On a November afternoon in 2014, my mother rang my office phone. I answered in professional mode, as a journalist for a biotech trade publication in New York, where I regularly probed physicians about the performance of new drugs in clinical trials. I must have said the word “cancer” 40 times or more every day in that job. But when my mother’s voice pronounced those two syllables—can-cer—my mind froze.
A lung oncologist in Florida had diagnosed her brother, my uncle, 71, with non-small cell lung cancer (NSCLC). CT scans revealed tumors less than two inches wide wedged throughout his lungs—too small and numerous for surgery. A couple of masses had spread to nearby lymph nodes. My mother, a nurse, and I briefly discussed chemoradiotherapy—a combination of chemotherapy infusion and radiation therapy—that his doctors chose as the first step in Uncle Ebba’s treatment. They hoped it would shrink his tumors.
But his fight for his survival, my mother and I knew, depended enormously on his second treatment. Chemoradiotherapy would give him more time but wouldn’t prevent the cancer from coming back. He needed a second drug tailored to his specific cancer. I promised to research—this was my job, after all—and deliver the next logical treatment step. At the time, this promise felt attainable.
Besides different chemotherapy combinations, certain targeted therapies for NSCLC had been on the market for some time. I confess I skipped looking into those drug types and dove into possibilities around the buzzword doctors couldn’t stop talking about that year: immunotherapy.
Despite being a reporter familiar with a handful of immunotherapy drugs in clinical trials in 2014, I didn’t cover lung cancer at all. A quick scan of websites designed for patients helped me grasp lung cancer’s complexity.
Lung cancer is divided into two types: NSCLC and small cell lung cancer (SCLC),which require very different treatment approaches. NSCLC makes up 80 to 85 percent of diagnoses and within it are three subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma, the kind Uncle Ebba had, is the most common and develops in the cells that produce the mucus lining of the airways.
One aspect of NSCLC that determines a person’s treatment plan is the stage at which it is found. Doctors will collect a sample of tumor tissue, called a biopsy, and send this to a pathologist who can examine the tissue cells under a microscope. By combining these results with other imaging evidence, doctors piece together information to calculate the stage of a tumor, or how far cancer cells have likely advanced. The stages range from 0 to IV, with the last including metastasis, which means the cancer cells have spread throughout the body, possibly to the bone or brain. Uncle Ebba was diagnosed with Stage IIIA.
Genetic sequencing has become a routine part of biopsies, too. Pathologists send a sample of tumor tissue to be sequenced to determine if certain genetic mutations might be driving the cancer’s growth. For some patients with lung cancer, mutated versions of specific genes can be found throughout their tumors. Drugs designed to fight tumors that are dominated by these gene variants are called targeted therapies.
What was striking to me in 2014 was the emphasis—the hope—that physicians placed on immunotherapy drugs for NSCLC at the American Society of Clinical Oncologists (ASCO), one of the world’s largest meeting of cancer experts, held that year in Chicago. In retrospect, it was not a misplaced hope. Immunotherapy drugs, which work by harnessing the body’s immune system to fight cancer, have produced promising rates of remission in some cancers, like melanoma.
But at that time, it was still too early to know the average effect on survival rates that immunotherapy could have on NSCLC patients. This didn’t stop me or my uncle from latching onto the beautiful-sounding (perhaps life-giving) names of immunotherapy drugs being tested on patients like him.
A new kind of treatment
Immunotherapy drugs help the body’s adaptive immune system recognize and fight cancer cells. As my uncle waited to enroll in a clinical trial in early 2015, nivolumab (marketed as Opdivo) became the first immunotherapy drug approved for NSCLC patients. Pembrolizumab, marketed as Keytruda, wasn’t far behind. Both drugs target PD-1, a protein receptor on the surface of certain immune system cells called T cells, which attack cancer cells.
T cells, like all cells, communicate through proteins. They use PD-1 as a probe, the same way a submarine operator relies on radar signals to detect enemy ships. The PD-L1 protein, which hangs out on the surface of healthy cells, acts like a friendly flag to let the T cell know it can move on. The trouble is that cancer cells have evolved to include PD-L1 protein on their surfaces, too. This means T cells ignore rather than attack them.
Nivolumab and pembrolizumab work by blocking PD-1 proteins on T cells. Other immunotherapies like atezolizumab, marketed as Tecentriq, block the PD-L1 protein. Still, the goal of all of these therapies remains the same: Allow T cells to once again recognize cancer cells and kill them.
In 2015, my uncle enrolled in a clinical trial in Florida. The trial was testing an even newer drug that didn’t yet have a name. It was referred to in his medical records as MEDI4736.
Uncle Ebba was excited to try it. He watched drug commercials and read news articles. He made up his mind early on that immunotherapy would save him. When we visited him, he shrugged off questions. Instead, he reached for his nieces’ hands when a Jimmy Buffett song came on and spun us in silly dances. When I attempted to show off my balancing skills on a low beach pier railing, he nimbly hopped up behind me and followed.
“Patients don’t necessarily have a realistic picture of what these drugs can do,” says Deborah Doroshow, MD, PhD, a clinical fellow at Yale Medicine, referring to immunotherapy drugs. “I want patients to know there is a lot of hope, but we have to be cautious and keep in mind that not everyone responds to these drugs, and there can be serious side effects.”
The sad truth about immunotherapy treatment in lung cancer is that it shrinks tumors in only about 1 or 2 out of 10 patients, explains Roy Herbst, MD, PhD, Yale Medicine’s chief of medical oncology. This means that about 80 percent of NSCLC lung patients still need more treatment options. “We are still in the infancy of the field and have to do more studies to understand how these drugs will work,” Dr. Herbst says.
Earlier this year, Dr. Herbst and Dr. Doroshow published an article in JAMA Oncology that provided a road map of treatment options that would have been impossible to formulate just four short years ago. They suggest the idea of using immunotherapy as the initial treatment, and sometimes in combination with chemotherapy, depending on the specific type of NSCLC present.
“That chart is already out of date,” Dr. Herbst says. “We are still understanding the immune system and the microenvironment of the tumor that might be causing resistance. Chemotherapy in combination is not the end-all here.”
Dr. Herbst leads several clinical trials at Yale designed to provide insight on which drug combinations might be most effective. At Smilow Cancer Hospital in New Haven, about 10 to 20 clinical trials testing innovative drug combinations or new treatments for lung cancer patients are open at any time. Whenever possible, patients are enrolled in clinical trials that may help treat their disease and which will also contribute to ongoing research that may benefit others in the future. “From the time a patient is first diagnosed, we offer clinical trials if we have one available,” Dr. Doroshow says.
Some of those trials happen at the Phase I Program at Yale Cancer Center (YCC), which aims to treat the cancer patients most in need with the latest drugs—some of which emerged through the work of researchers at Yale. “We are about to study a drug developed in the lab of Lieping Chen,” Dr. Herbst says, referring to one of Yale’s leaders in immunotherapy research who, with a team of scientists, was the first to discover the molecule B7-H1 (later renamed PD-L1).
Three short years
I know the question that loomed in Uncle Ebba’s mind every time he met with his oncologist or talked to my mother on the phone. How much more time do I have?
The five-year survival rate for Stage IIIA NSCLC patients is about 36 percent. Uncle Ebba made it three years and one month.
“We have a long way to go,” Dr. Doroshow told me when we met recently, and I summarized my uncle’s fight. “The question is, how do we figure out who is going to respond to this therapy, and how do we make more people respond to it?”
Dr. Herbst explained that ongoing studies at YCC’s Lung Specialized Program of Research Excellence (SPORE) program will eventually provide more information on why some people respond to immunotherapy while others do not.
In the meantime, multidisciplinary care at Yale Medicine continues to evolve. After a patient sees a lung oncologist, it’s possible to receive further specialty care or consults with a pulmonologist or thoracic surgeon. “If we are seeing a new patient, he or she could be evaluated by multiple doctors on the same day,” Dr. Doroshow says.
Patients at Yale Medicine also benefit from the close working relationships between scientists and physicians. A team of specialized pathologists collaborate with oncologists by examining patient biopsies at different stages in the treatment process to try to understand which patient might benefit most from a certain drug.
In the end, immunotherapy drugs are a huge leap for treatment of NSCLC and are widely available to patients outside of clinical trials. But they are not the final answer. “It takes a long time for new drug technology to move from the lab to the clinic,” Dr. Herbst says. “In the meantime, a patient might want to go to a place like Yale where that gap is as small as possible.”
Author’s note: In doing research for this article, I found a study published in The New England Journal of Medicine that showed the results of a trial testing durvalumab, a newer immunotherapy drug marketed as Imfinzi. It showed that patients who received it experienced a longer period of their tumors not progressing compared with the group that received a placebo. Durvalumab was formerly known as MEDI4736—the immunotherapy drug my uncle received.