ORIGINALLY PUBLISHED IN “LUNG OVERDUE,” CURE SPRING 2010

Following a lung cancer diagnosis, staging determines the best options for treatment. Many factors are evaluated, including the size of the tumor and the extent of spread.

The cancer is small (no larger than 3 cm for stage 1A; up to 5 cm for stage 1B) and has not spread to the lymph nodes.

The tumor is up to 7 cm in diameter and may have spread to nearby lymph nodes.

The cancer has started to extend into surrounding tissues and structures, such as the lining of the lung and chest wall, and has spread to lymph nodes on the same side of the chest as the tumor.

Two or more tumors are present, and the cancer has spread to the lung and lymph nodes on the opposite side of the chest.

The cancer has spread to form new tumors in other parts of the body, such as the bone, brain, liver and adrenal gland.

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Side Note

Medical Illustration: Non-Small Cell Lung Cancer

ADMIRABLE PROGRESS has been made in treating lung cancer in recent years, and more breakthroughs are on the horizon, but the process of making these gains has, admittedly, been a long trip down a winding road.

In most cases, lung cancer crops up as a result of having smoked tobacco products, and over the years public awareness campaigns and even smoking bans have been enacted to end this dangerous habit. It’s a strategy that seems to be working: According to a report released in 2014 by the U.S. Centers for Disease Control and Prevention, 17.8 percent of American adults were smokers in 2013, a drop from the 20.5 percent who smoked in 2005. Also in 2014, the National Cancer Institute reported that lung cancer rates, overall, have continued to drop over the past 20 years, with smoking cessation an important suspected factor. Meanwhile, a protection was added recently for current and former heavy smokers: recommended routine CT screening for early lung cancers. This, too, is expected to help stem the tide of deaths from this disease.

But what about the people who have never smoked tobacco yet still get lung cancer? We’re seeing a rise in these types of cases, and now are figuring out what makes them different, and how they can best be treated. It’s an avenue of discovery that is changing the old perception that lung cancer is both aggressive and fatal.

Improvements in surgery, which has become less invasive with techniques such as video-assisted thoracic surgery and robotic techniques, represent important cobblestones along that path. Also contributing to better treatment, specifically in non-small cell lung cancer (NSCLC), has been the discovery of mutations that drive some lung cancers, and the development of drugs that can target them. For instance, mutations to EGFR or rearrangements in the ALK gene can cause cancer cells to grow out of control. Medications have been developed and approved, in recent years, to target those aberrations and quiet them, slowing down the activity of NSCLC. While metastatic lung cancer remains incurable, these therapies are more effective and less toxic than chemotherapy as initial treatment when these mutations are present.

Unfortunately, there’s a drawback: these drugs work only in the small percentage of patients who have these specific abnormalities, leaving chemotherapy as a mainstay of therapy for the majority of patients. That’s why, right now, the focus is on sorting out who can be helped by novel medications, and how to add more patients to those groups.

Scientists have found that it’s often nonsmokers, Asians and women who have lung cancers that express these mutations, and who thus can be treated with these drugs. While smokers tend to be ineligible for targeted therapies, they can certainly benefit from newly developed and recently approved immunotherapies that stimulate their immune systems to fight the cancer. The revolution in immunotherapy being seen for many cancer types is a welcome addition to the lung cancer field and continues to move forward, with additional immune-modulating agents being tested.

Although small cell lung cancer has different characteristics and no novel therapies have yet been approved to treat it, some targeted drugs and immunotherapies also look promising in clinical trials.

What will we find around the next bend in the road? Further personalization of treatment is being explored in a number of basket and umbrella clinical trials, which treat patients based on the mutations that drive their cancers, rather than the tissue of origin.

Eventually, this could mean that each lung cancer will be treated quite individually based on the messages it sends, making precision medicine the norm in treating this disease.

Chair, Department of Breast Medical Oncology 

The University of Texas MD Anderson Cancer Center 

>> Read the Lung Cancer Special Issue here <<

Editor's Page

While there has been remarkable progress in the treatment of lung cancer in recent years, there is still a much more work to be done. 

Lung Cancer: A Road With Many Twists

Cyndi Price had been having some trouble breathing and went to her family physician in High Point, North Carolina. Thinking she might have pneumonia, the doctor sent her out for a chest X-ray. The report came back mixed — she had fluid in her lungs that was, in fact, caused by pneumonia, but there was also a suspicious shadow on her lower left lung.

“He called me, set-up a CT scan for Tuesday and that night called me to tell me there was definitely something there that they had to follow up,” says Price. “By Wednesday, I had a PET scan, on Friday I had seen a thoracic surgeon, and the next Tuesday I had surgery, followed by chemotherapy about a month later.”

In the cancer arena, Price’s is not an unusual story. Lung cancer is the second most common cancer in both men and women and the leading cause of cancer-related death. About 14 percent of all new cancers originate in the lungs, and the American Cancer Society estimates there will be about 224,000 new cases in 2016 and 158,000 deaths from the disease.

Like most with this disease, Price has non-small cell lung cancer (NSCLC), for which several novel treatments have been approved and more are on the horizon. Only 15 percent of cases are diagnosed as small cell lung cancer (SCLC), which has different characteristics and fewer treatment options.

What is unusual about Price’s experience is that her disease was diagnosed at an early stage, 1b. When this happens, it’s usually because the cancer is discovered by accident when the chest is screened for an unrelated reason. In fact, most lung cancers aren’t diagnosed until they have spread, because that’s when they tend to become symptomatic — although there’s hope that more lung cancers will be found early now that routine CT screening is recommended for current and former heavy smokers.

Early diagnosis represents an opportunity, since lung cancers are potentially curable in stages 1, 2 and sometimes 3. As a result, it’s vital that these patients be treated by specialists in the disease, possibly with backup from multidisciplinary teams that can carefully consider which combinations of surgery, medication and radiation therapy are likely to work best.

Some SCLCs are described as “limited stage,” meaning the cancer is found only on one side of the chest and involves a single part of the lung and possibly some nearby lymph nodes. Some of these cancers are curable. “Extensive stage” is when the cancer has spread into both lungs and/or has metastasized to other parts of the body.

“Treatment for SCLC is often limited, since the majority of patients don’t get diagnosed until they are in the later stages of the disease,” says Varun Puri, associate professor and associate program director of the cardiothoracic surgery resident program at Washington University School of Medicine, in St. Louis. “In that instance, surgery has minimal to no application, and chemotherapy or radiation are most commonly employed. For those found in an early stage, surgery is much more successful and can be followed by chemotherapy.”

> Adenocarcinoma, which starts in the glands of the body, is the most prevalent type among both men and women, and can occur in either smokers or non-smokers.

> Squamous cell carcinomas begin in newly forming squamous cells, the flat cells found along the airways inside the lungs, typically in smokers.

> Large cell carcinomas are usually diagnosed by excluding adenocarcinoma, squamous cell and small cell cancers, and often spreads quickly.

The staging of NSCLC is much more involved than in SCLC.

> In stage 1, the cancer is found only in the lungs and has not spread to any of the lymph nodes.

> In stage 2, there is lymph node involvement, but only in those near the tumor.

> Stage 3 is diagnosed when cancer is found in the lymph nodes toward the middle of the chest. It is more specifically typed as stage 3a when it is found in lymph nodes on the side of the chest where the cancer started, or 3b when it has spread to lymph nodes on the other side of the chest or above the collarbone.

> Stage 4 cancer is diagnosed when the disease has spread to both lungs, to fluid around the lungs or to another part of the body.

“The treatment for each stage is different,” says Chao H. Huang, director of thoracic oncology at the University of Kansas Medical Center. “A diagnosis at stage 1 is usually treated with surgery unless the patient is too sick or frail for anesthesia or surgery. Stage 1 cancers with a nodule bigger than 4 cm, or stage 2, may get a combination of radiation and/or chemotherapy, known as ‘neoadjuvant therapy,’ to shrink the tumor before surgery. Alternatively, patients with larger tumors who undergo surgery up front should also receive chemotherapy afterwards as ‘adjuvant therapy’ to help decrease risk of recurrence.”

For those with stage 3 disease, treatment decisions are more complex and depend on factors such as location of the tumor, the patient’s overall health, lung function and if the patient has a preference among possible therapies. Treatment could be a combination of chemotherapy and radiation therapy given together, sometimes followed by surgery in those who are surgical candidates. But for most, chemotherapy and radiation without surgery are the usual treatment.

When it comes to chemotherapy, lung cancers have mainly been treated with platinum-based medications, including cisplatin and carboplatin. After surgery in earlier stages of lung cancer, one of these drugs is typically paired with a “partner” agent: paclitaxel, docetaxel, gemcitabine or vinorelbine. Specifically for adenocarcinoma, some doctors prefer using Alimta (pemetrexed) as the partner drug, which causes fewer side effects. Side effects of these chemotherapy regimens can include nausea and vomiting, swelling in the hands and feet, fatigue, lowered white blood cell and platelet counts, and diarrhea.

New combinations of chemotherapies are being studied in clinical trials. In addition, researchers are considering lab tests that look for certain genes that might help determine in advance whether someone would benefit from chemotherapy in general, or even from a specific type of chemotherapy.

The second leg of the NSCLC triad is radiation therapy. This strategy, too, has undergone changes in both application and results. Although most early-stage (stage 1 and some stage 2) cancers are treated with surgery, some patients are too sick or frail to tolerate anesthesia. These, and those with more advanced cancers, are candidates for focused radiotherapy.

“The emerging paradigm in these patients is to use a specific type of radiation instead of resection,” says Thomas J. Dilling, director of thoracic radiotherapy at Moffitt Cancer Center in Tampa. “Previously, the treatments were at low doses, five times a week for many weeks. This was not giving a high enough dose of radiation to actually kill the cancer, so we were seeing only about a 50 percent chance of cure.” Called stereotactic radiation, the dosing has been changed so that it involves fewer treatments at higher doses than conventional radiation. Dilling likens it to giving the tumor a big knock-out punch instead of many slaps in the face. This can result in cure rates as high as 90 percent for cancers that have not spread to the lymph nodes.

Side effects of radiation to the lungs and/ or chest can include nausea and vomiting, fatigue, skin changes and hair loss in the area being treated, cough, shortness of breath and sore throat.

Radiation oncologists are also integrating newer imaging into their practices for NSCLC. Positron Emission Tomography (PET) scans use a radioactive tracer as contrast. The more metabolically active an area is, the more of the tracer it absorbs.

“In the past, we tried to hit every lymph node in the chest, fearing that if we left one untreated, the cancer would regrow,” says Dilling. “We use the scan to find nodes that have active cancer and target only those regions, sparing other lymph nodes in the chest. This makes it significantly less toxic without reducing the cure rate.”

Genetic profiling may soon have a use in radiation therapy as well.

“Tumors are genetically distinct in how sensitive they are to radiotherapy,” says Dilling. “An assay is now in development at Moffitt that may give us guidance on how to lower the dose for some, while identifying those others who might be better off with higher doses.”

Newer surgical techniques for lung cancers have helped lessen the trauma associated with removing parts of the lung that have tumors. Minimally invasive surgeries mean that smaller incisions are needed. This is most often used in stage 1 cancers. “For stage 1 cancers, the gold standard is removal of the lobe of the lung that contains the tumor, called a lobectomy,” says Puri. “In those with other medical problems that make surgery too dangerous, we can remove a smaller part of the lobe in a segmentectomy.”

For either patient, this is usually done using a minimally invasive approach. Instead of the 4- to 6-inch incision used in open surgeries, a minimally invasive approach requires one to three small punctures. It greatly reduces recovery time, there is less risk for infection, the ribs don’t have to be separated to get to the lung and there is less blood loss. One way this can be performed is through video-assisted thoracic surgery (VATS), during which physicians insert a long, thin tube with a video camera at the end. Another incision nearby allows instruments into the chest cavity to cut out and remove a part of the lung. Most patients are able to return home after only two or three days in the hospital. Another option is use of a robotic surgery device. Again using tiny incisions, the surgeon can control the robot from a console in the operating room. Because of three-dimensional video screens, the doctor has a better view of the area and improved ability to find and remove lymph nodes during the operation. “Around 50 to 55 percent of operations for early-stage lung cancer in the U.S. are minimally invasive,” says Puri. “For stage 2 disease, we usually will consider minimally invasive surgery. However, if you have a lymph node with cancer that is near a blood vessel or other important structure, the surgeon will often go with an open surgery to assure a safe and complete cancer operation.”

If the diagnosis is stage 3, induction therapy may be used. In this instance, chemotherapy or radiotherapy are used to shrink the tumor before removal.

GENETIC PROFILING MAY INDIVIDUALIZE TREATMENT

In some cases, the ability to genetically profile an individual’s cancer cells is allowing doctors to personalize treatment, using novel medications to specifically target an abnormality that is causing the cell to grow uncontrollably while avoiding some of the side effects that might come with chemotherapy or radiation.

“Not all tumors are the same; there are often genetic differences that impact on treatment,” says Huang. “We are now able to look at a patient’s tumor and often see what mutations or abnormalities have occurred that triggered the cancer. Then, oncologists can find specific drugs that best fit a person’s specific cancer.”

Targeted drugs are mainly approved for use in advanced, or stage 4, NSCLC, although one, Avastin (bevacizumab), which stops blood vessel growth to tumors, is approved for firstline use — in combination with chemotherapy &mdash; in unresectable or locally advanced NSCLC, as well as for more advanced disease.

In addition, many targeted drugs are being studied for potential use in earlier-stage disease.

For instance, a group of trials known as ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is asking whether patients who have undergone treatment for early-stage lung cancer might benefit by following that with targeted drugs in order to prevent recurrence. Enrolled are patients who underwent surgery to completely remove their tumors, and then completed post-surgery chemotherapy or radiation as prescribed by their doctors.

One of these trials includes patients whose tumors are driven by a problem with the ALK (anaplastic lymphoma kinase) gene, which is rearranged, sparking cancer cells to grow. This genetic rearrangement, which affects about 5 percent of people with certain types of NSCLC, causes excessive growth and spread of cells. In this trial, participants receive either placebo or Xalkori (crizotinib), a drug that blocks the cancer-promoting activity of the ALK abnormality.

Another component of the trial includes people with NSCLC who have a mutation in the gene controlling the activity of epidermal growth factor receptor (EGFR). EGFR causes a healthy cell to remain turned on and constantly stimulates the cells to grow and divide, but can be shut off by the cell’s control mechanism. When a mutation causes the receptors to be overactive, it continues to grow and divide past when it normally would have stopped.

“There are a group of medicines known as EGFR tyrosine kinase inhibitors that can shut off this switch telling the cancer to grow,” says Huang. “If the mutation is present, it tends to be the dominant one, and tumors respond dramatically to these medications.”

Participants in this ALCHEMIST trial receive placebo or Tarceva (erlotinib), which blocks EGFR activity. In addition, Tarceva and other EGFR-targeting drugs, such as Gilotrif (afatinib) or Iressa (gefitinib), have been, or are being, looked at in other clinical trials of patients with early-stage lung cancer. These trials consider whether treatment with EGFR-targeting drugs either before or after surgery will improve outcomes.

The side effects of drugs that target EGFR or ALK can include rash, nausea, diarrhea, mouth sores, shortness of breath and fatigue.

Targeted drugs are also being explored in the clinic to treat SCLC, including the tyrosine kinase inhibitor Iclusig (ponatinib), which is approved for use in leukemia, and drugs similar to Avastin.

Like many current or former smokers, Price was found not to have any mutations that are targetable by existing drugs. “I did genetic testing twice: once when I had my surgery, and when I started treatment again,” says Price, who smoked a pack of cigarettes a day for 41 years. “If patients did not have genetic testing initially and they have a recurrence, genetic testing is still available. My genetic testing revealed I had no targetable genes, but this can change (as more targets and more drugs emerge).”

IMMUNOTHERAPIES BOLSTER IMMUNE SYSTEM RESPONSE

Attempts to bolster the immune system, known as immunotherapy, so that the body can fight off the cancer have also been useful in expanding treatment options — but, again, specifically in advanced lung cancers.

One way to do this is through the use of checkpoint inhibitors. These drugs have activity against molecules on an immune cell that need to be turned either on or off to start an immune response. Cancer cells can use these checkpoints to avoid being attacked by the immune system. Newer treatments targeting these checkpoints leave cancer cells more exposed to the body’s normal defenses.

Opdivo (nivolumab) and Keytruda (pembrolizumab) block a protein (PD-1) that keeps immune cells known as T cells from attacking other cells in the body. This allows those immune cells to recognize and respond to cancer cells, shrinking tumors and slowing their growth. These types of drugs — which can cause side effects including fatigue, rash, cough, nausea, diarrhea, itching, joint pain, upper respiratory tract infection and swelling of the extremities &mdash; are approved for the treatment of stage 4 NSCLC, but trials will be investigating them for use in earlier-stage disease. In fact, ALCHEMIST will soon be amended to offer immunotherapy drugs to those who did not have one of the genetic abnormalities necessary to receive Xalkori or Tarceva in the trials. Study participants will be randomly assigned to receive Opdivo versus observation.

Meanwhile, the European STIMULI trial will test Opdivo and another immunotherapy, Yervoy (ipilimumab), in patients who have limited-stage small cell lung cancer. The phase 2 trial will compare standard chemoradiation alone versus chemoradiation followed by the immunotherapies.

Of course, either targeted treatments or immunotherapies can be the go-to drugs for some patients whose lung cancer is caught early, but later progresses to an advanced stage. Price turned out to be one of them.

After her initial treatment, Price’s lung cancer went into remission. However, the cancer returned, along with a small tumor in her brain. She tried a second course of standard chemotherapy for her lungs, but problems with her kidneys cut those short. Radiation was prescribed for the brain tumor, and she underwent 10 treatments.

Her doctor then suggested that Price follow that treatment with Opdivo. So far, there has been no growth in either her lung or brain tumors since starting this round of treatment. It’s a therapy she appreciates, she says, for its ability to stimulate her immune system without causing the kinds of major side effects chemotherapy can bring.

“With this new treatment, my tumor is not getting any bigger,” Price says. “I told my oncologist that I was on a 10-year plan of things I wanted to do. He said I should start thinking about what I will be doing 20 years from now.”

Features

Potentially curative therapy for each stage of early lung cancer is evolving.

Carefully Staged: Advances in Early Stage Lung Cancer

Elizabeth Lacasia - Photo by Nieshka Rutherford

Elizabeth Lacasia experienced a defining moment the day she found out that her rare form of lung cancer carried the ROS-1 gene alteration. The knowledge, she says, helped her to better understand the stage 4 in situ pulmonary

adenocarcinoma — previously known as bronchioalveolar carcinoma &mdash; for which she’s undergone years of treatment due to recurrences. "It was a eureka moment to finally find out which alteration my cancer had, what was driving my disease," says Lacasia, 54. Better yet, Lacasia's genomic status has allowed her to benefit from a targeted drug approved this spring for patients with the ROS-1 alteration.

Xalkori (crizotinib) was initially approved by the U.S. Food and Drug Administration (FDA) to treat patients whose non-small cell lung cancers (NSCLCs) harbor an alteration in a gene called ALK, which occurs in up to 8 percent of patients with the disease. In March, the FDA expanded the use of Xalkori to include lung cancers with a second abnormality, the ROS-1 gene alteration. Lacasia is one of the estimated 1 percent of patients with NSCLC who have the ROS-1 alteration.

After taking traditional treatments in the past, Lacasia says, targeted therapies like Xalkori have allowed her to live a relatively normal life again.

Lacasia started taking Xalkori orally daily over a year ago and currently has no evidence of disease. Her complete response to the drug was even better than that typically seen in a clinical trial of Xalkori, in which nearly 75 percent of patients' tumors had a significant response, but only three of 50 patients had a complete response.The average length of response among those in the trial was about 1.5 years.

ROS-1 is just the most recent of many genetic alterations that scientists have been able to target with drugs. This ongoing discovery of targets is changing the landscape of how patients with advanced NSCLC are treated, and extending the amount of time that they can live with this disease.

In addition to using targeted therapies, doctors apply a variety of other strategies to treat stage 4 NSCLC, including combinations of chemotherapy and radiation; the anti-angiogenic drug Avastin (bevacizumab), which stops blood vessels from growing and feeding tumors; as well as immunotherapy with drugs that inhibit the protein PD-1: Opdivo (nivolumab) and Keytruda (pembrolizumab).

The search for novel therapies is less advanced in small cell lung cancer, for which treatments mainly include surgery, chemotherapy and radiation.

In 40 percent of cases, NSCLC is diagnosed in stage 4, meaning it has metastasized or spread beyond the lung. Patients with stage 4 disease are not candidates for surgery. Instead, the goal of treatment is to extend life and maintain quality of life. At stage 4, the five-year survival rate for patients with NSCLC is about 1 percent. In the past, it was thought that NSCLC, which accounts for between 85 and 90 percent of all lung cancer diagnoses, was one disease, and patients often got one-size-fits-all treatment with chemotherapy, according to Benjamin Levy, medical director of Thoracic Medical Oncology at Mount Sinai Health System.

"What we have come to find out in the last five to 10 years is that NSCLC is not all the same," Levy says. "This cancer can be parsed out into what are called different driver mutations, or genetic alterations that dictate the tumor's behavior."

By identifying these driver mutations within lung cancer, Levy says doctors are not only able to define how a tumor is molecularly characterized, but can now pair some of the most common molecular alterations with drugs that target those mutations.

"When we talk about these mutated genes, these are not genes passed on from someone's parents; they are not hereditary," explains Alice T. Shaw, a thoracic oncologist and associate professor of medicine at the Massachusetts General Hospital. "These are specific changes that have occurred in the DNA of the cancer cell that are now driving its growth."

About one in four patients with lung cancer has a genomic glitch that is potentially targetable with medication, according to Shaw. For now, she says, these targets have been identified almost exclusively within a subset of NSCLC called adenocarcinomas.

"Prior to our understanding of any of these alterations, patients with metastatic lung cancer would live on average 12 months," Shaw says. "Nowadays, these targeted therapies have a huge impact in terms of extending life expectancy and improving quality of life."

One of the most commonly occurring mutations in NSCLC is the EGFR mutation, present in about 10 to 15 percent of patients in the United States and Europe. Increased production of EGFR, which stands for epidermal growth factor receptor, signals a tumor to grow better and escape the normal checks and balances that regulate cell survival. Drugs that target EGFR — EGFR inhibitors &mdash; slow the growth of the tumor by blocking that signal.

Tarceva (erlotinib), Gilotrif (afatinib) and Iressa (gefitinib) are three drugs approved by the FDA that target EGFR and can be used in patients with NSCLC; most, but not all, of those eligible for the treatment have the non-squamous form of the disease. A patient diagnosed with advanced or metastatic disease that expresses an EGFR mutation will receive one of these drugs in the first-line setting, and most will respond to the drug for about 10 to 12 months and potentially live several years or more, Shaw says.

Unfortunately, cancer treated with these targeted therapies will eventually stop responding to the drug, and will begin to grow again, Levy explains. In some of these cases, a new biopsy — which samples the tumor tissue &mdash; may reveal that the cancer has developed a new resistance mutation causing it to no longer respond to EGFR inhibitors.

"We have found that about 60 percent of patients who have relapsed have developed another new mutation in EGFR called T790M," Levy says.

In January, the FDA approved a targeted therapy called Tagrisso (osimertinib) for patients whose lung cancer has the EGFR T790M mutation and whose disease got worse after being treated with an EGFR-targeting drug. Clinical trials of Tagrisso showed that more than 60 percent of patients given the drug had a complete or partial reduction in tumor size.

In separate clinical trials of two other drugs targeting these T790M mutations, rociletinib (CO-1686) and BI-1482694, about 60 percent of patients with the EGFR T790M mutation had tumor response, but both drugs are still awaiting FDA approval. Since those results were first reported, with further analysis, the overall response rate for rociletinib has dropped to around 30 percent, and the FDA, in December 2015, extended its review period on the drug to consider this updated information. Meanwhile, the same month, the FDA granted breakthrough status to BI-1482694, a decision intended to speed up the review process for that drug.

At age 24, Matthew Hiznay found out that his lung cancer contained a rearrangement in the gene called ALK, and that he, like Lacasia, was a good candidate for Xalkori.

Similar to EGFR mutations, the ALK rearrangement produces a protein that causes cancer cells to grow and spread. ALK rearrangements can also be found in tumors other than lung cancer, including some types of lymphoma and sarcomas.

In many cases, Xalkori, and drugs that target EGFR, treat a more specific population than other lung cancer treatments — young, healthy non-smokers like Hiznay.

"When we think about the (known driver) mutations that occur in lung cancer, we associate them with never- smokers or former smokers, but that is not universally true — they do occur in smokers as well," explains Christine Lovly, assistant professor of medicine at Vanderbilt-Ingram Cancer Center. "However, for never-smokers, we detect lung cancers when patients are in their 40s, 30s or even as young as their 20s, several decades younger than we would think of for standard smoking-related lung cancer."

Hiznay had gone to see a physician after developing a dry cough in the middle of summer. Later, after a swollen lymph node in his neck was removed, his physicians told him they thought he had some form of cancer. Several tests later, Hiznay was diagnosed with stage 4 NSCLC.

Hiznay's physicians sent a sample of his tumor for molecular testing, and he began a two-week wait for the results. During that time, he became very sick and was admitted to the hospital, where he suffered a pulmonary arrest and had to be intubated for three days in order to breathe.

"They were not going to be able to give me chemotherapy while we waited for the test results, because I was too sick," Hiznay recalls. "Waiting for the results to see if I could get the targeted therapy was really my last chance at taking the disease out."

In early September 2011, Hiznay learned of the ALK rearrangement in his tumor, and the next day he began Xalkori. The drug had been approved just nine days after he was diagnosed with lung cancer.

"Within 11 days, the cancer had started clearing up, and two months after starting it, the cancer was in remission," Hiznay says.

As expected, Hiznay's cancer ultimately developed a resistance to Xalkori. In 2012, he enrolled in a clinical trial of another ALK-targeting drug, LDK378, which was approved in April 2014 as Zykadia (ceritinib) for patients who progress on Xalkori.

Although Zykadia helped to control his disease for several months, it began to grow again, and Hiznay started a more traditional course of chemotherapy and radiation to help keep the cancer's growth under control.

In March 2015, he enrolled in a trial of an experimental targeted therapy, lorlatinib (PF-06463922), which is designed to target the ALK rearrangement as well as ROS-1 rearrangements. Hiznay’s cancer again went into remission in July 2015, and now, as he approaches the five-year anniversary of his diagnosis this August, he continues to show no signs of progression.

In addition to Xalkori and Zykadia, a third ALK-targeting drug, Alecensa (alectinib), was approved in December to treat ALK-positive NSCLC that has progressed after treatment with Xalkori.

Lacasia and Hiznay can both compare the ravaging side effects of chemotherapy and radiation with those of the newer targeted therapies.

In the months ahead of and during his wedding, Hiznay underwent chemotherapy and radiation to his neck, upper chest and armpit, treatments he describes as "brutal." The radiation, in combination with the cancer itself and repeated testing, ultimately cost him the use of one of his arms, a very unusual outcome.

His left neck/shoulder area, the site of his cancer's metastasis when he was diagnosed, has weathered three biopsies, and radiation caused further problems by damaging the brachial plexus, a grouping of nerves that control muscular and vascular function in the same region, Hiznay explains.

Similarly, Lacasia describes her time on chemotherapy as leaving her with almost no quality of life.

"I could go on walks, but only slowly. I spent most of my time just trying to be comfortable," says Lacasia, who has developed a patient-to-patient website, LungPedia.com, that contains anecdotal advice on how to deal with the side effects of lung cancer treatment.

As a rule, targeted therapies seem to be much better tolerated than chemotherapy, Levy says. The most common side effects of EGFR-targeted therapies are rash and diarrhea. For ALK therapies, there are different side effects that include nausea, as well as liver function and vision abnormalities, but generally, all of these can be managed.

"When we think about targeted therapy, we often think about the scientific side, the rationale to target the gene, but another big side is the quality-of-life benefits they give to patients," Lovly adds. "For patients receiving standard chemotherapy, they have to be in the infusion room up to eight hours, compared with targeted therapy, where they are taking a pill at home. That is a huge issue, especially for patients with advanced-stage disease who may have a limited life span. Every moment spent with family or doing things they enjoy is important."

According to Levy, every person diagnosed with advanced non-squamous NSCLC should have molecular testing done for genetic alterations. When and how this testing occurs, though, still varies from institution to institution. "The testing is most commonly next-generation sequencing, but some institutions are testing for only a few genes, some are doing a 50-gene panel and some are testing for 300 genes," Levy says.

"At the minimum, every lung cancer should be tested for EGFR, ALK and ROS-1, because there are FDA-approved drugs for those indications in lung cancer," Lovly adds.

Although there are targeted therapies available for only three mutations, there is ongoing research into many of the other molecular abnormalities seen in NSCLC. For example, about 25 percent of patients with NSCLC have a mutation in the KRAS gene, but there is currently no therapy that can successfully target KRAS. Unlike EGFR, ALK and ROS-1, KRAS mutations are more commonly seen in patients with a history of smoking.

Other driver mutations found in less than 5 percent of patients with NSCLC affect levels of the protein HER2, also a common problem in breast cancer; the BRAF gene, sometimes also abnormal in melanoma; the RET gene; and a variety of others.

"We have many targeted therapies coming down the pike that may eventually receive FDA approval," Levy says. "With something like HER2, you intuitively think that we could use the same treatment used in breast cancer to target it, but it does not work that way. It is more complicated."

Additionally, targeted therapies are only the standard of care in patients with stage 4 disease. However, clinical trials are looking at their use in patients with earlier-stage disease, Lovly notes.

"With these targeted therapies, it seems like the sky is the limit. If patients are not doing well with one drug, there are other drugs approved," Levy says. "When a patient is diagnosed, they often want to know what their survival is (going to be), but now, if you have a target, we don't know anymore. Things are moving so quickly it is hard to say how many new targeted drugs will be approved."

For some with advanced non-small cell lung cancer, the rapidly growing field of targeted therapies is boosting survival expectations. 


A Moving Target: Targeted Therapies Boosting Lung Cancer Survival Rates

Pam Griffith’s days were filled with sunshine, golf and trip planning. She and her husband, Randy, were basking in retired life, living on Royal Lakes Golf Course in Lakewood Ranch, Florida. So when a nagging cough would not disappear, she blamed it on seasonal allergies and tried to ignore it. After all, she was too busy to go to the doctor: She played golf three to four days a week with friends and other couples, and she and Randy had just returned from one of their many trips, their first river cruise, down the Rhine River in Germany. “I didn’t want anything to interrupt our lifestyle, so I didn’t make time for that until I

had to,” says Griffith, age 67. “We don’t stay in the house, and we don’t sit around.”

But after six months of the persistent cough, she mentioned it to her family doctor, who referred her to a pulmonologist. A CT scan revealed a mass in the lower right lobe of her right lung in March 2013. After surgery to remove the lobe and the tumor, she was diagnosed with adenocarcinoma with sarcomatoid cells, a rare combination of non-small cell lung cancer (NSCLC) characteristics that, in the past, have been associated with a relatively poor prognosis because these tumors are resistant to some types of chemotherapy. Griffith began chemotherapy with cisplatin and etoposide, plus radiation, five days a week for seven weeks.

Not only did the treatment cause severe nausea, which led to dehydration, but the cancer began to rapidly spread throughout her body. Visible signs began to pop up: a lesion on the back of her head, a bump on her left shoulder blade, a bulge on the right side of her neck. The chemotherapy wasn’t working, so she and her husband decided to switch from the local oncologist to a large academic cancer center. They turned to Scott J. Antonia, chair of the Thoracic Oncology Department at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida.

In her first visit to Antonia, after a CT scan, he “gave us some news that was absolutely devastating,” Griffith says. “He turned to us and he said, ‘We can no longer hope to cure you.’ And that was shocking. My entire body just went numb. My mind was racing, but I couldn’t move.”

But Antonia did offer the Griffiths a ray of hope: an immunotherapy clinical trial. In September 2013, Griffith enrolled in phase 3 of the CheckMate 057 trial and began to receive the drug Opdivo (nivolumab) every other Wednesday. Just as she had been able to see the cancer bumps growing on her body, she soon was able to watch them shrink. Eventually, there was no sign of cancer. She stayed on Opdivo for almost two years, until August 2015, when she began having joint pain, thought to be a side effect of the drug. She continues to receive a CT scan every three months, but the cancer has stayed away. “The cancer I had was a death sentence,” she says, “but now it’s a whole different ball game, because people are surviving, and the doctors are learning as we all go along.”

Immunotherapy is revolutionizing lung cancer treatment, ushering in a new era of hope for those with a disease that is the leading cause of cancer-related death in the United States in both men and women, killing more people every year than breast, prostate and colon cancers combined. It was expected that about 221,000 cases of lung cancer would be diagnosed in 2015, with more than 80 percent of those occurring in patients over age 60.

NSCLC is the most common form of lung cancer, accounting for approximately 85 percent of cases. Small cell accounts for the other 15 percent. There are two main types of NSCLC: squamous cell and the more common nonsquamous cell, which is primarily adenocarcinoma.

Small cell lung cancer, which tends to progress quickly, is usually treated with chemotherapy and radiation, often palliatively, with most patients relapsing in just a few months. In the NSCLC realm, stages 1 and 2 disease can usually be treated first with surgery to remove the tumors, sometimes followed by chemotherapy and/ or radiation. However, because lung cancer often isn’t symptomatic until stages 3 or 4, the majority of people are diagnosed in later stages, when surgery is usually not an option because the cancer has spread throughout the body. In 40 percent of NSCLC cases, the cancer is diagnosed in stage 4; in this stage, fewer than half of patients live a year, and only 10 percent survive two years.

Immunotherapy is typically used only in stage 4 NSCLC, and the most promising type so far has been checkpoint inhibitors. In 2015, one such drug, Opdivo, the therapy that helped Griffith, became the first immunotherapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of lung cancer. Opdivo is approved for metastatic squamous or non-squamous NSCLC and has also been approved to treat the skin cancer melanoma. In NSCLC, the FDA has approved a second checkpoint inhibitor, Keytruda (pembrolizumab), only for patients whose tumors express the protein PD-L1. Both drugs are currently approved only as second-line therapies, to be tried after chemotherapy has stopped working.

Chemotherapy works by attacking any rapidly dividing cells, which include cancer cells. But several types of normal cells in the body that divide can also be affected, leading to chemotherapy side effects including hair loss, diarrhea and drops in blood counts, which in turn can cause increased susceptibility to infection and bleeding. Immunotherapy works differently. It activates the body’s immune system, or T cells, to fight foreign invaders. Side effects are mild for most people and are caused by an immune system working on overdrive. “Cancer puts the brake on the immune system, [and immunotherapy] can release that brake,” says Scott Gettinger, associate professor of medical oncology at Yale Cancer Center and the principal investigator on the Opdivo trials at Yale.

Opdivo and Keytruda are anti-PD-1 drugs. They target one of the cellular “immune checkpoint” pathways known as PD-1/PD-L1, which normally tones down an immune response after a virus or bacteria is dealt with, protecting a person from excessive uncontrolled inflammation. However, some cancers can hijack the PD-1 pathway, engaging PD-1 on immune cells to inactivate them, blunting an anti-tumor immune attack. By blocking PD-1 engagement by cancer, Opdivo and Keytruda allow anti-tumor immune cells to do what they are meant to — attack cancer. In the CheckMate 057 trial, patients on Opdivo lived an average of 12.2 months compared to 9.4 months for patients treated with the chemotherapy drug docetaxel. Additionally, 19 percent of those on Opdivo saw complete or partial tumor shrinkage, compared to 12 percent of those on docetaxel. Furthermore, response to Opdivo lasted substantially longer &mdash; the median duration was 17.2 months versus 5.6 months with docetaxel &mdash; and with far less severe toxicity (10 percent versus 54 percent). The drug was approved in 2015 for the treatment of patients with advanced squamous NSCLC whose disease has progressed despite platinum-based chemotherapy; later the same year, the approval was expanded to include patients with non-squamous NSCLC.

The FDA granted accelerated approval for Keytruda in October 2015 after it showed effectiveness in a subgroup of 73 patients with tumors that demonstrated high PD-L1 expression. Tumors shrank in 45 percent of patients, with half of the responses lasting at least 12.5 months. The drug is approved to treat patients whose tumors express PD-L1 and have progressed on or after platinum-containing chemotherapy or, in those with EGFR mutations or ALK translocations, after appropriate targeted therapies.

Small inroads of progress are being made in the testing of immunotherapies in small cell lung cancer (SCLC), too. In one 2015 study, patients with PD-L1-positive SCLC tolerated Keytruda well, and the response rate — all partial responses &mdash; was 35 percent.

Despite these results, PD-1 blockers work in only about 20 percent of NSCLC patients. They tend to be more effective in patients who demonstrate an over-expression of PD-L1. Paradoxically, some patients whose tumors are not found to express PD-L1 do well on immunotherapy, as well. PD-L1 is not always predictive of results, and oncologists have much more to learn about how it works.

“There’s also a lot of variability in the expression of PD-L1, depending on where the tumor was sampled,” says Rathi Pillai, assistant professor in the Department of Hematology and Medical Oncology at the Winship Cancer Institute at Emory University. “There could be variability between the different sites of disease, whether or not they have expression of PD-L1, and there have been reports that even within a single tumor, depending on the area of the tumor that is biopsied, there could be variability. So it’s not a perfect biomarker that clearly tells us what exactly is going on with the patient’s cancer and their immune system’s response to that cancer.”

However, the success of Opdivo and Keytruda throws open the door for immunotherapy clinical trials, as researchers study the new treatment possibilities from every angle: Does a combination of two immunotherapies work better than one? Does immunotherapy work with certain mutations or specific biomarkers? Does it work better before or simultaneously with chemotherapy, rather than as a second-line option? Is it as effective in never-smokers as it is in smokers? Multiple trials are examining these questions.

Studies are also researching other types of inhibitors of the PD-1/PD-L1 pathway — PD-L1 inhibitors like durvalumab and atezolizumab &mdash; and other kinds of checkpoint inhibitors, such as the anti-CTLA-4 drugs tremelimumab and Yervoy (ipilimumab), which has already been approved for the treatment of melanoma. One phase 3 trial that is now recruiting will compare Opdivo with or without Yervoy as a maintenance therapy after treatment for SCLC, pairing up a PD-L1 inhibitor with a CTLA-4 inhibitor. Another phase 3 trial, called Neptune, tests the possibility of using the immunotherapy combination of durvalumab and tremelimumab as a first-line treatment, as compared to standard chemotherapy. And other immunotherapy techniques are being considered too — for instance, vaccines. GV1001, which targets telomerase, an enzyme that extends chromosome length and may allow cells to proliferate continuously, is being tested in patients with inoperable stage 3 NSCLC. And the vaccine TG4010 with first-line chemotherapy is also being considered in a phase 3 trial in patients with advanced NSCLC. In the earlier-phase TIME trial, some subsets of untreated patients with NSCLC tumors that expressed the MUC-1 mutation experienced significantly improved progression-free survival and overall survival when that vaccine was added to standard first-line chemotherapy.

Finally, researchers are testing chimeric antigen receptor (CAR) T cell therapy in lung cancer patients in phase 2 trials. This strategy involves taking T cells from a patient, genetically engineering them in a lab so that they are better equipped to fight lung cancer, and then infusing them back into the patient.

“Many of us believe that PD-1 axis inhibitors will become the backbone of first-line therapy for advanced lung cancer, either alone or in combination with other therapies,” Gettinger says. Even if PD-L1 signaling is not active initially, tumor response to other standard therapies, such as chemotherapy or radiation, can lead to PD-L1 expression (aimed at) protecting the tumor from further attack.”

In a small percentage of patients, immunotherapy works remarkably well. Oncologists are trying to determine what makes these cases unique.

Sharon Long has been taking Opdivo since October 2014 and has no plans to go off the drug. She was diagnosed with adenocarcinoma in February 2014 after becoming severely short of breath after a 12-hour shift as a hospital nurse. “I was actually drugged when I was told. That helped quite a bit,” says Long, 55, of New Haven, Indiana, who had been given Ativan (lorazepam) before an emergency procedure to drain the large amount of fluid around her heart; the drug also relaxed her when she was given her cancer diagnosis. “I think it hit harder when I went to the doctor and he said ‘no surgery, no radiation,’ because stage 4 is chemo-only.”

After a combination of carboplatin and pemetrexed chemotherapy failed, Long joined an Opdivo trial, CheckMate 153, and her tumors — too numerous to count &mdash; began to shrink. She now has only a small tumor in her right lung, a node on her thyroid and a small tumor on her left adrenal gland, which have all been stable for about a year. “I’m amazed I’ve made it two and a half years,” Long says. “I have a new grandchild, and my first one turned 3. We’ve moved, and I’ve got a house now that I sit back and relax in. I’m in a really happy place.”

Unfortunately, a lot of patients don’t fare as well as Long has.

“A minority of the responders are long-term survivors, and we don’t know why as of yet,” says Chandra Belani, director of translational and clinical investigations at the Penn State Hershey Cancer Institute. “The long-term survival rate will be the best parameter to compare various agents and validate these predictive biomarkers.”

Another problem is that some patients develop a resistance to the drug, but oncologists hope a combination therapy will reduce the risk of resistance by fighting the cancer through different mechanisms simultaneously, says Yanis Boumber, assistant professor in the Department of Internal Medicine, Division of Hematology/Oncology, at the University of New Mexico School of Medicine. In addition, a combination might help increase the effectiveness in patients who are PD-L1 negative, who typically don’t do as well or for as long on the PD-L1 inhibitors as do patients who are PD-L1 positive, he says.

Side effects, too, can interfere with the success of immunotherapy. For most patients, immunotherapy side effects are much less severe than those generated by chemotherapy, potentially including fatigue, thyroid dysfunction, musculoskeletal pain, cough, constipation and loss of appetite. Most of these side effects are mild and can be effectively managed with drugs, Boumber says.

“This drug did not make me sick; I didn’t lose my hair, none of that,” Griffith says. After each treatment, a red rash would appear on the top of her feet but disappear after a few days. But after one year on Opdivo, she began to have inflammation and pain in her joints, and she stopped taking the drug at almost the two-year mark. She sees an arthritis specialist to manage her joint inflammation, a known potential side effect of Opdivo. It’s unknown whether the inflammation will eventually subside.

Other severe side effects, such as inflammation in the lung or colon, can also cause patients to stop taking immunotherapy. Ultimately, scientists hope to bring more patients with lung cancer into the fold among those who can benefit from immunotherapy.

“The idea is (that), if we can convert lung cancer to a chronic condition, we can keep patients on these drugs for a long time and make them live longer,” Boumber says. “This is just the beginning of a new era. There is a prediction that, in 10 years, immunotherapy will be more than 50 percent of all oncology drugs. It’s a revolution in oncology.”

Opdivo and Keytruda are just the tip of the iceberg, Gettinger adds. “The early success with PD-1 checkpoint inhibitors has provided just a glimpse into the potential of the immune system to attack and control cancer. We have entered a new era of cancer care, one in which a patient’s own immune system will be increasingly harnessed to treat cancer, leading to long-term survival with good quality of life.”

As immunotherapy revolutionizes lung cancer treatment, scientists are considering how to make it work for more of those affected by the disease.

A New Era of Hope in Lung Cancer

Cancer patients have traditionally been treated based on where their tumors originate — lung tumors with treatments for lung cancer, breast tumors with therapies developed specifically for breast cancer. But what if doctors started caring less about where a tumor first emerged and more about the genetic mutations that caused it to appear in the first place? That principle is at the essence of precision medicine, a science focused on understanding each particular tumor and the molecular messages it sends, and treating it accordingly.

Ultimately, this branch of investigation could mean that a breast and a prostate cancer are treated with the same medicine, or that two people with melanoma of the same stage and location are given entirely different therapies. It's something that's already happening more and more in the world of cancer treatment, and it's given rise to a host of clinical trials with a new type of design.

Known as "basket trials" or "umbrella trials," these studies enroll patients with a variety of cancer types, find the specific mutations or abnormalities that drive their tumors, and then match the patients with medications that target those glitches. It doesn't matter where a cancer first emerged; tumor genetics are what determine trial eligibility. In basket trials, patients are eligible if their tumor harbors a specific genetic mutation that is a target for the therapy in question. A basket trial could enroll patients with several different types of tumors (skin, lung or colon cancer), but all of the tumors would share the same genetic abnormality. Alternatively, an umbrella trial might enroll patients with the same underlying origin of cancer (such as breast or pancreatic), but allocate patients to treatment with one of several different targeted therapies.

An example of a large umbrella trial is ALCHEMIST, or the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial, a government-sponsored study that is enrolling patients with early-stage, nonsquamous non-small cell lung cancer (NSCLC) after surgery. The trial will screen patients for EGFR mutations and ALK rearrangements, and then place them in two separate trials based on those biomarkers, evaluating treatment with either EGFR-targetingTarceva (erlotinib) or ALK-targeting Xalkori (crizotinib) versus placebo. Other large trials, such as NCI-MATCH and TAPUR, are enrolling patients with numerous cancer types and looking for a variety of genetic abnormalities to treat with targeted drugs, and so combine both approaches.

Many clinical trials of cancer drugs include some degree of personalization these days, but basket and umbrella trials remain a minority among studies because the level of collaboration they involve can make them difficult to organize. The costs of biopsies and genomic sequencing are also challenges. Still, experts say, we can expect to see more and more of these trials emerging over time.

In February of 2001, The Human Genome Project announced that a sequencing of the human genome had been completed. That project identified the locations of, and provided information about, the structure and organization of specific genes. It was the breakthrough that ushered in a new era of oncology research that has allowed investigators to study the genetic makeup of cancer tumors and reclassify them according to their composition.

A decade-and-a-half later, in his January 2015 State of the Union address, President Barack Obama recognized the significance of this line of study, and its evolution into an actionable body of work, by announcing the launch of the Precision Medicine Initiative, calling for $215 million dollars in government spending for fiscal year 2016. Seventy million dollars of that initial allocation went to the National Cancer Institute (NCI) for research in targeted, precision oncology.

Indeed, within the last decade, a significant focus within cancer research has been the push to understand how tumor genetics drive different cancers, and how to develop more focused drugs to target these molecular abnormalities. "The last decade has seen the development of several targeted therapies that can be very effective for a subset of patients with certain types of cancers, including lung cancer or melanoma. The challenges now are to try and extend these developments to other patients and to develop strategies to treat resistant tumors," says Amanda Redig, a medical oncologist at Dana-Farber Cancer Institute.

The gene mutations that occur in cancer are numerous. Primo Lara, a clinician-scientist at UC Davis Comprehensive Cancer Center, uses the commonly mutated gene KRAS as an example. It appears in 25 percent of lung cancers, 90 percent of pancreatic cancers and about half of all colon cancers. Further, approximately one-half of all cancers have a mutation in the tumor suppressor gene p53; this mutation releases the brakes on tumor growth, allowing unfettered cancer cell proliferation. Efforts are underway to identify and develop drugs that specifically target KRAS and p53, and to identify and clinically validate many more cancer-related mutations that could be clinically actionable.

Among approved drugs are those that target EGFR, the epidermal growth factor receptor. Mutations to EGFR are found in 10 to 15 percent of lung cancers in the U.S. and in more than 50 percent of lung cancers in Asian populations, more prevalently in females than in males, according to Shakun Malik, head of thoracic and head and neck cancer therapeutics at NCI’s Cancer Therapy Evaluation Program.

Mutations to a different gene, BRAF, were at the heart of the first published results of a basket study — the Zelboraf (vemurafenib) trial &mdash; reported just last year by researchers at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. BRAF inhibitor Zelboraf was approved by the U.S. Food and Drug Administration (FDA) in August 2011 for the treatment of metastatic melanoma, but since BRAF mutations occur across a variety of cancers, investigators wanted to test the drug's effect on other cancer types, including lung, colorectal and ovarian. They enrolled 122 patients from centers around the world, all of whose cancers carried the BRAF mutation.

In general, results showed that Zelboraf was able to target this mutation across a wide variety of cancers, proving that cancer type does not always matter.

Medical oncologist David Hyman, acting director of developmental therapeutics at MSKCC and the study’s first author, says an advantage of basket studies is that they can democratize access to targeted therapy for those who have rare cancers, who are often underrepresented in clinical trials. "The discovery has been that some patients with very rare cancers have similar mutations (as more common cancers) at even higher rates, and some have no ongoing trials or therapies available (specifically for their disease types)," he says.

A number of large precision medicine trials are underway now, with the eyes of the scientific and patient communities watching closely to see where this kind of study will take us.

Throughout the country, lung cancer is the No. 1 cancer killer, causing over 27 percent of cancer deaths, or 150,000, each year. But because squamous cell lung cancers that are often caused by smoking include a wide variety of cell types and can be deadly, progress in finding treatments has been slow.

Mary Redman, the architect of the statistical design of the Lung-MAP trial and a biostatistician at Fred Hutchinson Cancer Center in Seattle, says the hope is that by using targeted therapy — both single-agent and combination regimens &mdash; treatments will be found that are effective and can prolong lives. Lung-MAP is a public-private collaboration composed of the NCI, SWOG Cancer Research (a worldwide network of researchers that designs and conducts clinical trials), Friends of Cancer Research, the Foundation for the National Institutes of Health, five pharmaceutical companies, Foundation Medicine and several lung cancer advocacy organizations. It's a large trial for individuals with advanced squamous NSCLCs who have undergone no more than one round of chemotherapy treatment and are not responding to that treatment.

Lung-MAP's co-principal investigator and co-chair of its trial oversight and drug selection committees, Roy S. Herbst, says patients can join the trial at any of more than 700 medical centers, where their cancer cells will be tested for over 200 possible gene alterations. Based on the results of this screening, eligible patients are assigned to one of four sub-studies testing investigational or FDA-approved treatments, based on which best suits their cancer's genomic profile. Three arms are testing targeted drugs, and the fourth is testing immunotherapeutic treatments that do not target a specific mutation, possibly benefiting patients whose cancers lack genetic alterations that match any of the targeted investigational therapies. Specifically, the immunotherapy arm is testing the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) compared with Opdivo alone.

Unlike most trials that require the development of a protocol for each drug to be tested, Lung-MAP uses a "master protocol" that can be changed and adapted quickly as new drugs become available or drugs that are proven not to be useful are removed from the study, says Herbst, professor of medical oncology at Yale Cancer Center-Smilow Cancer Hospital. Furthermore, the study design is unusual in that, if it demonstrates that a drug is safe and effective, that agent will automatically be eligible for approval by the FDA.

Jerry Valentino was diagnosed two years ago with squamous NSCLC at the Veterans Administration in West Haven, Connecticut, a teaching affiliate of Yale Medical School. The 69-year-old underwent 35 radiation treatments in addition to chemotherapy, resulting in the disappearance of the tumor in his lung. But in September 2015, he thought he was having a stroke. An MRI showed that his lung cancer had traveled to his brain.

After receiving brain radiation, with few standard treatment options available, Valentino instead entered the Lung-MAP trial at the VA and submitted his tissue for genome profiling. Based on the results, he was assigned to a sub-study and received an oral CDK4/CDK6 inhibitor called Ibrance (palbociblib), which was approved by the FDA in 2015 for the treatment of breast cancer. During each of three cycles, he took one pill a day for 21 days, followed by a one-week break. Valentino has undergone restaging scans as part of Lung-MAP's surveillance regimen, which confirmed stability in two lung lesions and partial response in another.

"I have experienced no side effects except fatigue, my brain tumor has shrunk and there is no lung nodule visible now," he says, adding that he is glad to be getting treatment that doesn't make him feel sick all the time.

The NCI’s Molecular Analysis for Therapy Choice (NCI-MATCH) trial, which opened for enrollment in August 2015, explores more genetic abnormalities and drugs than any other cancer trial — and in the largest number of cancer types ever, according to lead investigator Keith Flaherty.

Funded entirely by the NCI and with investigational drugs provided by pharmaceutical corporations, the trial was co-developed by the NCI and the ECOG-ACRIN Cancer Research Group. Its aim is to match tumor signals with targeted drugs and drug combinations, leading to further study of the strategies that prove effective.

Flaherty explains that the study arms, which will grow from 10 to 20 as the trial progresses, are for adults with advanced solid tumors and lymphomas that no longer respond to, or have never responded to, standard therapy, and for those with rare cancers for which there is no standard treatment. While patients with all kinds of cancers can enroll for screening, the goal is that at least 25 percent of enrollees will have cancers that are considered rare.

The trial is looking at 143 genes associated with cancer using cutting-edge molecular analysis. Tumor biopsies will be taken from about 3,000 patients. Those biopsies are sent to any of four labs, where the DNA is sequenced and analyzed in other ways to identify genetic abnormalities believed to be driving the growth of cancer. Drugs and drug combinations being tested have been approved by the FDA for specific cancers or have been used in other trials and have shown some effectiveness against certain genetic alterations.

When and if genetic abnormalities are found in participants, such as mutations in BRAF or EGFR, or HER2 amplification, these patients will be further evaluated for eligibility to enroll in the corresponding treatment arm; if they qualify, they will be treated for as long as their tumors shrink or remain stable.

So far, of 645 biopsies successfully evaluated, 9 percent (56 patients) had a gene mutation that matched a drug or drug combination being studied, 5.1 percent (33 patients) were assigned to a treatment arm and 16 patients actually entered into seven of the 10 available arms. Ultimately, investigators want to treat 1,000 patients across all arms of the trial. For an approach to be considered promising within any arm of the study, at least 16 percent of patients have to show tumor shrinkage. If a first drug treatment is unsuccessful, a patient may be eligible to receive therapy in another arm of the trial if there is a remaining drug that matches one of the mutations found in his or her tumor. For each arm of the trial, the major endpoint will be the overall response to treatment, with a second endpoint being six months of progression-free survival, time to disease progression, toxicity and biomarker status.

The trial was designed, says Flaherty, so that when 500 patients were accepted as eligible to submit tissue for mutation screening, the study would be paused for analysis to determine how it should proceed, with patients already being treated continuing to receive their medications. During the current pause that began in November 2015, the diversity of cancer types is being studied, data for those with mutations that correlate with treatments in the trial are being analyzed, and an assessment of changes needed to move forward is being worked out. Facilitating a steady flow of tissue screening through the participating labs is one task being addressed during the pause, but a more vital one has involved adding more study arms, which will lead to the treatment of more patients, leaders say.

The interim analysis will be completed soon, and enrollment in the trial is expected to resume in late May. "It was assumed years ago that cancers that harbored the same genetic mutation, for which we have targeted therapies in development, would be equally likely to respond," says Flaherty. "We have learned recently that there is a lot of variability based on the presence of co-occurring mutations or biology that stems from the tissue of origin for a given cancer. The MATCH trial is the largest endeavor undertaken to explore the consistency or variability of response to targeted therapy across the entire cancer population."

The first trial ever to be run by the American Society of Clinical Oncology (ASCO), the Targeted Agent and Profiling Utilization Registry (TAPUR) is being launched at the sites of the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan and the Levine Cancer Institute at Carolinas HealthCare System. Its aim is to simplify access to cancer treatments for patients with various tumor types that carry genetic variations known to be the targets of any existing approved drugs — including lung and other kinds of advanced solid tumors, multiple myeloma or non-Hodgkin lymphoma. Patients who have at least one genomic variant that can potentially be targeted by one or more available drugs and are not responding to standard therapies, or for whom no treatment is available, are eligible for enrollment in TAPUR.

In addition to providing drugs to which patients might not otherwise have had access, the objectives of TAPUR are to assess safety and efficacy and to target multiple tumor types. To begin with, the study will enroll patients at three sites nationally to evaluate 10 to 15 drugs, with up to 28 patients per drug treatment.

Unlike Lung-MAP, which is studying both investigational and approved drugs, TAPUR will look strictly at drugs that have been OK'd by the FDA. The study will include more genomic aberrations and more drugs than Lung-MAP, which exclusively targets squamous NSCLC. The trial has more in common with NCI-MATCH, because, like MATCH, it targets rare genetic aberrations with drugs designed to quiet them. However, it is simpler than MATCH, as there is not a different protocol for each drug being tested.

As those trials across a spectrum of cancers and mutations continue, others are popping up that consider more specific questions.

 study) is a phase 2 basket clinical trial that is open to enrollment in the U.S. for patients with solid tumors. Eligible patients will be treated with 

, an investigational drug that specifically targets certain cellular pathways that are involved in the development and progression of cancer. Recently launched by the drug’s developer, Ignyta, Inc., the clinical trial will seek to enroll patients with locally advanced or metastatic solid tumors that have a specific mutation (called a “gene rearrangement” or “fusion”) that is found in the 

 or ALK genes. It is believed that these types of mutations have the potential to be oncogenic drivers. Ignyta and other labs offer a test to help determine if one of these mutations is detected within a sample of tumor tissue. The trial will include a variety of cancer types (i.e., different baskets), among them non-small cell lung cancer, colorectal cancer, 

, papillary thyroid cancer, melanoma and 

. Depending on cancer type and gene rearrangement/fusion, eligible patients will be assigned to a specific basket for treatment with entrectinib.

When determining treatment plans, some doctors are turning to genetic mutations that caused the cancer instead of the cancer type. 

Lung Special Issue | CURE

Medical Illustration: Non-Small Cell Lung Cancer

Lung Cancer: A Road With Many Twists

Carefully Staged: Advances in Early Stage Lung Cancer

A Moving Target: Targeted Therapies Boosting Lung Cancer Survival Rates

A New Era of Hope in Lung Cancer

Basket Cases: Changing the Way Cancer Is Treated

Striving for Precision

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