Dr. Nagourney's Blog

The Many Faces of Lung Cancer

By Robert A. Nagourney, MD

As November is lung cancer awareness month, it is opportune to examine this disease and our changing understanding of its treatment.

Lung cancer is the leading cause of cancer death in the United States with 221,000 Americans diagnosed and 158,000 deaths attributed to this diagnosis in 2015.  Get Our Lung Cancer Guide

Responsible for 27% of all cancer deaths in the United States, lung cancer kills more people than colon, breast, and prostate combined. Despite some advances, the 5-year survival for lung cancer remains only16%, unchanged for several decades.  

Our understanding of lung cancer has continued to evolve. 

Only a few years ago, lung cancer was characterizelung-cancer-types.jpgd by a small number of sub-groups, including small cell, squamous cell, adenocarcinoma, and large cell.

In the last several years, however, we have come to realize that lung cancer constitutes panoply of distinct entities with characteristic molecular changes and the potential for targeted therapies.

Among the most common mutations is KRAS, with approximately 1/4 of NSCLC carrying this abnormality, often associated with cigarette smoking.

Today, KRAS remains a challenge, as there are no effective targeted agents for this mutation. Indeed over 1/2 of all lung cancer patients carry no known actionable mutations. For a growing subset of patients with lung cancer, however, there are important new findings. 

The EGFR mutation occurs in approximately 15% of lung cancer patients, often non-smoking females 

Lung_mutations.gifand Asian populations. A second mutation is the ALK rearrangement that is found in approximately 8% of patients. Both ALK and EGFR are targets for the new class of tyrosine kinase inhibitors that can provide prompt and dramatic responses.

Beyond that, there are small subsets of patients who carry other mutations including HER2 and BRAF for which Vemurafenib has shown effective. Other rare mutations have also been identified.

Perhaps the most exciting development in lung cancer is immunotherapy.

These immune checkpoint antibodies unleash the immune system, not unlike releasing the emergency brake on a car.

The anti-PD-1, PD-L1 and anti-CTLA-4 agents, alone and in combination, are among the most exciting breakthroughs in recent drug discovery. By allowing the immune system to recognize and attack lung cancer cells, responses in the range of 20-30%, many of them durable, have been seen even in the most aggressive cancers.  Interestingly, cigarette smokers may actually do better than nonsmokers.  

Lung cancer reveals a changing epidemiology. In the past, cigarette smoking was one of a few known risk factors and often resulted in squamous cell carcinomas. Today adenocarcinomas predominate with growing number of non-smokers being diagnosed. Non-smoking women constitute a rising percentage in this disease, partly associated with EGFR mutations.

As noted, these patients can respond well to drugs like Erlotinib, yet resistance is often observed at 1-2 years.

To address this, third generation EGFR inhibitors have been developed with one, AZD-9291, just approved by the FDA. Capable of inhibiting several mutant types of EGFR, these drugs are active against the T790M mutation responsible for resistance to the first and second generation EGFR drugs.

We stand at the edge of a new era in lung cancer management; an era characterized by actionable mutations, immunotherapy and a growing appreciation of the individual nature of each patient's cancer.

This offers a unique opportunity to apply personalized cancer therapy to select the most effective drugs and combinations at the time of initial diagnosis. Appropriate combination of cytotoxic drugs, targeted agents and immunotherapies, have the potential to provide more effective, less toxic options.  

Over the years, we have studied the first, second and third generation EGFR inhibitors, the first and second generation ALK inhibitors and many of the downstream inhibitors active in lung cancer.

We have reported our observations at the American Association and American Society meetings and are now studying novel drug combinations to discover the best treatment for each patient.

As always, I appreciate your thoughts and comments.