Immunotherapy revolutionized the way we treat cancer. And now, researchers are using drugs to help jumpstart the immune system alongside chemotherapy to keep treatment moving forward.

Cutting-edge clinical trials are monitoring how well these combinations work in patients with non-small cell lung cancer. In one of the features, these trials are discussed in more depth — the agents used, which protein or mutation they target, and, most important, how patients are faring. So far, researchers have seen positive results, and they are learning more about toxicities that can plague patients. One of those patients shares her journey with stage 4 disease that spread to her lymph nodes, bones and vertebrae. Finding the last spot in a combination immunotherapy clinical trial that was testing investigational therapies, she took a chance, despite her fears, and qualified.

, we feature an article on second cancers and the risk associated with them following lung cancer diagnosis and treatment. According to one of the leading experts in the field, the risk of a second lung cancer for small cell lung cancer survivors rises from about 2 percent a year to almost 10 percent a year after a decade. The feature delves into the research and discusses ways in which patients and survivors can lower their risk.

Another concern in cancer care are disparities that exist. For instance, findings from a new study shed light on the initial management of patients with nonmetastatic small cell lung cancer. Although a standard of care is in place, a large percentage of patients are not receiving that care, which negatively affects their survival. Not only disease type, but race and socioeconomic status may also be crucial impediments to care.

And what happens when lung cancer hits patients under 50? The vice president of support and survivorship programs for LUNGevity Foundation pulls back the curtain on the unmet needs of younger adults with the disease. Feelings of isolation or fear of being stigmatized, plus fertility, finances and dating/ relationship concerns top the list. LUNGevity provides advice, tools and resources that may be able to help individuals. Also in this issue, why surgery remains imperative in nonsmall cell lung cancer, a breakthrough blood test and a link between smoking, sex hormones and lung cancer.

Articles

From the Chairman

Immunotherapy revolutionized the way we treat cancer. And now, researchers are using drugs to help jumpstart the immune system alongside chemotherapy to keep treatment moving forward.
 

The Future of Lung Cancer Care Is Combinations

TWENTY YEARS AGO, PATIENTS who received an advanced lung cancer diagnosis had limited treatment options. The conversation with their oncologist likely led to this question: What platinum-based chemotherapy regimen should we use?

Because of evolving research and new treatment options, that conversation has drastically changed. Patients may now ask, “What does my gene sequencing data point to?” Genomic testing is used to help identify unique DNA changes that can be inherited or developed over a person’s lifetime and present only in the tumor. In recent years, researchers have begun to use genomic testing as a tool to help personalize treatment regimens for individuals and target specific genes or mutations.

Cancer care is changing at the speed of light. For instance, EGFR sequencing has taught researchers which cancers will respond to drugs that inhibit EGFR, a protein found on the surface of cells that can make them grow faster. However, sometimes these drugs stop working, which led to the discovery of the resistant-causing T790M mutation, detectable in the EGFR gene after drug resistance develops. A blood test can now detect this mutation, and there is even a specific drug, Tagrisso (osimertinib), approved by the Food and Drug Administration to target it. Most recently, clinical trial results show that Tagrisso is actually better to use in most people as initial therapy with EGFR mutations; however, if they do not have the mutation, they may qualify for immunotherapy.

The use of immunologic therapies have helped change the landscape of treatment and are now being used in combination with chemotherapy and other biological therapies. Within these pages, two features examine the newest developments being seen in clinical trials and what this news means for patients with lung cancer. The value of early palliative care, commonly known as supportive care, among people with advanced-stage disease is also explored. Recent studies find it to not only be helpful in alleviating the physical side effects, but also the psychological, such as depression.

But there are a few barriers. How can a patient stay on top of the everevolving developments? And how does the oncologist in a smaller practice, that sees all type of cancers, versus the academic oncologist navigate this?

Patients should ask questions and read patient-friendly resources that discuss the latest in cancer treatment, such as 

®. Community and academic oncologists can bridge gaps through data sharing and working with one another.

Lung cancer has gone from being a dismal diagnosis — it still is very serious &mdash; to one that is the poster child for targeted therapeutics, immunotherapy and molecular diagnostics. These advancements are just the beginning.

Chair, Department of Breast Medical Oncology 

The University of Texas MD Anderson Cancer Center

Editor's Page

Lung cancer has gone from being a dismal diagnosis &mdash; it still is very serious &mdash; to one that is the poster child for targeted therapeutics, immunotherapy and molecular diagnostics. These advancements are just the beginning.

Changing at the Speed of Light

IN THE UNITED STATES last year, roughly 30,000 people under the age of 50 were diagnosed with lung cancer, according to an article written by Lynne Eldridge, M.D., who is a medical journalist and lung cancer advocate.

Research is ongoing as to why younger adults get the disease. Hereditary, genetic and biologic factors may all play roles. Sometimes, these diagnoses bring with them different treatment protocols than those of older adults.

Being a young adult with lung cancer comes with unique physical and psychosocial needs that many patients feel are not adequately addressed. A recent survey of LUNGevity’s patient communities yielded insight into the unmet needs of younger adults with lung cancer.

Many of these patients reported feeling isolated because of their age, and some said they were stigmatized for having lung cancer. Others struggled with their loss of independence. The most commonly reported issues were related to fertility, employment, emotions, finances, legal concerns, children, disability and dating/ relationship issues.

In 2016, Amanda Nerstad was diagnosed with stage 4 non-small cell lung cancer. She has ALK rearrangement, which is an abnormality in one of her genes. As a young mom with no smoking history, her diagnosis was a complete shock for her and her family.

“I am always worried about my children and financial security for our family,” Nerstad said. “I’m trying to ‘be normal.’ I’m too young to stop working, but it’s weird to continue a career path.”

Nerstad chose to be up front with her children about her disease, even turning the experience into a positive by allowing them to fundraise with a lemonade stand to help raise money and awareness for lung cancer.

Similar to Nerstad, other patients in the lung cancer community wonder if they should continue to invest in their career or retirement plans when their futures are so uncertain or if they should retire early. Cancer and Careers provides expert advice, interactive tools and educational events to help patients understand their legal rights, file for disability and answer workplace questions.

Other younger patients seek information on reproductive and sexual health, a topic that isn’t always discussed in their doctor’s office. The SamFund offers a page of resources specifically for family building.

To help with emotional needs, patients desire in-person support groups with people who are going through the same experience. LUNGevity provides online communities and free peer-to-peer mentoring matches for patients and caregivers.

Patients who are considering participating in a clinical trial can connect with a volunteer Clinical Trial Ambassador to ask questions about what the experience is like. Personalized matches are made by diagnosis type, stage, gender and age.

LUNGevity also hosts the annual National HOPE Summit in the spring. The 2018 meeting took place April 27-29 in Washington, D.C. The three-day survivorship conference is a gathering spot for patients, survivors and caregivers. During the conference, they have the chance to attend meetups and breakouts that address the unmet needs of younger adults with lung cancer. Travel grants, although available in limited numbers, are available to patients attending for the first time.

Adolescent and young adult cancer advocacy groups, such as Stupid Cancer, work to address many of the aforementioned unmet needs. Young adults fighting cancer may feel isolated and unsupported in their communities. It’s up to advocates and advocacy organizations to help address these unmet needs to provide a better quality of life and greater chance of survival.

KATIE BROWN has worked in nonprofit and patient advocacy for over 15 years. She is the vice president of support and survivorship programs for LUNGevity Foundation, trained in patient navigation with Dr. Harold P. Freeman Institute in New York City and oncology patient navigation through the George Washington University, and is certified by the Academy of Oncology Nurse & Patient Navigators as an oncology patient navigator. She is also LUNGevity’s social media strategist and author of the books, Co-surviving Cancer and Navigating Advocacy.

Speaking Out

Unique challenges become permanent fixtures in the minds of young adults who receive a diagnosis of a life-changing disease, but can change through advocacy support.

When Lung Cancer Strikes People Under 50

MICHAEL LEVIN, 72, has faced lung cancer twice and was diagnosed with a third or possible recurrence of the disease. - PHOTO BY COURTNEY GOLDMAN

Michael Levin first noticed the unbearable pain while on a golf trip in Mexico during winter 2007. On the second day of practice rounds, he started to experience an ache from his knees down to his feet. Levin tried to mask it by taking ibuprofen but still felt miserable.

A month or two later, back home in Atlanta, Levin went to the doctor after his feet had swollen excessively. He was sent to a rheumatologist, who performed a chest X-ray and a bone scan. The next morning, the physician broke the news to Levin that he had a mass on the upper part of his right lung. He received a diagnosis of stage 2 non-small cell lung cancer (NSCLC), which had spread to nearby lymph nodes.

“When I picked up the phone and heard it was my doctor, I was delighted at first because I thought we were getting to the bottom of it,” recalls Levin, now 72 years old. “Then, when he said I had a mass, I went blank for about 10 minutes. The hardest part was telling my family.”

His treatment consisted of surgery and chemotherapy followed by regular surveillance. Every three months, Levin went back in for a chest CT scan along with an MRI of his brain. A few years later, the routine surveillance uncovered four metastatic tumors in his brain. Levin was treated successfully with gamma knife radiosurgery — he underwent this procedure three times &mdash; which uses beams of highly focused gamma rays to treat small- to medium-size lesions.

In 2014, a second lung cancer was diagnosed after doctors found a tumor on his left side. A new, unrelated cancer that develops in someone with a previous diagnosis of the disease is known as a second cancer.

Although a second cancer can occur anytime during survivorship, some studies show they commonly appear five to nine years after treatment. It differs from a recurrence, which refers to the initial cancer coming back after a period of time when it could no longer be detected. In particular, survivors of lung cancer remain at increased risk for second cancers, such as lung, esophageal, stomach, small intestine, colon, bladder and pancreatic.

“All patients with cancer hear about is the five-year survival rate, so you think that’s the end goal,” says Levin. “But that’s not really the goal. What isn’t communicated is that once you survive five years, the chance of a recurrence or second cancer increases.”

Once again, the regular scans led to the new tumor being found early, and surgeons successfully removed it. Levin did experience some complications during treatment — he contracted an infection of Clostridium difficile, which is a bacterium that causes inflammation of the colon, in the hospital &mdash; but still considers himself extremely fortunate to have survived all that he did. “My survival can be attributed to early diagnosis, and that’s really what gave me the best possible chance for a good outcome,” he says.

Nearly 1 in 5 cancers diagnosed today occur in a person who has survived a previous cancer. While improvements in early detection and treatment mean that people are living longer, the possibility of cancer striking again becomes a serious concern. People should consider certain actions like getting regular follow-up exams, which will allow doctors to catch and act on the disease earlier.

Lung cancer survivors remain at risk for developing second cancers. The most common in this population is a new lung cancer. Overall, the rate of developing second lung cancers and tumors in the aerodigestive tract — consisting of the combined organs and tissues in the respiratory tract and the upper part of the digestive tract &mdash; for these patients is about 10 times greater than that of other adults who smoke.

“This is about empowering individuals who have had lung cancer and may very well get a second cancer,” says James Mulshine, M.D., a professor in the Department of Internal Medicine at Rush Medical College in Chicago. “For example, improving their lifestyle can have significant positive benefits and staying in regular touch with a care provider who is aware of such possibilities is a good thing for these patients.”

Although the disease can occur in a person who has never smoked, smokers are at greatest risk. Physicians divide lung cancer into two major types based on the appearance of tumor cells when looked at under a microscope. Small cell lung cancer (SCLC) accounts for about 10 to 15 percent of all lung cancers. It develops almost exclusively in heavy smokers and spreads much more quickly than NSCLC. NSCLC is an umbrella term for three disease subtypes — squamous cell carcinoma, adenocarcinoma and large cell carcinoma &mdash; and makes up 80 to 85 percent of lung cancers.

Bruce Johnson, M.D., chief clinical research officer at Dana-Farber Cancer Institute in Boston and 2017- 2018 American Society of Clinical Oncology President, performed an extensive review of studies looking at survivors of lung cancer and their rates of second cancer. For patients who underwent surgical resection for NSCLC, the risk of a second lung cancer is approximately 1 to 2 percent per year and appears to increase over time. Those treated with chemotherapy and chest radiation for locally advanced lung cancer have a higher risk of a second lung cancer than those treated with a surgical resection alone. Johnson favors following patients at risk for a second lung cancer with chest CT scans. The patients followed with clinical examinations and chest radiographs rather than chest CT scans had a two-year survival of only 25 percent, so more intensive follow-up is warranted.

Data are much more limited for patients who had SCLC because only 7 percent of them survived for two years or longer. According to Johnson’s analysis, the risk of a second lung cancer for SCLC survivors rises from about 2 percent per year to rates approaching 10 percent per year after the passage of a decade.

The second lung cancers are typically NSCLC — namely, adenocarcinomas and squamous cell carcinomas &mdash; arising in a different anatomic site from the initial tumor.

The review paper and other studies also noted different factors that could possibly increase or decrease one’s risk of a second cancer. For example, Johnson looked at whether the studies included the effect of continued cigarette smoking, the type of initial and secondary treatment administered and the continuing surveillance of patients. “We published that the vast majority of people who get diagnosed with lung cancer no longer smoke, but those who keep smoking double their risk of getting a second tumor compared with those who quit smoking,” Johnson says. “So one thing that people can do if they’re still smoking is to quit.”

Tobacco products not only are a risk factor for developing cancer but also can exacerbate illnesses like heart disease and chronic obstructive pulmonary disease, more commonly known as COPD. In a study published in the Journal of the National Cancer Institute, of 611 SCLC survivors examined, no second lung cancers occurred in the small number of patients who were nonsmokers. Relative risk remained stable over time for patients who had stopped smoking before receiving a diagnosis of SCLC, but those who quit at the time of diagnosis had increasing likelihood of a second lung cancer over time.

“For our patients who have had a lung cancer, the most important thing that we tell them is to stop tobacco use or smoking because that’s usually the most common risk factor for developing lung cancer,” says Rathi Pillai, M.D., an assistant professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta.

“Plus, it can be a driver for developing another lung cancer or other types, such as head and neck or bladder cancer.”

The same study also investigated the contribution of initial treatment type to the development of second cancer. For instance, radiation is known to cause damage to healthy cells and possibly contribute to a second cancer. Patients who received chest irradiation had a thirteenfold greater risk compared with the general population, while those who got other types of treatment had a sevenfold greater risk. Overall, the type of chemotherapy used to treat the latter group was not associated with a significant difference in risk.

Generally, the risk of getting a second cancer after radiation therapy goes up as the dose increases. The area treated and the age of the patient when they were treated also affect cancer risk. Solid tumors take time to develop, and many are not seen for at least 10 years after initial treatment. Lastly, smoking increases the risk of a second cancer after radiation.

Survivors can lower the risk of developing second cancers by eliminating tobacco, maintaining a healthy weight, staying physically active, following a healthy diet and limiting alcohol consumption. They can also find out more about their family history and receive genetic testing to see if any predispositions or conditions exist that would further increase their cancer risk.

Making changes like these may help people sleep and eat better, which is important for people who want to maximize their quality of life after a first lung cancer, says Mulshine. Disease experts also emphasize regular surveillance to make sure there hasn’t been a recurrence or a second cancer. Many doctors recommend follow-up visits and CT scans every 6 to 12 months for the first two years after treatment, followed by yearly visits and CT scans. But no standardized guidelines exist for what the surveillance procedure should be for a lung cancer survivor. “There’s a lot of debate in the lung cancer community in regard to how to monitor a patient after being treated for early-stage lung cancer,” says Pillai. “Given the fact that we do find second lung cancers or recurrences, surveillance is certainly warranted, but what exactly that surveillance should be, and how frequently it should be performed, varies among providers.”

She suggests getting CT scans at least once a year to monitor for recurrence and the development of a second tumor. Also, survivors should make sure to keep up with other routine tests like mammograms and colonoscopies.

“I’ve had terrific quality of life despite the cancer, and much of it is due to the regular surveillance,” says Levin. “All my cancer diagnoses, after the initial one, happened early and resulted in fast treatment.”

Unfortunately, Levin recently received a diagnosis with what is likely to be his third lung cancer but could also be a recurrence, as well as prostate cancer. Despite the many setbacks, he isn’t ready to give up. Levin, who has been married for 51 years and is a father and grandfather, considers himself blessed to have his loved ones for support. He has also become heavily involved with patient advocacy and outreach with the Lung Cancer Alliance since his initial diagnosis.

“I’m happy to be here. I have a wonderful family, many friends and a terrific medical team,” says Levin. “Plus, I have some financial means to walk away from work for a while. I’m lucky in that respect.”

Features

Second cancers are common among patients with lung cancer, so how can risk be lowered?

Surveillance of Survivors Can Save Lives

ELAINE KOZIARJORDAN, 62, recieves an experimental drug through a clinical trial that she will participate in for two years. - PHOTO BY VALERIE BOGLE

When the lung cancer that Elaine Koziar-Jordan was successfully treated for in 2010 returned three years later, she initially responded well to chemotherapy. But then, in 2016, her cancer came back, and she learned it had spread to her brain and several lymph nodes near her lungs. Her doctors at H. Lee Moffitt Cancer Center in Tampa, Florida, determined that another course of chemotherapy wasn’t an option.

But Koziar-Jordan was fortunate because during the time she was fighting her cancer, scientists around the world were developing newer forms of immunotherapy — drugs that can train the immune system to recognize and eliminate tumors. And they were putting together clinical trials of innovative combination treatments designed to thwart the growth of lung tumors by attacking them from many different angles.

Koziar-Jordan was accepted into one of those trials in November 2017. Once a month she receives an infusion of a drug that blocks PD-1, a protein that normally allows cancer to hide from the immune system. Along with that treatment, she takes four capsules per day of an experimental drug called an adenosine A2a receptor antagonist. The drug is designed to inhibit a chemical produced by cancer cells that helps tumors to escape immune detection.

After Koziar-Jordan’s first few months on the experimental treatment, her scans already showed significant shrinkage of the cancer.

She had been struggling with a chronic cough and swallowing issues because of one tumor that was near her esophagus, but those symptoms subsided. “One day I woke up and I wasn’t coughing all day long,” says Koziar-Jordan, a 62-year-old retired human resources executive. “It was such a relief.” Koziar-Jordan’s brain metastases were successfully treated with radiation. She expects to stay in the drug trial for two years.

Immunotherapy is just one of several new choices that have revolutionized the treatment of advanced lung cancer over the past few years. In addition to drugs that inhibit immune “checkpoints” such as PD-1, tools for treating lung cancer now include targeted medicines that address genetic abnormalities found in tumors. As oncologists learn more about how to tailor treatments to the patients most likely to respond to them, and as combination approaches start to gain steam, it’s becoming more and more possible for many patients to keep lung cancer under control for many years or even be cured of the disease.

“When resistance to therapy develops, patients can move to other modalities like immunotherapy,” says Scott Antonia, M.D., Ph.D., chair of the Department of Thoracic Oncology at Moffitt. “We’re seeing an increasing number of people who are very long-term survivors.”

More than 234,000 cases of lung cancer are expected to be diagnosed this year in the United States, and it is the leading cause of cancer death, according to the American Cancer Society. About 80 to 85 percent of diagnoses are non-small cell lung cancer (NSCLC), and the rest are small cell lung cancer.

Because lung cancer rarely causes symptoms until it has reached an advanced stage, it’s common for the disease to have already spread by the time it’s diagnosed. About half of patients have metastatic cancer at the time of their initial diagnosis, estimates Howard (Jack) West, M.D., medical director of the Thoracic Oncology and Genitourinary Oncology Programs at Swedish Cancer Institute in Seattle.

The most common places for lung cancer to spread are to the adrenal glands, bone, brain and liver, according to the National Cancer Institute. “The first inkling of lung cancer is often symptoms related to the spread of the disease, such as shortness of breath and cough, or systemic symptoms like weakness and weight loss,” West says.

Patients diagnosed with advanced lung cancer will often start by being treated with chemotherapy and/or radiation. Patients who are in stage 3 of the disease — meaning their cancer is largely confined to the lungs and nearby lymph nodes &mdash; may be prescribed chemotherapy drugs, such as cisplatin or carboplatin, often alongside radiation, followed by immunotherapy. Surgery to remove lung tumors might also be recommended. Patients with stage 4, or metastatic lung cancer, are often prescribed chemotherapy as the first treatment. The initial treatment is usually 4 to 6 cycles.

One major advance over the past few years has been the introduction of lung cancer treatments that target specific tumor mutations or other aberrations, particularly the EGFR, ALK, ROS1 and BRAF 600E genes. They can be diagnosed with genetic tests of tumor samples — now a routine exercise in determining the best treatment strategy. “We can order tests for specific molecular drivers like EGFR, ALK and others, and expect to get results back within three to five days,” West says. “That allows us to make a decision about the best first-line treatment within a week of diagnosis.”

An estimated 10 percent of patients with NSCLC have EGFR mutations. Several drugs have been approved to target this abnormality, including Tarceva (erlotinib) and Iressa (gefitinib).

The increasing understanding of EGFR has given rise to drugs that target specific subsets of patients who have variations of the mutation that lessen their likelihood to respond to targeted treatments.

For example, Tagrisso (osimertinib) was approved by the Food and Drug Administration for the first-line treatment of patients with EGFR-sensitizing and EGFR T790M-resistance mutations, which increase the likelihood that patients will not respond to older treatments. In a pivotal clinical trial, patients taking the drug had a 54 percent lower risk of progression or death than did those taking standard therapies.

In January 2018, the drug Gilotrif (afatinib), which was initially approved in 2013 to treat some patients with metastatic NSCLC, gained an additional approval to treat patients with rare EGFR mutations known as L861Q, G719X and S768I. The objective response rate to the drug in a phase 3 trial was 66 percent, and more than half of patients continued to respond to the drug for more than a year.

“These mutations are rare, but we see them,” West says. “In the past, we didn’t have a clear sense of what to do for these patients. Now we have options that we didn’t have before, and treatments can make a big difference for them.”

About 3 percent of patients with NSCLC have what are known as gene rearrangements, which are not mutations but rather chromosome abnormalities. One such rearrangement, ALK, can be addressed with drugs including Alecensa (alectinib), Zykadia (ceritinib) and Xalkori (crizotinib). ROS1, another NSCLC rearrangement, is most common in people who have never smoked. Xalkori was approved to treat ROS1-positive metastatic NSCLC in 2016. Side effects of targeted treatments can be similar to those of chemotherapy, including nausea, fatigue and rash.

Immunotherapy has become a popular option for patients who progress after receiving targeted drugs or older treatments. Two PD-1 inhibitors, Opdivo (nivolumab) and Keytruda (pembrolizumab), are approved for the treatment of NSCLC, as are the PD-L1 inhibitors, Tecentriq (atezolizumab) and Imfinzi (durvalumab). In a trial reported in 2017, 16 percent of patients taking Opdivo survived beyond five years with their disease — quadruple the survival rate typically seen with chemotherapy.

Keytruda is approved for both second-line treatment of patients with metastatic NSCLC and for firstline treatment in combination with the chemotherapy drugs pemetrexed and carboplatin. In the trial that led to the approval of the combination treatment, 55 percent of patients had a partial response or better, compared with just 29 percent of patients taking chemotherapy alone.

Side effects of immunotherapy drugs include fatigue, nausea and shortness of breath. In the trial of chemotherapy combined with Keytruda, some patients developed kidney injuries, but only 10 percent of patients experienced side effects that were severe enough to force them to stop the treatment.

There are multiple clinical trials underway combining different approaches to attacking lung cancer. For example, Opdivo is being tested along with another immunotherapy drug, Yervoy (ipilimumab), which targets the checkpoint receptor CTLA-4. In a recently released trial, the overall response rate to the combination was 25 percent, compared with 11 percent for Opdivo alone. In another trial, Keytruda is being combined with an EGFR inhibitor called Portrazza (necitumumab). That combination produced an overall response rate of 29.4 percent in an early trial.

Combinations may help patients with lung cancer who don’t respond to current therapies or become resistant to them. “Cancer is able to grow and spread in the body because it adapts in different ways to hide from the immune system,” says Rachel Sanborn, M.D., a medical oncologist at Providence Cancer Institute in Portland, Oregon. “The future is with combinations of immune therapies. I think we’ll see drastic strides over the next 10 years.”

Darcy White, one of Sanborn’s patients, is receiving Opdivo with high-dose radiation. White’s NSCLC was diagnosed in 2009 and was initially treated with surgery and chemotherapy, followed by a trial of Tarceva, an EGFR-targeted drug. But, in 2016, she was diagnosed with a new primary cancer. An intial treatment with chemotherapy didn’t clear the cancer, so she was given high-dose radiation in April 2017, followed by Opdivo every two weeks. White’s cancer has disappeared.

The drug causes a bit of fatigue and dry eyes and mouth, but those side effects “are nothing compared to chemo,” says White, 58, a health insurance executive who has gone back to work full time. She looks forward to discussing the possibility of going off all treatments with her doctors this year but feels fortunate to be responding well to an immunotherapy drug with relatively minor side effects. “The research advances, even just in the last two years, have been incredible,” she says. “I feel so lucky.”

Because the side effects of immune-boosting drugs are relatively benign compared with those of chemotherapy, it’s feasible for some patients to stay on them for many years to keep their lung cancer under control. And some recent studies are showing a long-term benefit with immunotherapy treatments. In February, data were released from a trial comparing Opdivo with the chemotherapy drug docetaxel in patients with advanced NSCLC. The three-year overall survival rate was 17 percent in patients taking Opdivo, compared with 8 percent in those who received docetaxel. The rate at which patients survived for three years without their disease progressing was 10 percent with Opdivo, compared with less than 1 percent for docetaxel, and the median duration of response to Opdivo was about two years — far outlasting the response to docetaxel, which was under six months. “This shows that a substantial number of patients achieve very sustainable, long-term responses,” says Everett Vokes, M.D., chief of the Department of Medicine at the University of Chicago and the lead author of the study. “Of the patients who benefited on (Opdivo), it was impressive how long the benefit lasted.”

Immune and targeted therapies build hope for patients with advanced lung cancer.

Bountiful Treatment Options Offer Optimism for Lung Cancer

TERI KENNEDY, 54, took the last spot earlier this year in a combination immunotherapy clinical trial and appears to be responding. - PHOTO BY PENNY SYLVIA

During summer 2015, Teri Kennedy was at a yoga festival in Squaw Valley, California, when she started to wheeze and had trouble breathing. The inhaler her doctor gave her didn’t help. When the then 51-year-old from Sacramento returned home, she went for an X-ray that showed a cloudy right lung. Antibiotics didn’t work, and her doctor called for more tests: a CT scan revealed a tumor the size of a fist in her right lung.

“I felt really good otherwise,” says Kennedy, now 54, a tennis player who enjoys power yoga, too. “I was very fit and active, never smoked, and am very conscientious about diet and exercise. But I do have some family history.” Kennedy explains that her father, aunt and uncle (all siblings) died of lung cancer and were never tested for any genetic mutations.

A few more tests showed the tumor was stage 4 non-small cell lung cancer (NSCLC) that had metastasized to her lymph nodes, bones and back vertebrae. Kennedy’s cancer had spread too far for surgery, so she began chemotherapy while waiting for DNA testing results.

Lung cancer is the second most common cancer among men and women in the United States, but it causes the most cancer-related deaths — more than colon, breast and prostate cancers combined. Although disease rates have declined alongside smoking rates, lung cancer is still responsible for 1 in 4 cancer deaths in the U.S.

NSCLC makes up about 85 percent of all lung cancers. The leading risk factor remains tobacco smoking, which accounts for approximately 80 to 90 percent of lung cancers. In addition, the risk of lung cancer or death from the disease is 15 to 30 times greater for those who smoke than those who don’t, according to the Centers for Disease Control and Prevention. The other major risk factors include exposure to radon gas and asbestos; cancercausing agents in the workplace, such as uranium and nickel compounds; secondhand smoke; air pollution, even indoor smoke from cooking oil; and family history. The five-year survival rate for stage 1 NSCLC ranges from 68 to 92 percent, but drops to 1 to 10 percent for stage 4.

Still, in the last decade new therapies have proven to be effective. Patients now have an ever-expanding range of options for treatment, including emerging therapies that combine chemotherapy with drugs that kick the immune system into action against the cancer.

When cancer attacks the body, it switches off many of the immune system’s mechanisms for fighting it at certain so-called checkpoints.

“The human body has a system of checks and balances to regulate the immune response and prevent damage to healthy tissues,” explains Rafael Santana-Davila, M.D., an assistant professor at the University of Washington School of Medicine in Seattle. “Cancers take advantage of many of those checkpoints to evade the immune system.”

Immunotherapy attempts to switch those mechanisms back on to bring the body’s immune system back on board. In 2011, the Food and Drug Administration (FDA) approved Yervoy (ipilimumab), the first checkpoint inhibitor to target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is a protein receptor that holds back immune response. Approved for unresectable or metastatic melanoma, Yervoy is being studied in patients with NSCLC. However, CTLA-4 isn’t the only pathway to explore. Programmed cell death protein 1 (PD-1) also plays a role.

“One of the main mechanisms by which the tumors evade the immune system is activation of the PD-1 pathway, which causes exhaustion of the T cells that are responsible for killing cancer cells,” explains Suresh S. Ramalingam, M.D., assistant dean for cancer research and deputy director of the Winship Cancer Institute at Emory University School of Medicine in Atlanta. “By blocking PD-1, now we know that we can turn on the anti-cancer immunity, which can cause tumor shrinkage.”

A protein called programmed death-ligand 1 (PD-L1) connects to the PD-1 receptor and puts the brakes on the immune system. Immunotherapy drugs called checkpoint inhibitors inhibit either the PD-1 checkpoint or PD-L1 to lift those brakes so the immune system can go after the tumor. One of the standard tests after a cancer diagnosis looks for the level of PD-L1 expression in the tumor. “If it’s really rich, then that provides the milieu where an immune checkpoint inhibitor will be very effective,” says Ramalingam.

Keytruda (pembrolizumab) was the first PD-1 checkpoint inhibitor approved by the FDA for first-line treatment of lung cancer in patients whose tumors have high expression of PD-L1, which is approximately 25 to 30 percent of patients with NSCLC. Now researchers are exploring whether the combination of immunotherapy with chemotherapy, or with other immunotherapy drugs, might lead to an even better response in patients with cancer.

“Combining checkpoint inhibition with chemotherapy has yielded positive results for patients,” says Daniel Haggstrom, M.D., an oncologist for Levine Cancer Institute within Carolinas HealthCare System. “For patients without a driver mutation and PD-L1 expression of less than 50 percent, the standard is to provide combination chemotherapy and immunotherapy, and if expression is greater than 50 percent, then immunotherapy alone. For patients who possess low or minimal PD-L1 expression, additional combination regimens are certainly on the horizon.”

New optimism came out of the phase 3 KEYNOTE-189 trial which showed a more than 50 percent reduced risk of death in patients with nonsquamous NSCLC without EGFR or ALK mutations when Keytruda was added to a chemotherapy combination of Alimta (pemetrexed) and either cisplatin or carboplatin in the frontline setting. At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2 percent in the Keytruda group compared with 49.4 percent in the control group.

In the KEYNOTE-024 phase 3 clinical trial, two-year results presented late last year found that Keytruda more than doubled the median OS in patients with high PD-L1- expressing NSCLC compared with chemotherapy (30.2 vs 14.2 months). Keytruda also showed a better overall response rate, 45.5 percent compared with 29.8 percent in the chemotherapy group. Fewer side effects were also seen in the Keytruda group.

The KEYNOTE-021 trial’s cohort G found that combining Keytruda with chemotherapy led to a 55 percent objective response rate in patients with nonsquamous NSCLC, regardless of PD-L1 expression, compared with 29 percent who received chemotherapy alone.

“What we’re learning now is that PD-L1 status may not be the most accurate way to gauge a person’s response to immunotherapy, either in terms of the magnitude or the duration of response,” says Haggstrom.

Another biomarker gaining attention is tumor mutation burden (TMB). “Mutation burden is looking at the whole genetic makeup of the tumor and seeing how many total mutations are there, seeing if their tumor is high or low in mutation burden” says Ramalingam. “If the mutation burden is high, there is indication that immunotherapy might work well.”

A higher burden often means there are more neoantigens. These are altered proteins that may be more recognizable by the immune system, allowing it to identify tumors and produce specific T cells to fight the cancer. The CheckMate-227 trial, which involved more than 2,500 patients and examined the combination of Opdivo plus Yervoy versus chemotherapy, reported positive frontline treatment results for patients with a high TMB. Phase 3 data show the one-year progression-free survival (PFS) rate was more than triple with the combination versus chemotherapy (43 percent vs 13 percent). The overall response rate was nearly double and patients had fewer treatment-related side effects.

The fact that TMB is emerging as a helpful biomarker in immunotherapy also suggests alternatives for patients who don’t respond to prior therapies or who develop resistance to prior therapies. In Kennedy’s case, doctors found she had the EGFR gene mutation, which occurs in 15 to 20 percent of NSCLCs. She began Gilotrif (afatinib), a targeted therapy for EGFR mutations, which stops tumors from activating the gene and related growth factor receptors. Other mutations in NSCLC that have existing targeted therapies include ALK, MET, ROS1, T790M and BRAF.

Over the next nine months, Kennedy’s bone tumors calcified and disappeared and the primary lung tumor gradually shrunk to the size of a nickel. But then a scan showed more scattered small nodules in her lungs. That led to trying one therapy after another until Kennedy decided to try a combination immunotherapy on trial early this year. She qualified for the one remaining spot in an early clinical trial in Los Angeles that was testing investigational drugs INCAGN01876, a type of immunotherapy known as a GITR agonist, and epacadostat, an IDO1 inhibitor, with Keytruda.

“It was a ‘do it or the opportunity is gone’ situation, so I decided to try it,” says Kennedy. “With EGFR, immunotherapy is typically the last straw when you’re dying and your back is up against the wall. I was advised a toxic chemo combination had a much higher chance of being effective. I was feeling strong and my symptoms were manageable, so I thought, ‘OK, I’m going to go for it.’ If it didn’t work, I would know quickly enough and move on.”

Kennedy’s decision was scary because of past failures of immunotherapy with EGFR mutations, the risk of rapid progression of her cancer and the possibility of serious side effects. In February, she received her first infusion and dealt with flu-like symptoms — fever, extreme fatigue and achiness &mdash; but is now feeling better and recently learned from her doctor that she appears to be responding. Her trial is one of hundreds exploring various combinations of immunotherapy and other drugs.

Kennedy experienced extreme toxicity with some of her earlier regimens, requiring hospitalization for low heart rate and a severe rash. “My skin reacted like a chemical peel,” she recalls. She has been fortunate on her current trial. Toxicities can vary widely by drug, combination and patient. “By taking the brakes off the immune system, you unleash the ability of the immune system to be more effective against the cancer, but the downside to any immunotherapy is you run the risk of having the immune system attack healthy tissues, such as the colon, skin or the lung,” says Santana-Davila.

Rates of colitis or pneumonitis remain below 10 percent with a single agent, he adds, but combining agents brings those complications’ rates closer to 25 percent. Damage to the endocrine system and thyroid is another common risk, and combining chemotherapy adds its usual side effects, such as fatigue, nausea and blood count issues, to sometimes less predictable immunotherapy ones.

“Any organ you can think of can be affected if the immune system goes haywire,” says Sukhmani Padda, M.D., an assistant professor of medicine at Stanford University in California. “We need to be mindful of that, and we always counsel our patients to call us sooner than later if they’re having an unusual side effect, because it is important to catch these autoimmune toxicities early.”

Taking a very detailed medical history, especially for autoimmune conditions, is especially important for patients considering immunotherapy, says Padda. “At times of treatment decisions, we try to objectively evaluate what we think our patients can tolerate,” says Padda. “It’s always important to do no harm. We know our therapies have promise for activity and making patients feel better, but we also know that there are side effects for all of our therapies, including immunotherapy.”

Fortunately, doctors are learning more about what to monitor and how to treat it. “As these immunotherapy agents are being more commonly used, we’re learning the right questions to ask patients and knowing when to tell patients to contact their doctors,” says Haggstrom. “We’re much more deft at catching higher toxicities now.”

About a half dozen clinical trials exploring combination immunotherapy in the frontline setting have started reporting promising results, most involving combinations with chemotherapy.

“We’re moving rapidly into an era of combination therapy for this disease and tailoring the chemotherapy to squamous and nonsquamous carcinomas,” Haggstrom says. “There’s still going to be enthusiasm for the combination immunotherapies, but currently there is a bit of an uphill climb to make those more efficacious than combos with chemo or a single agent.”

In late 2017, IMpower150, a phase 3 trial involving the immunotherapy drug Tecentriq (atezolizumab) and the tumor blood vessel-inhibiting drug Avastin (bevacizumab) with two chemotherapy drugs, became the first to show longer PFS for advanced nonsquamous NSCLC with frontline combination immunotherapy in patients without ALK or EGFR mutations.

“I’m really optimistic about how immunotherapy is going to help patients with cancer beyond where it is today,” says Ramalingam. “PD-1 inhibitors are clearly a breakthrough, and now we’re testing them not just in advanced stage cancers but in earlier stages and developing combination approaches.”

But there have been setbacks, too. The phase 3 MYSTIC trial tested Imfinzi (durvalumab) with or without tremelimumab — an immunotherapy drug not yet approved by the FDA for any treatment &mdash; against chemotherapy standard of care. Researchers found no PFS benefit to combining Imfinzi and tremelimumab compared with chemotherapy.

However, the PACIFIC trial found that Imfinzi monotherapy extended PFS by nearly a year in those with inoperable stage 3 cancer that had not progressed with chemoradiation. These findings led to the FDA’s expanded approval of Imfinzi for the treatment of patients with locally advanced unresectable stage 3 NSCLC. PACIFIC’s findings underscore how much there is to learn about immunotherapy alone or in combination with other treatments.

“It’s important for patients to understand that lung cancer is not one disease and that their physicians are going to be looking at all of these various biomarkers to tailor the right treatment for them,” says Padda. “Lung cancer has moved from a treat-all-patients-the-same-way to a very nuanced approach. Even though immunotherapy is a fantastic advance for NSCLC, it may not be the right step for a specific patient. It’s a very personalized approach.”

Ideally, findings from the KEYNOTE, CheckMate and other clinical trials will help doctors determine how to do that personalization.

“Developing biomarkers to determine who will benefit from which approach will be critical to how we use these clinical drugs in practice,” says Ramalingam. “Timing and sequences are critical questions that upcoming trials will answer.” Many questions remain too: How much does a tumor’s PD-L1 expression influence the level of response to combining one or more immunotherapy drugs with chemotherapy? Are there better biomarkers? What order of immunotherapy, chemotherapy and radiation therapy, or a combination of these, will lead to the best response rates? How does that answer change according to a patient’s biomarkers?

“There’s a lot more for us to understand,” says Padda. “Even though better biomarker-guided strategies are going to be much more prominent and identify more subsets of patients who will benefit from treatments, I do think chemotherapy is going to continue to play an important role, because we need to use as many tools in our toolbox as we can.”

The combination of immunotherapy and chemotherapy, and more, is changing the landscape of the disease.

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