Real World Health Care Blog

Tag Archives: targeted therapies

Non-Small Cell Lung Cancer: EGFR Mutations and Targeted Therapies

Continuing our series on non-small cell lung cancer, this week Real World Health Care speaks with Lecia V. Sequist, MD, MPH, Associate Professor of Medicine at Harvard Medical School and the Mary B. Soltonstall endowed chair in oncology at Massachusetts General Hospital. Dr. Sequist’s research focuses on studying novel targets and targeted agents for lung cancer treatment, particularly those that target the epidermal growth factor receptor (EGFR) and in detecting and studying the significance of tumor cells circulating in the bloodstream.

Real World Health Care: Tell us about what you do at Massachusetts General Hospital, especially in relation to research and treatment of non-small cell lung cancer.

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia Sequist: I’m a medical oncologist with a busy practice, seeing and treating patients with lung cancer. I also conduct clinical and translational research on new drugs, looking at the molecular aspects of tumors and biopsies as patients go through various forms of treatment. My focus is on personalizing treatment for each patient.

RWHC: Can you share some highlights of your recent research in non-small cell lung cancer?

LS: Most of my recent research has revolved around EGFR mutations. One of the biggest advances in lung cancer in recent years is that we’ve come to understand lung cancer is not one disease. It’s many diseases. We can now tell the difference between one cancer and another by looking at the tumor genetics. These are not the genes we inherit from our parents, rather they are genes that reside only in cancer cells. These genes are at the core of what causes cancer. By identifying these genes in a lung cancer patient’s tumor, we can be more successful with treatments that target those genes and the proteins they produce.

EGFR mutations were first discovered here at Mass General, right around the time I started in oncology. It was a very exciting time, and ushered in a new era of personalized treatment for cancer. Since those early days, we’ve done a tremendous amount of research with patients who have the EGFR mutation, and we’ve found treatments that work better than standard chemotherapy.

RWHC: What are some of the biggest challenges you face as a researcher studying non-small cell lung cancer?

LS: I think of the challenges in two categories: scientific and societal. From the scientific point of view, we can’t currently identify mutations in every lung cancer, though we’re constantly working to uncover more of them. The group of lung cancer patients who have no identifiable mutation, or who have a mutation with no matching drug therapies at this time, are effectively left out of the “molecular revolution.” For those groups, the challenge is to find alternative approaches. Luckily some of the newer immunotherapies may work particularly well in such patients. Then down the road, we know that targeted therapies eventually “wear off,” in the sense that cancer cells get smart and find ways to work around the roadblocks we put in their path. For example, we saw this with the first generation of tyrosine kinase inhibitors (TKIs) developed to target EGFR mutations. Most patients initially responded, but subsequently developed a resistance after about a year, because they developed a second mutation that prevents the TKIs from binding to the cancer cells. Last year, a new EGFR drug was FDA approved that is able to effectively target this second mutation. Now we’re racing trying to learn how the cancers may get around the newer drug and also looking at strategies to prevent resistance.

From a societal standpoint, one of our biggest challenges in the lung cancer research community is the stigma that still exists around lung cancer. In the United States, we were fortunate to have had a very successful public health campaign around the dangers of smoking over the last generation. Those dangers are important to understand, but one of the unexpected consequences of this was to popularize the opinion that lung cancer is a self-inflicted disease and therefore patients carry some degree of blame. Not only does this end up negatively affecting individual patients, it also cuts into research funding. The fact is, some smokers get lung cancer while others don’t. And more importantly, many lung cancer patients have never smoked. No one deserves lung cancer and research must push forward to stop this, the deadliest of all cancers.

RWHC: What are some of the biggest challenges you face as a clinician treating patients with non-small cell lung cancer?

LS: There are promising treatments being studied in clinical trials, but many patients don’t have access to those treatments because the trials are concentrated in academic centers. Even if patients have geographic access to research studies, clinical trials have fairly high thresholds for eligibility, so if a patient has other medical conditions — which many lung cancer patients have — or if their cancer has certain characteristics, they won’t be eligible for the trial. We need to keep pressure on the pharmaceutical industry to include broader groups of patients in trials so all patients can get access to promising new treatments.

RWHC: What do you think are some of the biggest opportunities for advancement in how we research non-small cell lung cancer and treat people with the disease?

LS: Immunotherapy has really changed the paradigm for non-small cell lung cancer. Years of failed vaccine studies led us to believe that it wasn’t possible to affect the human immune system in meaningful ways against lung cancer. Now that we’ve hit upon a different way to activate the immune system, new discoveries are tumbling out the door every day. Unlike past treatments, immunotherapy has true promise for long-term disease control. There are already three FDA-approved lung cancer immune therapy treatments over the last year and likely many more to come. I think someday we’ll look back on this time and say that this is when the needle really started to move.

RWHC: Why did you get into this field of research? What continues to inspire you?

LS: I was initially drawn to studying lung cancer when I was in training by the doctors who were mentoring me and the patients I met. At the time, there weren’t many treatments available for non-small cell lung cancer, so there was a lot of room for improvement. This was attractive to me as a clinician and a researcher and it has remained a vibrant and ever-changing field. I enjoy being involved in the exponentially increasing number of treatments available and how these new treatments can bring hope to patients. It has ended up being an intellectually stimulating and extremely fulfilling career and I continue to be inspired by the patients I meet every day.

NSCLC: Targeting What Drives People’s Cancer

This week, Real World Health Care talks with Edward B. Garon, M.D., Associate Professor of Medicine at the David Geffen School of Medicine at UCLA Health. He specializes in hematology and oncology, with an interest in lung cancer and chest malignancies.

Dr. Garon’s research focuses on the testing and development of targeted therapies and immunotherapies in the treatment of non-small cell lung cancer (NSCLC), including the development of a class of drugs known as PD-1 (programmed cell death-1) inhibitors, which allow immune cells to eliminate cancer. We spoke with Dr. Garon about checkpoint inhibitors, immunotherapies and targeted therapies for NSCLC.

Real World Health Care: Describe your role at UCLA’s David Geffen School of Medicine, especially as it relates to research of non-small lung cancer.

Edward Garon, MD, UCLA Health

Edward Garon, MD, UCLA Health

Edward Garon: I serve as director of thoracic oncology and conduct both clinical and laboratory research with a focus on translational research to determine lung cancer patient subgroups that are most likely to respond to certain therapies. Instead of looking at NSCLC as one disease, it’s important to personalize therapy and give people the therapies that are appropriate, not just for the disease site origin, but for a disease that’s driven by a particular set of molecular events.

RWHC: What do you think are the biggest challenges relating to NSCLC research and how are those challenges being addressed?

EG: We’ve seen some real progress in NSCLC research, especially in terms of immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors. But we’re not yet where we want to be. One of the biggest priorities is identifying more people who will respond to therapies and connecting the right research with the right patient population, especially since targeted therapies currently only apply to a small percentage of the patient population. Although early-phase lung cancer studies in non-metastatic patients have hinted at the potential to use biomarkers to select patients, data from clinical studies have tempered expectations.

RWHC: What do you think are the biggest challenges relating to current NSCLC treatment and how are those challenges being addressed?

EG: In the past 10 years, there has been a push to individualize care for NSCLC, to evaluate individual tumors on individual patients and determine if there are molecular changes or abnormalities in the tumor itself that can dictate whether there are certain therapies that are more or less likely to be effective in any given patient. Treatments for NSCLC have improved somewhat over time, but in patients whose tumors have progressed during or after their initial therapy, the outcomes for additional treatment have been quite poor.

Another challenge for clinicians is the emergence of checkpoint inhibitors, immunotherapies and targeted therapies. We currently have two PD-1 inhibitors available for treating advanced NSCLC, both of which are well-tolerated among patients. The quality and duration of responses to anti-PD-1 therapy can be profound in NSCLC, but some clinicians are not overly familiar with them and how to use them. Much of the experience with these drugs is concentrated in select academic centers. We need wider clinician awareness of which patients are most likely to benefit from therapy, when therapy should be stopped and how toxicity should be managed.

RWHC: Where do you think the biggest opportunities for future advances in NSCLC research and treatment lie?

EG: We will soon see a tremendous amount of data on the combination of checkpoint inhibitors and additional agents. It will be interesting to see both what the data from randomized studies show and how researchers interpret that data in terms of what constitutes a signal and what doesn’t. Careful selection of patients, doses of each agent, and information supporting strategies — concomitant or sequential — is still needed. Another exciting avenue is the potential incorporation of immunotherapy in early-stage disease, locally advanced disease and in first-line therapy for metastatic disease. These agents could become the frontline choice for select patients with stage IV disease versus standard chemotherapy.

RWHC: Why did you get into this field and what continues to inspire you about it?

EG: I became involved in lung cancer as a young physician coming from fellowship training. While there was not a lot of excitement in the field at that exact moment, I saw a good opportunity to be on the leading edge of therapy development. I am fortunate here at UCLA to be part of many of the studies of new drugs that have changed the course of patients’ disease and don’t have the toxicity associated with many chemotherapies. It’s certainly been gratifying to see how new therapies can positively impact patients. Just a few short years ago, NSCLC was seen as a disease that wasn’t particularly immunogenic. Ten years from now, I hope to look back on this exciting time and realize that we have come much farther still.

Non-Small Cell Lung Cancer: With Greater Understanding Comes Greater Challenges

This week, Real World Health Care speaks with lung cancer specialist, Gregory Masters, MD, FASCO, attending physician at the Helen F. Graham Cancer Center and associate professor at the Thomas Jefferson University Medical School. In addition to being Fellow of the American Society for Clinical Oncology, Dr. Masters is co-chair of the ASCO Committee for Updated Guidelines on Chemotherapy for stage IV non-small cell lung cancer. We talked about some of the challenges facing both researchers and clinicians treating patients with non-small cell lung cancer (NSCLC).

Real World Health Care: What do you see as the biggest challenges facing NSCLC researchers, and how can those challenges be overcome?

Gregory Masters, MD, FASCO

Gregory Masters, MD, FASCO

Gregory Masters: The field of lung cancer treatment is exploding in terms of our ability to understand the molecular biology of NSCLC, immunotherapies, targeted therapies and surgical techniques. We’re improving our ability to treat the disease, but we’re also challenged in terms of clinical trials. There’s a limited amount of time, limited number of patients and limited resources to design and implement those studies. More treatments mean more ways to design trials to compare and evaluate the efficacy of those treatments. So in some senses, the field is a victim of its success.

Collaboration is key, and the Cancer Moonshot program is a great example of this because it focuses on the pooling of data and resources to improve our ability to tackle the many challenges we face. We need the large cancer centers working together with community oncologists and the pharmaceutical industry to design studies, get patients enrolled and evaluate results.

RWHC: What do you see as the biggest challenges facing NSCLC clinicians, and how can those challenges be overcome?

GM: As our understanding of the biology of NSCLC increases, it adds a level of complexity for oncologists to keep up with. This is an issue that becomes more acute when you consider that the same oncologists treating NSCLC are treating other types of cancers as well, and there has been an equal explosion of research in other cancers.

We need to make sure that practicing oncologists have the resources they need for ongoing education. They need to attend relevant meetings and stay up on the latest research. They need to avail themselves of the resources available through the National Cancer Institute. They also need access to clinical trials. The real-life challenge in all of this is finding the time and energy to keep up with the latest research and opportunities. In all honesty, there are often not enough hours in the day.

RWHC: What do you think have been the most important advances in NSCLC research over the past decade? And how are those research advances changing the face of clinical treatments?

GM: The biggest advances have been in our understanding of the molecular biology and molecular genetics of NSCLC, which allow for targeted therapies. Each targeted therapy has a targeted population, which helps us make good on the promise of personalized medicine. Plus, we now have immunotherapies that allow us to “turn off” immune system regulators. In a practical sense, this means that patients who, until recently had few options if they were coming to the end of the line in terms of the ability of chemotherapies to treat their disease, now have new clinical options. Those options not only increase our ability to treat the disease, they give our patients the emotional boost they need to take the next step.

RWHC: Where do you see NSCLC research going in the next decade?

GM: It’s hard to predict. I don’t think anyone would have predicted ten years ago where we are today. But one area of promise is the further characterization of molecular changes in tumors as well as secondary changes in patients who have mutations, such as ALK mutations. This work is exciting and just in its infancy. Another area of promise is in our understanding of the immune system to determine which patients will benefit from a course of treatment and which won’t. We’re also developing a better understanding of the importance of palliative care and quality of life. All cancer patients can benefit from palliative care, but we need to expand the care team to include more people who can help, especially because oncologists are stretched so thin. We need additional resources to help our patients manage their symptoms and provide for a better quality of life.

RWHC: While exposure to cigarette smoke, asbestos and certain chemicals have been linked to NSCLC, many patients have not experienced such exposures. At the same time, other people with high exposure don’t get lung cancer. Does this mean the disease may be linked to genetics or some other factor?

GM: This is a question we’ve been asking for many years. How do we differentiate between environmental factors and intrinsic risk in a patient or a population? It’s the old nature versus nurture debate. We’re certainly improving our understanding of risk factors, but we still do not yet know why some people have a higher risk while other who smoke two packs a day don’t. We need more research in epidemiology and population-based studies. Unfortunately, those studies are hard to do.

RWHC: Why did you get into this field? What continues to inspire you?

GM: Choosing a career can be tricky. I was exposed to some great role models when I first started studying medicine and developed a deep respect for oncologists and the relationships they have with their patients. I continue to have great interest in research and learning more about cancer, but more than that, I enjoy having a positive impact on my patients—seeing them improve and seeing the gratitude of family members who appreciate what I do to help their loved ones. That’s what makes me excited to come to work every day.