Understanding of genetics crucial to improve lung cancer diagnosis, treatment
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Healio spoke with Karen L. Reckamp, MD, MS, medical director of clinical research operations, co-director of the thoracic oncology program, and professor in the department of medical oncology at City of Hope Comprehensive Cancer Center in Duarte, California, about her research in immunotherapy treatments for non-small cell lung cancer and the role of genetics to better target individual therapies for patients with lung cancer.
In your opinion, how has the field of lung cancer evolved in the past decade?
The field of lung cancer has evolved significantly over the past 10 years. One of the biggest aspects that has changed in lung cancer is that we now know that lung cancer is a multitude of diseases — it is not just one disease. Lung cancer is constituted of multiple molecular subtypes, and patients should be treated specifically for their subtype of lung cancer, whether it be differentiated by histology or by genetic subtype. Now, as oncologists are learning, immunologic subtype is another subtype, which may be reflected in the genetics of the tumor and other biological aspects of the tumor.
Why is treating by subtype so important to the direction of lung cancer research today?
Knowing that there is a significant amount of heterogeneity within lung cancer and different types of lung cancer helps researchers understand that the biology behind what is driving each patient’s lung cancer is important, and it leads to more specific treatments and hopefully, treatments with less toxicity. Researchers now approach lung cancer at the specific patient level rather than taking the approach that all patients receive the same therapy and will achieve the exact same endpoint or outcome; this has significantly changed the way we think about and perform research in lung cancer today.
Why is the identification of biomarkers important?
Biomarkers come in many varieties. The most significant over the last decade have been genetic biomarkers. Specific gene mutations occur within lung cancer, and some of these are specific drivers of lung cancer. Therapies can target these drivers to stop lung cancer growth, and they have helped patients live longer than ever before with improved quality of life. Researchers are now looking into biomarkers associated with the immune aspects of lung cancer, such as PD-L1 — a marker for benefit with immunotherapy. Previously, lung cancer was thought to be a highly immunoresistant tumor, but over this last decade, we have developed immunotherapy that works as single agents and in combination with chemotherapy and other agents to help people live substantially longer, even with metastatic lung cancer.
What recent research has been most significant in the field of lung cancer?
I conduct clinical research on novel therapies for patients with lung cancer, and I have had a role in evaluating epidermal growth factor receptor (EGFR) inhibitors and, specifically, resistance to EGFR inhibitor therapy, to develop more beneficial combinations of therapies for patients. As it becomes clear that lung cancer is heterogeneous, researchers have found that as treatments are given, the tumor can progress and develop resistance to therapy. Therefore, although great strides have been made in lung cancer research, there is still much to understand about tumor progression and resistance to both targeted therapies and immunotherapy.
As researchers work to understand resistance and the heterogeneity associated with resistance, new therapies and combinations of therapy for lung cancers with EGFR and anaplastic lymphoma kinase inhibition (ALK) alterations are being explored. I have been involved in several trials looking at combinations of EGFR inhibitors, novel ALK inhibitors, and immunotherapy trials that have led to new therapies and FDA approvals of new drugs for lung cancer. We are now running several combination trials using immunotherapy to try to overcome resistance to checkpoint inhibition, and help those patients who are not achieving significant benefit of immunotherapy. One exciting advance for patients is that some tests can be conducted on blood, rather than biopsy, to help us understand resistance. Analysis of biomarkers through blood and even urine can help us understand levels of resistance and provide a more comprehensive picture of what is occurring in the tumor because they provide a glimpse into tumor cells in all areas rather than one specific tumor as is analyzed by a tissue biopsy. This has been invaluable to understanding the development and progression of lung cancer and response to therapies.
What recent research has contributed to improving treatment options for patients with lung cancer?
At the 2018 ASCO Annual Meeting, several significant trials were presented, demonstrating researchers’ advancing understanding of immunotherapy in the field of lung cancer. One phase 3 trial presented by Gilberto Lopes, MD, MBA, medical director of international programs at Sylvester Comprehensive Cancer Center of University of Miami Health System, showed pembrolizumab (Keytruda, Merck) to be a more effective first-line treatment for patients with NSCLC who had 1% or greater PD-L1 expression. Currently, pembrolizumab is approved by the FDA for patients with 50% or more expression in PD-L1 as a single-agent, first-line treatment for patients with metastatic disease. In the presented trial, 50% of the patients did have 50% or more expression, so a large portion of the results were based on those patients with high expression. But overall, results showed a benefit in progression-free and overall survival for the group with greater than 1%. Although the results were led by the patients who had 50% or more expression, the findings still show an increase in the number of patients who can potentially benefit from single-agent pembrolizumab if it is approved for patients with 1% or more PD-L1 expression.
Phase 3 trial data were also presented at the 2018 American Association for Cancer Research Annual Meeting showing the addition of pembrolizumab to standard chemotherapy resulted in significantly longer OS and PFS than chemotherapy alone in patients with nonsquamous NSCLC. Therefore, patients who would not necessarily be eligible to receive immunotherapy alone potentially could receive chemotherapy with immunotherapy. Researchers are seeing that for many patients, especially those who do not significantly benefit from single-agent immunotherapy, administering immunotherapy plus chemotherapy is better than chemotherapy alone, and this trial changes the standard of care.
What current areas of research do you feel are on the most promising path to impact treatment for patients with NSCLC?
Researchers are now making strides in understanding which populations benefit most from certain treatments, as well as which combinations help patients who demonstrate resistance.
Data from another study with which I am involved were presented at the 2018 ASCO Annual Meeting. Alexander E. Drilon, MD, clinical director of earlydrug development service at Memorial Sloan Kettering Cancer Center in New York, presented phase 1 trial data on LOXO-292 (Loxo Oncology), a targeted, highly selective RET inhibitor therapy that inhibits fusions, mutations, resistance and brain metastases. This trial found LOXO-292 demonstrated antitumor activity in patients with RET-altered cancers, including those with resistance to prior multikinase inhibitors and brain metastases. The treatment was also well tolerated by patients.
As immunotherapy moves forward, researchers will find better combinations of treatment, as well as refine patient populations that will benefit. Researchers are also learning about new targeted therapies that best benefit specific patients. The field of lung cancer is essentially splitting into smaller cohorts with focused treatments, and as a result, oncologists can treat each patient with the best treatment that has the most likelihood of helping improve his or her quality and duration of life.
What areas of research need further focus?
A decade ago, the conversation with patients who had metastatic lung cancer included a discussion that only 50% of patients were expected to live beyond 1 year. This is no longer true for most patients. Recent data have shown, especially with patients who received targeted therapy, 5-year survival rate for patients with advanced lung cancer is approximately 15%4 which was unheard of a decade ago. Today, even with immunotherapy as a relatively new treatment, a proportion of patients come off therapy and remain off therapy without evidence of active cancer 5 years later, even when they have metastatic disease — that has been promising.
Most lung cancer research is conducted with patients with metastatic or late-stage disease because that is still the stage in which most patients present with symptoms and are diagnosed. Still, diagnosing lung cancer earlier and performing more curative surgeries to cure patients up front is the aim. Most patients are diagnosed with late-stage disease because screening has only been available for less than a decade, and screening is only for patients over the age of 55 who have had a 30-pack-year or more history of smoking. Increasing screening rates and continued impact on smoking cessation will decrease lung cancer deaths.
Approval for most drugs in lung cancer occur for patients in the later stages, so it is my hope to start moving treatments into the earlier stage disease. For example, immunotherapy is being evaluated as a treatment option before or after surgery. It is approved for use after chemoradiation in patients with locally advanced disease. Hopefully, as targeted therapies and immune therapies begin to shift to earlier in the treatment paradigm in clinical trials, more patients can be cured. Therefore, an understanding of the genetics of lung cancer is crucial. With a better understanding of genetics and the familial aspects of lung cancer, physicians may be better able to screen patients in the future for early diagnosis.
What pearls can you offer to today’s physicians who treat patients with lung cancer?
For primary care physicians or pulmonologists, I encourage earlier screening and counseling on smoking cessation. For oncologists, I encourage more multiplex sequencing to identify the genetics from one sample. For example, patients with lung cancer, at a minimum, should have testing performed for PD-L1, EGFR, ALK, ROS1 and BRAF. Multiplex testing is sensible because most patients who get single-gene testing will ultimately run out of tissue and, therefore, do not actually get all the testing they should because tissue is sparse.
Where do you hope to see research moving in the next decade?
The field of lung cancer is heading in a positive direction with a better understanding of smaller and specific patient cohorts, as well as a better understanding of the individual patient and his or her individual lung cancer at a molecular level. As patients live longer on current therapies, they have a better chance of living to that next discovery and that next new treatment. It is a promising and hopeful time for patients with lung cancer.
References:
Lopes G, Wu Y, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(18)(suppl):LBA4.
Gandhi L, Rodriguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. Presented at: American Society of Clinical Oncology Annual Meeting; June 2, 2018; Chicago, IL. Abstract 102.
Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cacner Res. 2016;5(3):288-300.
Gettinger S, Horn L, Jackman D, et al. Five-year follow-up of nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study. J Clin Oncol. 2018;36(17):1675-1684.
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