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Advancing Melanoma Research & Supporting Patients

Our series on melanoma concludes as we shine the spotlight on the Melanoma Research Foundation (MRF). We spoke with the MRF’s Director of Education, Shelby Moneer, MS, CHES and MRF’s Scientific Advisory Committee Co-Chair, Michael B. Atkins, MD, PhD, Deputy Director of the Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University.

The MRF is the largest independent organization devoted to melanoma. Its mission is three-fold. It supports medical research that leads to more effective treatments and eventually a cure for melanoma. It educates patients, physicians and the public about the prevention, diagnosis and treatment of melanoma. And it serves as an advocate for the melanoma community to raise awareness of melanoma and the need for a cure.

Research & Patient Support Priorities

Real World Health Care: What type of research programs does the MRF support?

Shelby Moneer, Melanoma Research Foundation

Shelby Moneer: The Melanoma Research Foundation is committed to advancing a broad scientific agenda across the disciplines of prevention, diagnosis and treatment. As part of the MRF’s mission to support medical research to find effective treatments and a cure for melanoma, we are proud to collaborate with internationally recognized research institutions, investigators, government entities and leading melanoma organizations. The MRF currently offers research awards for medical students, junior investigators and senior investigators in both clinical and translational science. We fund research related to cutaneous, mucosal and ocular melanoma.

RWHC: How does the MRF support the patient community?

SM: The MRF provides a broad range of patient support programs offering access to peer-to-peer educational information, as well as professionally moderated support networks, financial and treatment assistance and more. These are continually updated and expanded as new resources become available because we believe that educated and informed patients with a strong support network live longer, better lives.

The MRF advocates for the melanoma community on the local, state and federal level on issues that promote melanoma awareness, prevention and treatment. Current priorities include increased federal funding for melanoma research, restrictions on the use of indoor tanning devices and expanded access to sunscreen in schools. The MRF trains and supports a nationwide network of dedicated volunteers who serve as advocates everywhere from their local communities to the halls of Congress.

RWHC: What are some of the biggest challenges facing researchers studying melanoma?

Dr. Michael B. Atkins, Georgetown-Lombardi Comprehensive Cancer Center

Michael Atkins: The MRF feels that the biggest challenge is helping to launch the careers of young investigators who are interested in doing research into the biology and treatment of patients with melanoma. The MRF is addressing this challenge by offering an expanded number of Career Development grants in the coming year targeted toward young investigators.

Treating Melanoma Patients

RWHC: How are clinicians addressing the challenges of treating patients with melanoma?

MA: For clinicians, the big challenges are learning how to optimally use new treatment options for patients with melanoma. For example, identifying how to integrate targeted therapy with immune therapy, when to stop immune therapy, how to treat patients with variant melanoma presentations (acral, mucosal, uveal) and patients with CNS metastases, how to treat patients with resistance to immunotherapy, determining the best adjuvant therapy for patients with resected high and intermediate risk melanoma, identifying predictive biomarkers for particular treatment approaches, identifying safe and effective combination regimens, and learning how to manage the novel toxicities of immunotherapies.

These questions can only be answered through continued clinical research. The MRF is addressing these challenges through the Melanoma Research Foundation Breakthrough Consortium (MRFBC), which brings together clinical investigators from 20 leading academic melanoma centers to design and conduct clinical trials addressing these types of questions.

RWHC: How can patients work with clinicians to optimize their treatment?

MA: Melanoma patients face the challenge of getting the best treatments for their disease in a setting that is convenient for them and will get them back to their normal lives as quickly and as functionally intact as possible. Patients can work with clinicians by participating in clinical trials aimed at both providing tomorrow’s treatments today and addressing the important unanswered questions facing researchers. Patients can also go to organizations like the MRF to gather information about optimal management of their disease, unanswered questions and available clinical trials. Their support community can work with and contribute to MRF to foster the clinical and basic research that will lead to even further advances in the treatment of patients with melanoma.

RWHC: What does the MRF see as the most promising treatments on the horizon for melanoma?

MA: The MRF sees many promising new treatment opportunities including novel combination immunotherapies, triple combination of BRAF/MEK and anti-PD1 regimens and moving effective treatments for advanced disease into the adjuvant high risk setting.

Categories: General, Melanoma

Cutting-Edge Melanoma Treatment at Rutgers Cancer Institute of New Jersey

This week, Real World Health Care continues our series on melanoma by interviewing two colleagues from the Rutgers Cancer Institute of New Jersey, a National Cancer Institute-designated Comprehensive Cancer Center.

Sharad Goyal, MD, is Associate Professor and Director of Clinical and Translational Research in the department of Radiation Oncology. He treats patients with brain tumors, melanoma and skin cancers, providing comprehensive cancer evaluation and the latest treatment planning technology to “map” tumors. He designs radiation treatments with pinpoint accuracy, ensuring that tumors get the most effective dose while healthy tissues and organs are spared.

Ann W. Silk, MD, is a medical oncologist who cares for patients with melanoma, and other skin cancers. She also leads clinical trials focused on combination treatment with immunotherapy and viral therapy for melanoma and other cancers.

Drs. Goyal and Silk discuss their work as part of a multidisciplinary team that translates research of investigational treatments and directly applies them to patient therapies.

Managing Multiple Melanoma Brain Metastases

Real World Health Care: How is treatment advancing for patients with multiple brain metastases (MBM) from melanoma?

Sharad Goyal; Faculty and Staff, Rutgers – Robert Wood Johnson Medical School, New Brunswick, NJ. 05/01/2014 Photo by Steve Hockstein/HarvardStudio.com

Sharad Goyal: The treatment of brain metastases from melanoma is controversial and includes surgical resection, stereotactic radiosurgery (SRS) and whole brain radiation (WBRT). Several new classes of agents have revolutionized the treatment of metastatic melanoma, allowing for subsets of patients to have long-term survival. Given this, management of MBM from melanoma is continually evolving.

As patients are living longer due to more effective systemic therapy, surveillance and management of intracranial disease is increasingly important. At this time, the standard of management for patients with MBM from melanoma includes SRS, WBRT, or a combination of both.

In addition, emerging data supports the notion that SRS, in combination with targeted therapies or immune therapy, may reduce the need for whole brain radiation. Prospective studies are required to fully evaluate the efficacy of these novel regimens in combination with radiation therapy. Given the advances in systemic therapy of melanoma, it is critical that oncologists treating these patients be aware of new treatment paradigms to optimize the outcomes for all patients with metastatic melanoma.

RWHC: Are there ways to treat melanoma in order to avoid or lessen the chances of brain metastases? Does early initial detection of melanoma help?

SG: Early detection of melanoma will always help reduce the chance a patient develops brain metastases. There is usually a fairly lengthy period when the tumor expands beneath the top layer of skin but doesn’t go any deeper. This allows time for screening, early detection, treatment, and a full recovery if the tumor is discovered before it spreads.

After a patient is diagnosed with melanoma, the use of certain anticancer treatments that are given after a cancer is surgically removed, such as interferon alfa and ipilimumab, will allow for an improvement in overall survival in patients with stage III or IV melanoma. In addition, the use of anti-PD-1 checkpoint inhibitors prolongs overall survival in patients with stage IV melanoma. Currently, many studies are underway investigating the optimal anticancer treatment in patients with Stage III melanoma.

Promising Therapies

RWHC: What are the most promising therapies on the horizon for metastatic melanoma?

Ann W. Silk, MD, Rutgers Cancer Institute of New Jersey

Ann Silk: Melanoma is the “posterchild” for breakthrough immunotherapies. At Rutgers CINJ, we are testing novel combinations of new agents coupled with immunotherapies. Those novel agents help to “prime” tumors so immunotherapies work better. One example of this is combining an immune checkpoint inhibitor pembrolizumab with intra-tumoral injections of talimogene laherperepvec, which is a live herpesvirus that infects cancer cells, replicates within them, and lyses the cancer cell, thus killing the cell. We’re also seeing promising early results in trials that combine intra-tumoral injections of coxsackievirus with injections of pembrolizumab, with response rate of 60%, which we reported at this year’s American Association of Cancer Research Annual Meeting. We have just recently opened a study in which we will combine IL-2 cytokine therapy with pembrolizumab, a combination of two drugs that have already demonstrated good activity in metastatic melanoma.  They are each FDA-approved as single-agents, but we are studying them as a combination therapy. The goal of these studies is to build on the success of immunotherapies to increase response rates, particularly complete response rates.

Access to Clinical Trials

RWHC: What are some of the biggest challenges facing researchers studying metastatic melanoma?

AS: Access to clinical trials is a challenge, from a patient or participant status. Running clinical trials requires vast resources and numerous support personnel, so they tend to be concentrated at large medical centers. As a result, only about five percent of the patient population has access to these trials. I think that number should be closer to 80 percent. Trials aren’t only important for the patients receiving the treatment; the knowledge we gain also helps future patients.

Treating Melanoma

RWHC: What are the biggest challenges facing clinicians treating patients with metastatic melanoma?

SG: One of the most challenging types of cancer to treat is melanoma and the most challenging area it can spread to is the brain. With the advancements being made in cancer treatment, the odds of survival for many of these patients are changing dramatically.

In recent years, our understanding of cancer biology has progressed substantially and this has led to the development of targeted therapies and immunotherapies. These novel therapies have prolonged survival in a disease which previously had a dismal outcome. As patients are living longer due to more effective systemic therapy, surveillance and management of intracranial disease is of increasing importance.

AS: There are many standard therapies approved to treat melanoma, and as indicated earlier, there’s lots of research activity in this area as well. Patients benefit from the wealth of approved therapies on the market. But while about 30-40 percent of patients will respond very well to these therapies, the majority still struggle and succumb to their disease. Patients who don’t respond to the first line of treatment must move on to a second line of treatment. Once those treatment options are exhausted, the only course of action is to try and get the patient enrolled in an investigational therapy trial. In many cases, the patient would benefit from earlier involvement in clinical trials.

Early and Current Inspirations

RWHC: What initially interested you in researching melanoma and treating people with the disease? What continues to inspire you?

AS: I became interested in the interplay between cancer and the immune system in my first job as a data manager at the Dana-Farber Cancer Institute, where I managed one of the first clinical trials of ipilumumab, which was later FDA approved with the distinction of being the first drug that prolonged survival in melanoma. I was inspired by researchers who were on the forefront of personalizing medicine by using the immune system to attack cancer cells. Ever since then, in both my research and clinical practice, I haven’t found any better ally in the fight against cancer than retraining the immune system to attack cancer cells.

SG: Throughout my career, I have been inspired by the cancer patients I treat.  The relationships that I have developed with patients and their families are unlike those in almost any other medical specialty. Once a patient has a diagnosis of cancer, I am able to see the patient and his or her family members on a regular basis and develop a long-lasting relationship with them.

Fighting Melanoma with Immunotherapy

For this week’s post in our series on melanoma melanoma, Real World Health Care interviewed Kelly M. McMasters, MD, PhD. Dr. McMasters serves as the director of the Multidisciplinary Melanoma Clinic at the University of Louisville’s James Graham Brown Cancer Center. Here, he works with colleagues to identify the most effective combination of therapeutic modalities including surgery, immunotherapies, and targeted therapies for stage I-IV melanoma patients.

Dr. McMasters also directs a basic and translational science laboratory studying adenovirus-mediated cancer gene therapy and melanoma biomarkers, which has been funded by the National Institutes of Health, the American Cancer Society, the Melanoma Research Foundation and other agencies.

Sunbelt Melanoma Trial

Real World Health Care: You are the author and principal investigator of the Sunbelt Melanoma Trial. Can you briefly summarize the focus of this trial and its results?

Dr. Kelly McMasters, James Graham Brown Cancer Center, University of Louisville

Kelly McMasters: This was a multi-institutional study involving 3,500 patients from 79 institutions across North America. We studied whether interferon should be used for patients with minimal spread of melanoma to their lymph nodes. We found that this toxic, expensive treatment — which is like having the flu, but worse, for a whole year — was not necessary and did not result in survival benefits. This is important because many patients have been spared unnecessary treatment.

While interferon is still approved for adjuvant therapy for high-risk melanoma, other options now in the pipeline, and further research into the molecular basis of melanoma metastasis and immune system evasion will result in improvements in adjuvant therapy for patients at high risk of recurrence.

We also evaluated molecular tests to find patients at high risk of recurrence, but these tests turned out to not be clinically useful.

Immunotherapy Studies

RWHC: Are you currently working on any new studies or trials relating to melanoma?

KM: We currently are conducting and participating in several studies of immunotherapy for melanoma. Immunotherapy has revolutionized the treatment of melanoma in the past few years. Five years ago, there were essentially no treatments that were effective for patients with advanced melanoma. Now, we frequently can use immunotherapy that results in durable, complete remissions and even cure in such patients.

Former President Jimmy Carter is an example. He had metastatic melanoma in his brain and elsewhere, with a life expectancy of a few months. He got an immune checkpoint inhibitor and his cancer went away.

Immunotherapy Combinations and Resistance

RWHC: What are some of the biggest challenges facing researchers studying melanoma?

KM: Right now, the challenge is to figure out the best combination of immune therapies to get the greatest benefit for patients with the least side effects. We need to better understand the immune system and how it fights cancer.

Newer studies of melanoma adjuvant therapy using immune checkpoint agents, such as PD-1 inhibitors, show much promise. More work needs to be performed to understand the significance of molecular detection of melanoma cells in the lymph nodes and in the circulating bloodstream. We now suspect that melanoma, like other cancers, routinely sheds cancer cells into the lymphatic system and bloodstream. A small minority of these cells that have the ability to evade the immune system, attach, invade, develop their own blood supply and grow, becoming metastatic tumors.

RWHC: What are some of the biggest challenges facing clinicians studying melanoma?

KM: We need to find out why some patients have miraculous responses to immunotherapy and why some are resistant. Finding out how these mechanisms of resistance work will help us design treatments that are more effective for most people.

Clinicians also need to pay attention to side effects, which are variable, from very mild or virtually none, to potentially life-threatening. Early recognition and treatment — often immediately with corticosteroids — can be lifesaving, especially for autoimmune colitis, which can lead to bowel perforation and serious infection.

Beyond Surgery

RWHC: What interests you in studying melanoma, and treating patients with the disease?

KM: After so many years in which surgery was about the only truly effective treatment for melanoma, it is encouraging to see the development of other effective therapies. I find it gratifying when I now refer patients with advanced melanoma to my medical oncology colleagues for immunotherapy with realistic hope of remission or even cure, rather than engage in desperate attempts to surgically resect all of the cancer. Surgery still has a very important role, but we now have a lot of other possibilities.

Harnessing the Immune System to Treat Melanoma

Real World Health Care continues our series on melanoma with a discussion with Howard Kaufman, MD, FACS, surgical oncologist at Rutgers Cancer Institute of New Jersey. Dr. Kaufman’s clinical and research work focuses on using the immune system to fight cancer. He also runs a scientific laboratory focusing on oncolytic viruses and had his first agent approved in 2015. He authored The Melanoma Book as a resource for patients and family members dealing with the diagnosis of melanoma and currently serves as editor-in-chief for the Journal of Immunotherapy Applications.

Directions in Research & Treatment

Real World Health Care: How can the immune system be used to treat melanoma?

Dr. Howard Kaufman, Rutgers Cancer Institute of New Jersey

Howard Kaufman: We’ve known for many years that the immune system can recognize some cancer cells, and when this happens the immune system can eradicate the cancer cell. We’ve seen this most prominently in melanoma, where a small percentage of patients with advanced melanoma don’t even know they have the disease because their immune system eradicates it without treatment.

About two decades ago, interleukin-2 (IL-2) was approved to treat melanoma. IL-2 is a natural part of the immune system. It’s a messenger protein called a cytokine, which activates part of the immune system. IL-2 doesn’t kill tumor cells directly like chemotherapy. Instead, it activates and stimulates the growth of immune cells: T-cells and Natural Killer Cells, both of which are capable of destroying cancer cells directly.

I trained under IL-2’s developer, Dr. Steven Rosenberg, at the National Cancer Institute, and was one of the first oncologists in the country to start treating patients with the therapy. It worked well, and it even cured some patients. But only about 15-20 percent of patients responded, and the research community began to ask why more patients didn’t respond.

We subsequently found that melanoma cells express a protein, called PDL-1, that shuts off the T-cells in the immune system (by binding to PD-1, which is expressed by the T-cells) so the cancer can grow. Over the last five years or so, antibodies have been developed to block PDL-1 immune inhibitory receptors. We started to see dramatic results in patients, similar to that of IL-2. Even though large numbers of patients are not responding, when responses do occur, they are sometimes complete and often long-term.

Now, other researchers and I are starting to use oncolytic viruses, which are injected directly into tumor cells. The viruses replicate in cancer cells, but not in normal cells. This replication generates an immune response in the cancer cells and overcomes the immune inhibitory receptors. We’ve seen benefit of this therapy in clinical trials for about 25 percent of patients. Even for patients with metastatic melanoma, if the virus is injected in a melanoma cell in the arm or the leg, it will eradicate melanoma in the lung as well.

Our next step in terms of research is to look at putting immunotherapy together with oncolytic virus therapy to see if we can increase response rates among more patients.

Immunotherapy Challenges

RWHC: What are some of the biggest challenges in using immunotherapy to treat melanoma patients?

HK: Like every drug, there are side effects, but not the type of side effects typically associated with chemotherapy or radiation therapy. These side effects relate to over-active immune response. Typical side effects include inflammation of the colon, liver or even lungs. These side effects are manageable, if treated quickly with corticosteroids. Unfortunately, if they’re not treated quickly, immunotherapy needs to be stopped. I’m a member of the Society for Immunotherapy of Cancer (SITC), which is working with the American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) to develop guidelines to teach the clinical community how to best recognize and treat side effects due to immunotherapy drugs.

Another challenge facing the clinical community is how long to treat patients with these newer drugs. There’s not a lot of consensus on whether treatments should last one year, or two years, or if therapies should be stopped as soon as the patient responds to avoid the risk of side effects. It’s possible that some patients are being over-treated. Ideally, we will be able to find biomarkers that indicate whether a patient will be cured or will need more treatment.

Melanoma is an interesting field. Ten years ago there were very few treatment options, and today we have many. We’re just beginning to understand how to sequence therapies so patients get the right treatment at the right time. We also need better therapies for patients with mucosal melanoma and ocular melanoma, because they don’t respond as well to immunotherapy.

Promise of Combination Therapies

RWHC: What are some of the most promising combination therapies on the horizon to treat melanoma patients?

HK: Right now, I’m excited about combining oncolytic viruses with anti-PD-1 and anti-PDL-1 agents. We’re seeing high response rates in clinical studies, without the increase in side effects common with other combinations. Other than a mild fever, chills and injection site reactions, the viruses have been very safe. This could be a powerful way to increase the number of patients who respond and cut down on side effects.

RWHC: How did you get interested in melanoma?

HK: I did a fellowship at the National Cancer Institute and became interested in how patients’ immune systems responded to IL-2. Melanoma seemed to be the most sensitive to immune system manipulation, and I’ve been honored to help develop what is today considered the paradigm in cancer care. During my fellowship, I became comfortable working with melanoma patients and was fortunate to build my practice quickly.

Melanoma knows no boundaries. It can affect people of all ages; I have personally treated patients as young as 5 years of age and up to 98 years of age. It’s such an evil type of cancer and it can spread anywhere. Offering hope to patients has been very rewarding, and I’ve enjoyed the opportunity to get students and residents interested in treating the disease and studying immunotherapies.

Profiling Melanoma to Predict Immune Therapy Success

May is Melanoma awareness month, and our series on melanoma continues with a discussion with Dr. Douglas B. Johnson of the Vanderbilt-Ingram Cancer Center. Dr. Johnson leads Vanderbilt’s melanoma clinical and research program, overseeing clinical trials, patient care and translational research. His research interests focus on developing new immune and targeted therapies for melanoma, and in using existing treatments in the most effective ways. Specifically, he is exploring ways to profile cancers to predict which patients will benefit from immune therapies.

Combination and Targeted Therapies Allow Long-Term Survival

Real World Health Care: You published a review of therapeutic advances and treatment options in metastatic melanoma. Can you summarize the review and discuss its implications for patients with the disease?

Dr. Douglas Johnson, Vanderbilt-Ingram Cancer Center

Douglas Johnson: Treatment options for advanced melanoma have been rapidly advancing. We now have multiple options for patients with this disease, when even 5-10 years ago very few existed. Immune therapies, which unleash the immune system against the cancer, result in long-lasting responses in a large fraction of patients. The number of patients who benefit from treatment increases when two immune therapy treatments are combined, although at the cost of increased side effects. Targeted therapies, which block the effects of particular genetic mutations, have also made a big difference, particularly for patients who have mutations in the gene BRAF, which represents about half of melanoma patients. These treatments have transformed a disease which was essentially uniformly fatal to one that is often associated with long-term survival.

RWHC: Are you currently working on any new studies or trials relating to melanoma?

DJ: We have a number of combination immunotherapy trials. These types of trials are attempting to use strategies that extend the benefits of immune therapy to more patients. We are also working on developing biomarkers for immune therapy responses. In particular, we are evaluating whether the number and types of mutations in melanoma, as well as the expression of particular immune proteins, can predict which patients will respond to immune therapy. We also are studying the side effects and toxicities of immune therapy, to understand why they occur, who is affected, and develop effective prevention and treatment strategies.

Melanoma Research and Treatment 

RWHC: What do you see as the most promising treatments on the horizon for melanoma?

DJ: A number of promising immune therapy combinations are being developed. It is very difficult to say which is the most promising, but likely some combination of anti-PD-1 therapy with other immune or targeted therapy agents.

RWHC: What are the biggest challenges facing melanoma researchers?

DJ: One of the biggest challenges is predicting who will respond to current immune and/or targeted therapies so we can assign the right treatment to the right patient. Researchers also are challenged to develop the most effective combination therapies and to prevent and manage toxicities. In some ways, the development of effective therapies has made it more difficult to enroll patients in clinical trials. This is a good problem to have, but it limits the speed of developing new effective therapies.

RWHC: What are the biggest challenges facing clinicians treating patients with melanoma?

DJ: From a clinical standpoint, the challenges are similar. Despite the current advances, there is still a large subset of patients who do not respond well to treatments. We need to understand who those patients are upfront, and develop more effective treatment strategies for them.

Toxicities are also a major consideration, particularly for patients with other medical problems or who have limited functional status. It is always a difficult balancing act deciding between single agent and combination immune therapy. On one side is the potential for a somewhat higher response rate, on the other side is the significant increase in side effects (which are typically manageable). Every clinician and patient has a different threshold regarding when to offer these therapies.

Improving the Lives of Melanoma Patients

RWHC: What initially interested you in studying and treating melanoma? What continues to inspire you?

DJ: I had a friend during my medical training who developed stage III melanoma and I was struck by the lack of treatment options at the time. When I joined Vanderbilt, my mentor Dr. Jeff Sosman was doing amazing research, and I become very excited about the prospect of doing groundbreaking research that would affect patient lives. That approach continues to drive and inspire me.

Accelerating Melanoma Research

It’s Melanoma Awareness Month and this week, Real World Health Care is pleased to shine a light on The Society for Melanoma Research. We spoke with the Society’s President, Keith Flaherty, MD. In addition to his role with SMR, Dr. Flaherty serves as director of the Henri & Belinda Termeer Center for Targeted Therapy and the Richard Saltonstall Chair in Oncology at the Massachusetts General Hospital Cancer Center.

Supporting a Diverse Melanoma Research Community

Real World Health Care: Please describe the mission of the Society for Melanoma Research.

Dr. Keith Flaherty, Society for Melanoma Research

Keith Flaherty: The Society for Melanoma Research was intended to be a scientific home for the melanoma research community. When it was created in 2003, there was no organization run by and for melanoma scientists that convened regular scientific meetings to provide a venue for publication of melanoma research. Our research community is quite diverse, spanning many medical specialties and numerous scientific disciplines. Simply bridging the divide between the clinical research community and laboratory-based investigators was central to the SMR mission.

RWHC: What type of research programs do you support and how do you support them?

KF: Our primary supporting role is served by organizing and hosting an annual, international, scientific conference focused on melanoma research. We support travel to the meeting for trainees and young scientists. Plus, we maintain a web-based presence and newsletter to update our members on emerging discoveries. Additionally, we partnered with the International Federation of Pigment Cell Societies to transform a pre-existing Journal (Pigment Cell Research) into Pigment Cell and Melanoma Research in order to have a peer-reviewed journal supported by SMR with scientific leadership by melanoma researchers.

Combination Therapy Research

RWHC: Are there any studies your members are involved in that are particularly promising at this moment?

KF: As ours is the only international scientific society focused on melanoma research, our membership includes all of the clinical investigators from the major academic centers who have been conducting groundbreaking clinical trials in melanoma over the past eight years. Outcomes for patients with metastatic melanoma have been transformed by the development of molecularly targeted and immunotherapies. The most promising current trials have been investigating combinations of these two approaches at the same time. Preliminary results presented at the 2016 SMR Congress suggest that these combination approaches may further improve outcome significantly.

Multidisciplinary Collaboration

RWHC: Why are multidisciplinary collaborations so important in developing new therapies for melanoma? How is the SMR working to encourage or create such collaborations?

KF: Multidisciplinary collaborations can be defined by teams of clinical investigators, such as medical oncologists, surgical oncologists, pathologist, and radiologists. Or, they can encompass clinical and laboratory-based investigators partnering together. We have numerous examples of each kind within and across the major academic medical centers with a focus on melanoma research.

For years, the melanoma research community was characterized by empiric clinical trials in which therapies that had been successful in other cancer types were tried in melanoma, but with little scientific basis and focus on understanding whether those therapies were doing their molecular “job” or not. Since the late 2000s, the emergence of BRAF, MEK, CTLA-4 and PD-1 inhibitors has provided not only substantial benefit to patients, but it has transformed the research approach by bringing clinical and laboratory-based scientists together. Even for these FDA approved therapies, there remain questions regarding mechanisms of action and resistance which are critical to informing rational combination therapies that will be the focus of the next generation of clinical trials. This approach literally taught us how to define the limits of these partially effective therapies and will hopefully accelerate our pace of progress.

More Funding, More Time

RWHC: What are the biggest challenges melanoma researchers face today and how can they be overcome?

KF: Funding and time. For a decade, we have seen a decline in publicly funded research. The U.S. has always been the largest investor in biomedical research, and pairing that down has had global impact. New discoveries are made through publicly funded research before private sector research comes in to take those discoveries and reduce them to practice. This has made the melanoma research field increasingly dependent on philanthropic foundations and individuals.

Additionally, clinical researchers are constantly pulled between clinical duties and research activities. Many medical centers cannot afford to have their clinicians spending time on research. Therefore, research funding is needed to cover the portion of their time that is away from direct patient care. With the accelerated pace of technology development relevant to biomedical research and the inroads that we have made in the past eight years with regard to therapeutic approaches, there is more opportunity now than ever to accelerate the application of science to medicine for melanoma patients. But, these rate limiting factors are unquestionably slowing us down.

Industry’s Role

RWHC: What role do you think the biopharmaceutical industry should play in furthering research into new melanoma therapies?

KF: As always, advancing diagnostic and therapeutic approaches to widespread use requires risk-taking and investment by the biopharmaceutical industry.

In the cancer field overall and melanoma specifically, we have seen tighter integration between the public and private sectors that has come as a consequence of the initial successes with the now FDA-approved drugs. This has drawn in more interest from companies developing novel diagnostic technology that may allow us not only to find localized, advanced melanoma at an earlier point, but also allow us to deploy the optimal therapy for each patient in a personalized way. And, of course, the very costly process of drug development requires involvement of the biopharmaceutical industry from beginning to end.

Through close collaboration with the academic scientific community, we are able to discern very early in development whether a new therapy is accomplishing its biological task before investing massive additional resources in large-scale clinical trials to prove whether or not it has a clinical impact.

Dramatic Unmet Need

RWHC: What initially attracted you to the field of melanoma research?

KF: I was attracted to the melanoma field first and foremost by the dramatic unmet need. It is a cancer that has an awe-inspiring ability to metastasize from tiny primary tumors, making the challenge of early detection a key hurdle. And, when melanoma metastasizes, it is one of the most aggressive cancer types. Melanoma affects a far greater proportion of young adults than other more common cancers, making it one of the leading cancers with regard to aggregate years of life lost. At the time that I was entering the field, it seemed that the pace with which biologic insights into melanoma were being made was increasing. And, right at the end of my training, BRAF mutations were discovered and that drew my focus for all of the years since.

A MESSAGE FROM OUR SPONSOR:

The HealthWell Foundation, sponsor of Real World Health Care, is proud to have supported the melanoma patient community in recent years with copayment and premium assistance. We have helped more than 2,230 melanoma patients afford their treatments since approving our first Melanoma grant in 2011 — thanks to the generous support of our corporate partners. Due to high patient volume, our melanoma fund is temporarily closed until we receive additional funding. We invite corporations and individuals to help us meet this demand by contributing to our Melanoma-Medicare Access Fund, so nobody goes without essential medications because they cannot afford them.

Categories: General, Melanoma

The Mechanics of Melanoma

May is Melanoma Awareness Month. This article originally appeared in the Biotech Primer WEEKLY. For more on the science behind the headlines, subscribe. 

Melanoma 101 

Emily Burke, BiotechPrimer.com

Melanoma accounts for less than one percent of skin cancer cases, yet accounts for the vast majority of skin cancer deaths (skincancer.org). If detected early enough, melanoma is almost always curable. If it is not detected early, it is likely to spread to other parts of the body, where it is more difficult to treat. It’s estimated that in 2017, there will be 87,110 new cases of melanoma in the U.S., and 9,730 melanoma-related deaths (Aim at Melanoma Foundation). Melanoma is one of the types of cancers most common in young adults, with 25 percent of new cases occurring in people under age 45. Its prevalence is growing – the number of new cases/year relative to the total population has doubled since 1973.

In this column, we’ll review the basics of melanoma, and discuss the latest new therapies recently approved and in development.

Melanoma’s Method

Melanoma is the uncontrolled growth of the pigment-producing cells known as melanocytes, which are located in the bottom layer of the skin’s top layer (the epidermis). Like other types of cancers, melanoma arises from gene mutations in these cells that impact cell growth and division. In the case of melanoma and other skin cancers, the DNA damage is usually caused by ultraviolet (UV) radiation, resulting in a tumor that initially grows in the skin, spreading along the epidermis. If the melanoma is detected at this stage, it can often be surgically removed. If the out of control cell growth is not caught in these early stages, it penetrates deeper layers of the skin, eventually coming into contact with lymph and blood vessels which enable it to spread to other parts of the body. When the melanoma reaches this stage, it is called metastatic melanoma.

Although anyone can get melanoma, fair-skinned people are at higher risk for all types of skin cancer, since increased skin pigmentation helps to block the damaging UV rays from penetrating and damaging skin cell DNA. However, darker-skinned people can and do get skin cancer, and thus should also be vigilant about sun protection.

Atypical moles have also been linked to an increased risk of melanoma. Moles are clusters of melanocytes, and there is a slightly increased risk of melanoma arising within these clusters. Of course, most moles are harmless and do not lead to melanoma. However, any sudden changes in the color, shape, or size of a mole should be evaluated by a doctor.

Genetic Factors: p53 & BRAF 

Although most cases of all types of skin cancer are traceable to excessive sun exposure, about 10% are likely due to genetic factors. The gene most commonly mutated in familial melanoma is p53. p53 is a “tumor suppressor,” which means that it detects DNA damage in cells, and triggers either DNA repair pathways or activates cell death if the DNA damage cannot be repaired. Another gene, known as the BRAF gene, regulates cell growth and is mutated in inherited forms of melanoma. About half of all genetically-based melanomas have the BRAF mutation.

Let’s take a closer look at BRAF. BRAF codes for a protein required for the transmission of a growth signal from a cell surface receptor to the cell nucleus (growth signal transduction). Growth signaling is initiated by a growth factor binding to its receptor. This binding transmits a signal through the membrane, causing the internal portion of the receptor to interact with and activate a protein inside of the cell. This activation is then transferred to the next protein in the pathway, and so on until the signal reaches the last protein in the pathway. When this protein is activated, it enters the nucleus, where it turns on specific genes that make proteins which initiate cell division. BRAF is one of the proteins in this pathway. In BRAF-associated melanoma, the mutated BRAF is always turned on even when no growth factor is present.

Small molecule drugs that inhibit overactive BRAF have been developed and approved for the treatment of late-stage melanoma.

Immunotherapies in the Fight 

A few different checkpoint inhibitor therapies have been approved to treat metastatic melanoma. These are drugs that enable killer T-cells – immune system cells that recognize and kill threats such as cancer cells – to become fully active against a tumor cell target. These drugs target inhibitory proteins on the surface of T-cells such us CTLA-4 and PD-1. These proteins act as “off switches” for killer T-cells. By inhibiting these off switches, the killer T-cells become fully activated, and able to target and kill melanoma cells.

A second type of immunotherapy that has been approved for melanoma is an oncolytic virus therapy. An oncolytic virus is a virus that infects and kills cancer cells. The cancer cells are killed through cell lysis – as the virus multiplies inside of the cells, it causes them to burst open. This in turn releases new infectious particles that can target remaining tumor cells. In addition to direct killing of cancer cells via lysis, the presence of an actively replicating virus helps to activate the patient’s immune response to target the area.

In the Pipeline 

A new type of immunotherapy drug is in Phase 3 clinical development. The drug is a small molecule inhibitor of the enzyme IDO1. IDO1 helps regulatory T-cells to develop and become activated. Regulatory T-cells suppress the immune response, and therefore help cancer cells to escape immune surveillance. Inhibiting IDO1 should suppress the development of regulatory T-cells, bolstering the immune response against melanoma.

Implications of microRNA 

Last year, researchers at Tel Aviv University published a report describing how melanoma metastasizes. Their work suggests that melanoma cells release tiny vesicles that contain microRNA, a type of regulatory RNA produced by all cells. These micro-RNA filled vesicles induce changes in the dermis – the layer of skin just below the epidermis where the melanoma begins. The dermis contains blood vessels, and thus a pathway for metastasis. The changes in the dermis induced by the small vesicles released from the melanoma cells makes the cancer cells able to access those blood vessels. The Tel Aviv team is identifying drug candidates that may interfere with this process, preventing the metastasis that makes melanoma so deadly.

The best strategy for melanoma remains prevention and proactive monitoring – limiting sun exposure and monitoring the skin for any unusual growths or changes in moles. Increased understanding of the molecular pathways that contribute to melanoma’s development and spread will provide physicians with additional tools to fight those cases of metastatic melanoma that inevitably will continue to arise.

Categories: General, Melanoma

NSCLC: The Emerging Role of Liquid Biopsies

Real World Health Care concludes its series on non-small cell lung cancer by speaking with Erica Carpenter, MBA, PhD, Research Assistant Professor in the Department of Medicine at the Perelman School of Medicine at the University of Pennsylvania. Dr. Carpenter also serves as Director of the Circulating Tumor Material Laboratory in the Division of Hematology/Oncology at the Abramson Cancer Center.

Dr. Carpenter served as senior author on a recent study that suggests for patients with advanced lung cancer, a non-invasive liquid biopsy may be a more effective and suitable alternative to the gold standard tissue biopsy to detect clinically relevant mutations and help guide the course of treatment.

Real World Health Care: Explain your role at the Perelman School of Medicine.

carpenter_erica_businessErica Carpenter: I am Director of the Circulating Tumor Material Laboratory and an Assistant Professor in the Division of Hematology-Oncology at the Perelman School of Medicine. My lab focuses on the identification, capture, and analysis of Circulating Tumor Cells (CTCs) and cell-free DNA (cfDNA), exosomes and other material shed from cancer patient tumors.  Blood, bone marrow, pleural effusions, and other non-invasively captured patient samples are used to detect biomarkers which will allow: early detection of disease as well as post-therapy monitoring of minimal residual disease, an efficient means of determining clinical and biological response to therapy and, thus, clinical decision making, and cancer genetic phenotyping to drive personalized medicine that obviates the need for serial biopsies in a population of patients for whom these procedures can be difficult, risky, and insufficient.

RWHC: Can you give us an overview of your recent research as it relates to non-small cell lung cancer and liquid biopsies?

EC: While the work described in the Clinical Cancer Research paper is the only NSCLC liquid biopsy study we have completed, we have several studies currently enrolling, including studies on the use of liquid biopsies to monitor and predict response of patients receiving a form of immunotherapy known as checkpoint inhibitors, and characterization of the tumor cells and circulating tumor DNA found in the pleural effusions (excess fluid that sometimes builds up in patients’ lungs) of lung cancer patients as another method for monitoring without an invasive biopsy.

RWHC: Just a few months ago, the FDA approved the first liquid biopsy test for patients with metastatic NSCLC. Why is this an important development?

EC: This is important for a number of reasons. First, the cobas test detects mutations in a gene called EGFR that can be targeted with specific drugs that have been shown to be effective in NSCLC patients with these specific mutations. In addition, liquid biopsies in general can greatly improve sensitivity of mutation detection in metastatic patients. Metastatic disease means that a patient has tumors in multiple sites in the body, and this can make surgical biopsy or fine needle aspirate very difficult to perform without great discomfort to the patient. Metastases can sometimes occur in places like the bone or brain where it is impossible to invasively obtain tumor tissue. Moreover, the genetic profile of a tumor tends to evolve over the course of a patient’s therapy, and it is not unusual for a metastatic patient to exhibit mutational heterogeneity where not all mutations are expressed in all tumor locations. In these cases, it is thought that a liquid biopsy will detect all or most mutations as all tumor sites, whether primary or metastatic, are thought to shed DNA into the blood. Finally, when a next-generation sequencing panel, such as the one used in our study, is applied to a liquid biopsy, comprehensive and clinically actionable data can be obtained with a single blood test, including mutations in multiple genes associated with therapy resistance.

RWHC: Do you think that liquid biopsies will become a standard of care for NSCLC patients? Will they, or should they replace tissue biopsy? Why or why not?

EC: Liquid biopsies are already becoming a routine part of care for NSCLC and other cancer patients here at the Abramson Cancer Center at Penn Medicine. These tests can be incorporated into the blood draw procedure for other standard of care monitoring blood tests and performed at already scheduled outpatient visits, thus causing no additional pain or inconvenience to the patient. We are working to better understand the different ways in which liquid biopsies can be used to better manage the care of these patients. However, while I expect liquid biopsy use for NSCLC and other cancer patients to continue to expand, I do not expect that they will replace tissue biopsy. Next-generation sequencing of circulating tumor DNA cannot provide crucial phenotypic information, such as information about the physical characteristics of the tumor, that are essential for initial diagnosis. Tissue biopsies can also play a unique role in monitoring of patients for the development of neuroendocrine disease, which can be associated with therapy resistance but is not detectable using ctDNA.

RWHC: What challenges need to be overcome to make them a standard of care?

EC: More studies need to be done, and this is an area of active focus for us, to measure whether the use of liquid biopsies has a positive effect on patient outcomes. In addition, clinical ctDNA tests tend to be ordered for detection of mutations that can be therapeutically targeted, or the emergence of mutations that signal the development of therapy resistance. To become a larger part of the standard of care for NSCLC and other cancer patients, we must better understand whether liquid biopsies can be used to effectively monitor patients receiving other important forms of therapy, including recently approved types of immunotherapy.

RWHC: This approved liquid biopsy test detects a specific type of gene mutation that is present in about 10-20 percent of NSCLC patients. Do you think other liquid biopsy tests will eventually be able to do the same for the remaining 80-90 percent of NSCLC patients? If yes, where does the biggest opportunity exist? If no, why not?

EC: In our study, we detected 275 mutations in 45 different genes, with at least one alteration found in the liquid biopsy for 84 percent of patients. Further underscoring the clinical utility of such a comprehensive liquid biopsy approach, 70 percent of patients were deemed to have a relevant clinical trial available on the basis of their ctDNA result, 55 percent of patients had an off-label targeted therapy that could possibly be used, and 31 percent of patients had an FDA-approved therapy available. So, I would say that liquid biopsy tests are already providing meaningful results for the majority of NSCLC patients.

RWHC: Beyond detecting the gene mutation responsible for NSCLC, how can liquid biopsies be used to monitor the progression of the disease?

EC: As I mentioned earlier, circulating tumor DNA tests for NSCLC patients are typically used to detect driver mutations and/or mutations that indicate the development of therapy resistance, some of which can also be therapeutically targeted. However, sometimes the physical characteristics of the tumor, including the number of circulating tumor cells in blood and expression of certain protein markers, can be measured by liquid biopsy and used to monitor disease progression. For instance, an increase or decrease in the number of circulating tumor cells (CTCs) detected in a tube of blood can be an indication of disease progression or response to therapy, respectively. Moreover, these CTCs can be isolated and gene expression measured to detect signatures associated with sensitivity or resistance to certain forms of chemotherapy in other cancers. CTCs can also be used to non-invasively assess expression of a protein known as PDL-1 which has been shown to be associated with a response to a form of immune therapy known as checkpoint inhibitors.

RWHC: How can NSCLC liquid biopsy tests be used to help increase the length of NSCLC patient survival?

EC: This is an area of active study for us. We will seek to measure whether repeat, non-invasive liquid biopsies can be used to detect therapeutic targets when a tissue biopsy isn’t possible, thus possibly enhancing the chance of a clinical response to therapy. Others have shown that a liquid biopsy can detect therapy resistance weeks or even months before standard of care imaging. It will be important to determine whether such early detection, especially when used to guide re-stratification of the patient onto a different therapy, has a positive effect on outcomes. Additionally, one of the most significant predictors of prognosis in NSCLC is the stage of disease at presentation, and our lab is actively focused on determining whether liquid biopsies can be utilized to identify patients with early stage disease.

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.