Precision Cancer Medicine

The purpose of precision cancer medicine is to define the genomic alterations in a cancers DNA that are driving that specific cancer. Cancer used to be diagnosed solely by a visual microscopic examination of tumor tissue and all patients received the same chemotherapy. But now there is no longer a “one-size-fits-all” approach to cancer treatment. Even among patients with the same type of cancer, the behavior of the cancer and its response to treatment can vary widely. By exploring the reasons for this variation, researchers have begun to pave the way for more personalized cancer treatment.

Not all cancer cells are alike

Cancer cells may differ from one another based on what genes have mutations.  Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome.  Currently this “genomic testing” is performed on a biopsy sample of the cancer.

Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be developed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.

Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.  Precision cancer medicines can be used both instead of and in addition to chemotherapy to improve treatment outcomes.

Lung Cancer Biomarkers & Medicines to Target Them

Not all lung cancer cells are alike. They may differ from one another based on what genes have mutations. By testing an individual’s lung cancer for specific unique biomarkers or genomic alterations doctors can identify genetic mutations or the proteins they produce and offer the most personalized treatment approach utilizing precision medicines.  Individuals not previously tested should discuss genomic testing with their physician to determine whether newer precision cancer medicines are a treatment option.

PD-1 Checkpoint Inhibitors

Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD -L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade an attack by the body’s immune cells. Checkpoint inhibitor drugs that block the PD-1 pathway enhance the ability of the immune system to fight cancer.  By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the lung cancer cells.

Overall two thirds of lung cancer patients have some expression of PD-1, and one third are “high expressers” meaning over 50% of the tested tumor expresses PD-1. A diagnostic test to measure the level of PD-L1 is available and checkpoint inhibitors are effective in the management of many lung cancers.1,2

Keytruda® (pembrolizumab) is the first checkpoint inhibitor to have received FDA approval in the U.S for the treatment of cancer. Data from an ongoing clinical trial evaluating Keytruda® have demonstrated promising survival rates among patients with advanced certain lung cancers.1

  • Keytruda® (pembrolizumab)
  • Opdivo (nivolumab)
  • Imfinzi (durvalumab)
  • Tecentriq® (atezolizumab)

Epidermal growth factor receptor (EGFR): The EGFR pathway is a normal biologic pathway found in healthy cells. It is involved in regular cellular division and growth. However, certain mutations within the EGFR gene can lead to an overactive EGFR pathway, leading to the development and/or spread of cancer. These cancers are referred to as EGFR-positive, and there are several FDA-approved medications to block the activity of EGFR and slow cancer growth for EGFR-positive cancers. EGFR mutations are most common in individuals who never smoked, woman, people of Asian ethnicity, and those with a type of lung cancer known as adenocarcinoma.3,4

  • Tagrisso (osimertinib)
  • Tarceva (erlotinib)

ALK+ Lung Cancer: Approximately 5% of all NSCLC have an identified mutation referred to as the anaplastic lymphoma kinase (ALK) mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, and are a type of NSCLC referred to as adenocarcinoma (based upon the cells affected); and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation.5

  • Zykadia® (ceritinib)
  • Alecensa (alectinib)
  • Xalkori (crizotinib)
  • Alunbrig (brigatinib)

ROS-1+ Lung Cancer: The ROS-1 mutation is an uncommon mutation found in only 1% of individuals with NSCLC. Research has indicated that the ROS-1 mutation plays a role in the development and progression of some lung cancers, and patient characteristics are similar to those who have ALK+ NSCLC.6

BRAF & MEK Kinase Inhibitors: The BRAF and MEK genes are known to play a role in cell growth, and mutations of these genes are common in several types of cancer. Lung cancers may carry the BRAF mutation known as V600E. This mutation produces an abnormal version of the BRAF kinase that stimulates cancer growth. Another mutation known as V600K may also be present. BRAF and MEK inhibitors are precision cancer medicines that block the activity of the V600E and V600K mutations respectively.7

  • Zelboraf®(vemurafenib) BRAF V600E kinase inhibitor
  • Tafinlar®(dabrafenib) BRAF V600E kinase inhibitor

MEK inhibitors

  • Mekinist®(trametinib) MEK V600 kinase inhibitor
  • Cotellic® (cobimetinib) MEK V600 kinase inhibitor

Combination Therapy

A combination of a BRAF and a MEK inhibitor appears to decrease the emergence of disease resistance that occurs in patients treated with a BRAF mutation.  The combination of Taflinar plus Mekinist has been evaluated and FDA approved.7

Next: Management of Non Small Cell Lung Cancer

Next: Management of Small Cell Lung Cancer

References


1 Keytruda (pembrolizumab) demonstrates superior progression-free and overall survival compared to chemotherapy as first line treatment in patients with advanced non-small cell lung cancer. [Press release.] http://www.mercknewsroom.com/news-release/oncology-newsroom/mercks-keytruda%C2%A0pembrolizumab-demonstrates-superior-progression-free- Accessed June 21, 2016.

2 Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2015; 373:1627-1639.

3 OSI Pharmaceuticals. FDA Approves Tarceva as a Maintenance Therapy for Advanced Non-small Cell Lung Cancer. Available at: http://investor.osip.com/releasedetail.cfm?ReleaseID=460783. Accessed April 19, 2010.

4 Zhou C, Wu Y-L, Chen G et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomized, phase 3 study. Lancet Oncology. Early online publication July 22, 2011.

5 Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine. 2014; 370: 1189-1197.

6 United States Food and Drug Administration (FDA). FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm490329.htm. Accessed March 11, 2016.

7 https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564331.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery