Targeting Lung Cancer

Govindan, Ramaswamy, MD
Professor of Medicine
Co-Director of the Section of Medical Oncology
Washington University School of Medicine
St. Louis, Missouri
Also by this Author 

Lung cancer is the leading cause of cancer-related deaths among both men and women – by far. In fact, more people die from lung cancer than from colon, breast and prostate cancer combined1.

In considering the challenge of treating lung cancer patients, Dr Ramaswamy Govindan, Professor, Division of Medical Oncology, Washington University School of Medicine, believes the most important issue is how best to harness to the potential of targeted therapy. It’s very simple,” he observes: “How can we select patients for targeted therapies and what tests should we be doing to select therapy?”

Refining Patient Selection

The dilemma for physicians today is how to select patients appropriately for therapy. As Dr Govindan explains, “The question, first and foremost, is should we be selecting all patients for testing or just some? And if you select all patients, there are three fundamental issues:
First, do we have enough tissue? Most of the time we don’t, so should you subject patients to a repeat biopsy?

Second, who should be doing the testing? Some of the mutation testing needed to target therapy is not done routinely in hospitals – they require a level of expertise and need to be done in specialized facilities.

Thirdly, what data are there to support use of this testing?”

Genetic Profiling to Direct Individualized Therapy

Addressing the last question, Dr Govindan says that certain tests for genetic mutation profiling have been validated and are being adopted to direct therapy. Advances in molecular diagnostics are enabling physicians to personalize medication regimens based on an individual’s unique genetic makeup. These biological indicators, or biomarkers, will help identify which patients to treat with which therapy, ultimately leading to better outcomes.

The test for EGFR mutation indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib or gefitinib, which are used to treat NSCLC.  Since the identification of EGFR mutations in 2004, a number of prospective studies, including several that have reported recently, such as IPASS2, OPTIMAL3 and SATURN4, have shown benefit from EGFR-TKI therapy in mutation-positive patients and indicate that certain subsets of patients are appropriate candidates for EGFR-targeted therapies, using either gefitinib or erlotinibas first-line therapy or as maintenance therapy following cytotoxic chemotherapy5.

The National Comprehensive Cancer Network (NCCN) Guidelines for NSCLC issued in 2010 now includes erlotinib as a first-line treatment option for EGFR mutation positive patients with advanced or metastatic disease6.

Tests for other gene mutations to help direct treatment include a test for KRAS mutation, which indicates a likely resistance to EGFR-targeted TKIs, and the test for ALK mutation, which will be of paramount importance should the ALK inhibitor crizotinib, currently being investigated in Phase III clinical trials, be approved for use in the future.

Biomarker Identification and Relative Sequencing – Keys to Therapeutic Advances

Looking ahead, Dr Govindan believes the promise of genetic profiling will increasingly come to fruition. “In the next ten years, we will be involved in sequencing large-scale genomics. This will unearth many new genes and new pathways, providing a platform for new drugs to be studied.”

In parallel, he expects to see a move away from delivering targeted therapies to unselected patients. “As this trend continues we will see clinical and drug development move in the direction of selecting biomarkers very early.”

Furthermore, testing will incorporate a range of markers at one time. “We’ll be doing gene sequencing and looking for a panel of, say, twenty-one markers in one go. Eventually, it will become routine. It won’t be a matter of doing the whole genome sequencing, but selecting the relative sequencing. So we’ll be getting information on a range of genes, not just on one.”

Advances in laboratory testing will help realize the promise of new targeted therapies in development.  A number of second-generation agents are currently in clinical trials, including compounds that are irreversible dual kinase inhibitors of both EGFR and HER2, which may prove to be potentially superior first-line drugs for mutation-positive patients7.Most recently a Phase I study has shown that the compound BIBW 2992 is safe and has durable antitumor activity for patients with advanced solid tumors. It is currently being evaluated in phase III trials as an irreversible inhibitorof EGFR/HER1 and mutated EGFR/HER1 receptors8.

References

  1. Key Statistics About Lung Cancer, American Cancer Society www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-key-statistics
  2. First Line EGFR TKI vs Chemo for EGFR-Mutation Positive Advanced NSCLC: Consistent Themes. West. Jan 14, 2011. http://boards.medscape.com/forums/?128@927.jJk0a4eZWvd@.2a064293!comment=1

  3. October 10, 2010 (Milan, Italy) First-Line Erlotinib Triples Progression-Free Survival in NSCLC in Chinese Population. Medscape October 10, 2010. http://www.medscape.com/viewarticle/730214

  4. New SATURN Results Show Survival Benefit From Erlotinib in NSC. Medscape Aug 1, 2009. http://www.medscape.com/viewarticle/706862

  5. Fong T. Morgensztern D. Govindan R. EGFR inhibitors as first-line therapy in advanced non-small cell lung cancer. J Thorac Oncol.2008 Mar;3(3):303-10.

  6. NCCN Guidelines for Patients Non-Small Cell Lung Cancer http://www.nccn.com/images/patient-guidelines/pdf/nsclc.pdf

  7. EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992. Target Oncol.2010 Dec;5(4):245-55. Epub 2010 Jun 24.http://www.ncbi.nlm.nih.gov/pubmed/20574858

  8. Yap et al. Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors. Journal of Clinical Oncology. http://jco.ascopubs.org/content/28/25/3965.abstract


Released on Wednesday, August 10, 2011