Biomarker identification: Connecting the right patients to the right lung cancer therapies
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Healio spoke with Fred R. Hirsch, MD, PhD, professor of medicine and pathology at the University of Colorado Cancer Center in Denver and CEO of the International Association for the Study of Lung Cancer, about the multiple clinical trials being performed in the United States and Europe that study biomarkers and personalized medicine in the field of lung cancer.
You have spent more than 25 years in lung cancer research. How has lung cancer treatment evolved over the course of your career?
As a medical student in the 1970s I was interested in research, and I was fortunate to study under Prof. Heine H. Hansen, MD. He was a pioneer in chemotherapy development for solid tumors and drew me into the field of lung cancer research while I was a medical student in Copenhagen, Denmark. At that time, little progress had been made in the treatment of small cell lung cancer. Although the prevalence has fallen significantly over the years, at that time, small cell lung cancer represented about 40% of lung cancer incidence. No standardized treatment for advanced lung cancer existed.
Chemotherapy for small cell lung cancer seemed promising, but unfortunately, treatment for small cell lung cancer over the years did not improve prognosis as expected.
In the meantime, treatment for non-small cell lung cancer (NSCLC) started to evolve with the first applications of chemotherapy. Within the last 2 decades, we also have made great strides with the development of targeted therapies such as epidermal growth factor receptor tyrosine kinase inhibitors, ALK-inhibitors and most recently, with immunotherapy.
Since I moved to the United States in 2000, I have focused on using biomarkers to select patients for appropriate targeted therapies, and more recently, for immunotherapy. My research focuses on how to connect the right patients to the right therapies, based on biomarker research.
What needs to happen for us to connect the right patient to the right therapy?
We are now learning so much about sensitive- and resistance mechanisms for targeted therapies and for immunotherapies, and how these mechanisms affect a patient’s response to one therapy vs. another. The more we learn about resistance mechanisms, the better we will be able to hone the best combination of therapies for each patient’s unique profile. We want to take these treatments even further.
We are just beginning to see how different mutations respond to different sequences of therapies as well.
In patients with loco-regional disease (stage III) in which chemotherapy and radiotherapy in combination has been standard, we are now seeing interesting results develop from adding immunotherapy to their treatment plans as well. I think this will lead to increasing interest to use immunotherapy as adjuvant- or neo-adjuvant treatment for patients with early stage disease.
Early in my career, I was very much involved in developing the chemotherapy medication etoposide for small cell lung cancer, and one of our large randomized studies was used for its approval.1 That was exciting for me as a young investigator. Etoposide is still the cornerstone of treatment for patients with small cell lung cancer today. Unfortunately, treatment for small cell lung cancer has not significantly improved since then.
Recently, I have been involved in the development of EGFR-targeted therapies and biomarkers for EGFR-targeted therapies, which is an exciting area. Amazing progress is occurring in NSCLC, both in terms of treatment and in terms of screening for lung cancer, so there is a great deal of optimism in the lung cancer field in general.
Also, it has been a blessing for me over the last few years to be the CEO of the International Association for the Study of Lung Cancer, which is the only global organization entirely focused on thoracic malignancies. We have almost 8,000 members in more than 100 countries, and our reach continues to expand, thanks to the increased interest and activities in lung cancer research. Because of my role in this organization, I get to see the great strides taking place up close. I have never been so enthusiastic about the field as I am these days.
Is EGFR inhibition a promising path for lung cancer research?
The breakthroughs we have made regarding EGFR inhibitors – we now have several generations of EGFR inhibitors – are encouraging for the subgroup of patients who harbor EGFR mutations in their tumors.
For chemoprevention, the use of EGFR inhibitors is still an open arena. In the future, immunotherapy could be suitable for chemoprevention. Although ongoing studies are evaluating chemoprevention for lung cancer, results have not been encouraging thus far. But, we are learning much more about the biology of pre-neoplastic lesions and immunology reactions, both in lung carcinogenesis and in the microenvironment, and this knowledge hopefully will lead to immunopreventive strategies.
Has what we have learned about biomarker identification impacted prognosis for a patient who receives a diagnosis of lung cancer today?
Yes, the prognosis for patients with certain subtypes of NSCLC has been impacted by this research. We now know so much about the relationships between EGFR mutations and response to EGFR inhibitors, ALK gene rearrangements and response to ALK inhibitors, ROS gene rearrangements and response to ROS inhibitors, and BRAF mutations and response to BRAF inhibitors in combination with MEK inhibitors. We have transformed our knowledge into clinical practice for some subpopulations of patients with NSCLC, and the train is going very fast. What we learn about molecular abnormalities leads quickly now to treatment progress. We have new targets and new potential treatments, but we must perform classical clinical trials to validate and evaluate for clinical relevancy.
The world has certainly changed for patients with lung cancer. Today, we recommend next-generation sequencing to identify molecular abnormalities. As we continue to create more sensitive and more advanced technology, the number of abnormalities we can detect continues to grow.
We already have some examples of how identifying biomarkers of resistance can lead to drug discovery. After identifying T790M as a mutation resistant to EGFR TKIs, we developed a drug targeting T790M mutations, and this drug has already been approved and been incorporated into clinical practice. We also identified ALK mutations and developed drugs that are now approved for this subtype.
In what areas should future lung cancer research focus?
The encouraging data on results of monotherapy is exciting; however, I think the future will lie in finding the best combination therapies. Thousands of studies are currently exploring different combinations of therapies; some of them seem truly groundbreaking. After finding the best combination therapies, the focus should turn to how to best match patients for the different therapies. That will come from learning more about molecular or immunological sensitive- and resistance mechanisms that each patient has for individual drugs.
References:
Hirsch FR, Hansen HH, Hansen M, et al. The superiority of combination chemotherapy including etoposide based on in vivo cell cycle analysis in the treatment of extensive small-cell lung cancer: a randomized trial of 288 consecutive patients. J Clin Oncol. 19875(4): 585-591.
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