is that more true than in lung cancer, which has spurred efforts by researchers in the field of cancer genomics to determine how a cancer behaves and to identify its Achilles’ heel.

Through large-scale efforts to sequence the entire genomes of hundreds of non-small cell lung cancers (NSCLC), we now understand that lung cancer is not one disease or even several different diseases, but instead is made up of dozens of different types of cancer, all of which just happen to originate in the lungs.

Cleveland Clinic partnered with the National Cancer Institute (NCI) on The Cancer Genome Atlas (TCGA) Program, whose goal is to understand the complete genetic makeup of 1,000 NSCLC cases to find targets for new treatments. As a result of this and similar efforts, many unique and exploitable targets have been identified, and a number of revolutionary clinical trials are available that aim to bring active treatments to lung cancer patients in a few years rather than decades.

Master Protocol for Squamous Cell Lung Cancer

Squamous cell carcinoma (SCC) of the lung is a formidable disease, with a median survival of about 10 months in its advanced stage, and is treated in 2015 very much like it was 20 years ago. As a result of the TCGA project, several promising genetic targets were identified in SCC for which potential drugs were available.

Instead of testing each drug individually in hundreds of SCC patients in hopes of achieving efficacy in a select few, the NCI designed a new trial in which Cleveland Clinic is participating called the Master Protocol, or Lung-MAP, to test many targets simultaneously. Patients with previously treated, advanced SCC of the lung have their tumor tissue sent for broad genomic analysis. Using the so-called umbrella trial design, patients are then entered into one of four arms of the trial based on the genomic analysis results. Each of the arms ‒ targeting PI-3 kinase (PIK3CA) mutations, cyclin dependent kinase (CDK) abnormalities, fibroblast growth factor receptor (FGFR) amplifications or, in the final group, using immunotherapy ‒ will be compared in a randomized fashion to the FDA-approved second-line chemotherapy agent docetaxel.

The trial, aside from assigning patients to arms based on tumor genetics, also is unique in that if any of these drugs shows promise in the phase 2 portion, the investigation will immediately expand into a registration phase 3 trial, cutting the time to possible drug approval by years. As new targets in NSCLC are discovered, they can be seamlessly added to the design, essentially creating a pipeline for targeted drug approvals in SCC.

Figure 1. Lung-MAP Sub-Studies for Treatment of patients with squamous cell lung cancer

Can ALCHEMIST Turn Genes Into Gold?

Another important trial open at Cleveland Clinic is the NCI-sponsored ALCHEMIST trial, which is testing the idea that giving targeted drugs as adjuvant therapy in early-stage lung cancer will lead to higher cure rates. In an earlier pivotal phase 2 trial presented at the American Society of Clinical Oncology’s 2014 annual meeting, Cleveland Clinic investigators led an adjuvant trial of erlotinib in epidermal growth factor receptor (EGFR) mutant early-stage NSCLC, which resulted in a significant increase in disease-free survival in these patients.

In ALCHEMIST, patients with stage IB-IIIA nonsquamous NSCLC who undergo surgery will have their tumors sequenced for either EGFR mutations or anaplastic lymphoma receptor tyrosine kinase (ALK) gene translocations, which are common genetic alterations with approved targeted treatments in advanced disease. EGFR mutant or ALK+ patients will then randomly be assigned to two years of adjuvant erlotinib (EGFR) or crizotinib (ALK) or placebo, with a primary goal of improving overall survival. As both of these targeted drugs are significantly superior to chemotherapy in these molecular subtypes of NSCLC when the disease is incurable, there are high hopes that they will make a similar impact in curable patients.

Figure 2. Break-apart fluorescent in situ hybridization (FISH) in a patient with anaplastic lymphoma kinase (ALK) gene translocation-positive NSCLC. The gene translocation is present when the red and green probes are distinctly separated, while normal ALK (negative) would be represented by fused probes in yellow. All of the ALK signals are positive for translocation in this patient’s tissue sample.

RET Targeted Agents Aren’t Just for Thyroid Cancer Anymore

Aside from the umbrella trials that test multiple genes and drugs in a single study, Cleveland Clinic’s Lung Cancer Program also has a large panel of clinical trials testing single drugs in molecular subtypes of NSCLC.

In one exciting trial recently highlighted at the Santa Monica Targeted Therapies of Lung Cancer meeting, patients with NSCLC harboring activating RET gene fusions are being treated with the oral RET inhibitor lenvatinib. RET fusions are common in thyroid cancer, but are now also recognized to be present in about 2 percent of NSCLC cases, and may benefit from the same type of therapy. My Cleveland Clinic colleague Vamsidhar Velcheti, MD, is one of the lead investigators on this phase 2 trial, which screens patients for the presence of RET fusions to identify 20 patients for treatment with once-daily lenvatinib, with a primary endpoint of objective response rate.

Together, these trials will try to prove that genetic alterations in cancer are more important than the site of origin. With that information, we may one day force lung cancer to relinquish its position as the No. 1 cause of cancer-related mortality worldwide.

Dr. Pennell is Director of Medical Oncology for Cleveland Clinic’s Lung and Thoracic Cancer Program. He can be reached at penneln@ccf.org or 216.445.9282. Find him on Twitter:@n8pennell.

Photo Credit ©Russell Lee