Hitting a Target in Advanced Non-Small Cell Lung Cancer

By a sheer stroke of good luck, on the day Matt Hiznay was diagnosed with stage 4 non-small cell lung cancer in 2011, the FDA approved a new type of targeted treatment called Xalkori (crizotinib). The drug was designed for patients whose tumors have a specific abnormality in a gene called ALK. Less than 7 percent of lung cancer patients possess the wayward gene, but Hiznay, then just 24, was one of them.

Hiznay took the drug twice a day without any chemotherapy or other treatments, and his cancer went into remission for almost a year. His response was typical: More than half of patients in the clinical trials for Xalkori responded well to the drug, which produced a median duration of response of 42 to 48 weeks. Hiznay’s cancer eventually developed resistance to Xalkori, but then he was able to enter a trial for another ALK-targeted drug, Zykadia (ceritinib). That drug helped control his cancer for several more months, after which he had traditional chemotherapy and radiation to keep the disease at bay.

In March 2015, Hiznay entered yet another trial, this one of an experimental drug, PF-06463922, which targets not only ALK but also another tumor abnormality called ROS1 (C-ros oncogene 1). Hiznay, now 28, is in remission again and earning his Ph.D. in molecular medicine at Case Western Reserve University in Cleveland. The drug is now in midstage trials. Hiznay says he has no side effects and will be on the drug indefinitely.

“Targeted therapies are here and more are coming, and that’s good,” Hiznay says. “I’ve been fortunate. If I had gotten cancer four or five years earlier, I wouldn’t have access to all these drugs.”

The rise of targeted treatments has significantly improved the outlook for patients who are in the late stages of lung cancer. The past few years have witnessed the discovery of ALK and several other genetic mutations that can drive non-small cell lung cancer (NSCLC), the subtype that accounts for 85 to 90 percent of all lung cancer diagnoses, according to the American Cancer Society. Unlike chemotherapy, targeted drugs have relatively mild side effects — Xalkori, for example, commonly causes fatigue and stomach discomfort that can be easily managed — so they can be taken over long periods of time to control the disease. Unfortunately, the majority of patients with NSCLC don’t have genetic mutations that will respond to targeted therapies. Patients without the mutations are generally treated with chemotherapy drugs such as cisplatin or carboplatin, sometimes in combination. Radiation therapy is sometimes used after chemotherapy to help eliminate stray cancer cells, although this happens less commonly in stage 4 lung cancers than in earlier-stage disease.

At the same time, immunotherapy drugs, medicines that free up patients’ immune systems to fight cancer, are showing promise in lung cancer. All of these new developments have greatly expanded the toolbox for oncologists, says Guneet Walia, senior director of research and medical affairs at the Bonnie J. Addario Lung Cancer Foundation.

Targeting Mutations

“For the longest time, it was about controlling the disease. Now we can start talking about trying to cure it,” Walia says.About 221,000 cases of lung cancer were expected to be diagnosed in 2015, with more than 80 percent of those occurring in patients over age 60. In 40 percent of cases, the cancer is already in stage 4 — meaning it has spread to the other lung or beyond — when it is diagnosed, at which point the five-year survival rate for patients is just 4 percent. The disease is more common in men than women, and African Americans are more likely to get lung cancer than any other racial group.

The discovery of genetic mutations that drive NSCLC is rapidly improving the outlook for some patients in stage 4. One of the first breakthroughs was the discovery of the EGFR mutation, which is present in about 10 percent of Americans who are diagnosed with the disease. Tumors with this mutation produce too much EGFR (epidermal growth factor receptor), which signals cancer cells to grow at a fast pace. EGFR-targeting drugs — which include Tarceva (erlotinib) and Iressa (gefitinib) — halt that signal, thus slowing down the rate of tumor growth.

Most lung cancer patients with EGFR mutations who respond well to targeted treatments develop resistance to the drugs after a year or so, Walia says. “The cancer finds other ways to grow,” she says. “But now there are newer drugs that can be used as second-line treatments, so patients have a Plan B.”

Scientists are also discovering particular mutations that cause drug resistance in lung cancer and learning how to target them. For example, on Nov. 13, the FDA approved Tagrisso (osimertinib) for patients with a specific EGFR mutation called T790M. It was approved for patients who relapse after being treated with a different EGFR-targeted drug. A similar drug called rociletinib (CO-1686) is in late-stage trials in patients with the T790M resistance mutation.

Certain subtypes of NSCLC have genetic abnormalities that can now be detected with diagnostic tests. Some patients with the non-squamous form of the disease have the ROS1 mutation, which predicts a good response to drugs that were developed to target ALK mutations, seen in 2 to 7 percent of patients with NSCLC adenocarcinomas. The ROS1 mutation is rare — fewer than 1 percent of tumors test positive for it — but identifying those patients can be important for choosing the right therapy, says Gregory Masters, an oncologist at Christiana Care Health System’s Helen F. Graham Cancer Center in Newark, Delaware, and co-chair of an American Society of Clinical Oncology (ASCO) panel that recently revised the guidelines for treating NSCLC. “Many of us are now ordering this test even though it’s a very small group of patients,” Masters says.

Engaging the Immune System

Targeted treatments have proven so effective that it has now become standard practice for patients to have their tumors genetically sequenced as soon as they’re diagnosed. The 10 percent or so of patients with NSCLC who are eligible for targeted treatments are put straight on them. Chemotherapy only comes into play for patients who don’t test positive for targetable mutations or who stop responding to the new drugs. “Now that we have drugs that target certain mutations, we have a better chance of controlling the disease for a longer time,” Masters says.Immunotherapy drugs promise to extend survival in stage 4 lung cancer even further. The idea behind these drugs is to block “checkpoints” that prevent the immune system from recognizing and destroying cancer cells. Checkpoints exist naturally to keep the immune system from being overactive and damaging normal tissue. In 2015, the FDA approved two checkpoint inhibitors for the treatment of lung cancer: Opdivo (nivolumab) and Keytruda (pembrolizumab). Both inhibit an immune checkpoint called PD-1 and are approved for patients with NSCLC who have stopped responding to chemotherapy.

People who never smoked are more likely to harbor EGFR mutations and ALK rearrangements that can be targeted. By contrast, smokers or ex-smokers are more likely to have many random mutations induced by tobacco carcinogens. There are more of these patients than those who have targetable mutations, and they seem to be responding particularly well to immunotherapy treatments, perhaps because smoking-related mutations make the tumor cells more recognizable by the immune system. “We’re still learning why that is, but it may be that the more mutated the tumor, the more likely the immune system is to recognize it as foreign,” Masters says.

In trials, patients on Opdivo had a 40 percent reduced risk of death compared with those on chemotherapy. With Keytruda, oncologists can use diagnostic testing to predict which patients will respond best to the drug. In trials, 41 percent of patients who tested high for PD-L1 — a protein that binds to PD-1 — responded well to the drug. Both drugs are useful in either squamous or non-squamous NSCLCs. In September, Bristol-Myers Squibb, which makes Opdivo, presented more evidence that the drug works in non-squamous NSCLC when it released results from a trial showing that 39 percent of patients who took Opdivo were still alive after 18 months, versus 23 percent who took the commonly used chemotherapy drug docetaxel.

Some oncologists believe that the longer these immunotherapies are used, the longer the survival benefit will be for some patients. “It seems a small group of patients may have a very durable response,” says Giuseppe Giaccone, associate director for clinical research at Georgetown Lombardi Comprehensive Cancer Center. In melanoma, for which these drugs were first approved, some patients have responded to immunotherapy drugs for as long as five years, he says.

Drugs that inhibit the immune checkpoint PD-L1 are also under development for NSCLC, including atezolizumab (MPDL3280A), which was granted “breakthrough therapy” designation, a type of priority review, by the FDA in February 2015.

Stephan Silverman, 73, who was diagnosed with stage 4 lung cancer in November 2014, is in a trial of atezolizumab at Georgetown. His treatment consisted of 12 sessions of chemotherapy, followed by the immunotherapy every three weeks. Silverman, a retired school psychologist, says his primary tumor went from the size of a peach to the size of a cherry tomato, and his lymph nodes are now clear of cancer.

Silverman will stay on atezolizumab indefinitely, and says he’s not aware of any significant side effects. “I feel like I’m 80 percent,” he says. “I walk more than I did before, I gained weight. I’m grateful to the immunotherapy for saving my life.”

Now oncologists are testing combinations of immunotherapies in NSCLC in the hopes that activating the immune system from more than one angle will amplify the positive response. One idea currently being tested is to combine PD-1 inhibitors with drugs that block another immune checkpoint called CTLA-4. A late-stage trial of Opdivo plus Yervoy (ipilimumab), which inhibits CTLA-4, is currently underway in lung cancer, as is a combination of durvalumab (an anti-PD-L1 drug) with tremelimumab (an anti-CTLA-4 agent).

“Anti-CTLA-4 antibodies work to prime the T cells within lymph nodes, and anti-PD-1 or anti-PD-L1 antibodies work directly within the tumor, so combining these agents makes sense,” says Naiyer Rizvi, director of thoracic oncology and immunotherapeutics at Columbia University. “Combinations of CTLA-4 and PD-1 have clearly shown a benefit in melanoma. The question of whether you can use combinations to drive the immune system harder is now being studied in lung cancer.” Although more immune side effects can be expected with this more aggressive immunotherapy combination treatment, the preliminary studies with these combinations show a nearly doubling of response rate in NSCLC.

Rizvi adds that, because the side effects of these immunotherapies are relatively minimal and easily managed, they offer hope to many patients who might not have been able to be treated before. Similar to targeted drugs, immunotherapies typically produce side effects such as fatigue and stomach upset.

Sub-Typing Tumors

“About a quarter to a third of lung cancer patients who are newly diagnosed don’t even get to chemotherapy, because they are too sick and they can’t tolerate it,” Rizvi says. “But that paradigm doesn’t really apply to immunotherapy. These drugs are not that difficult to take, and we see activity in a broad range of patients.”Immunotherapy is also proving useful in treating the squamous cell form of NSCLC, which affects about 25 percent of all patients and is most common in smokers. In two late-stage studies presented in 2015, Opdivo extended median overall survival (OS) rates for patients with this form of the disease by two to three months over docetaxel. In the larger of the two studies, the OS rate at an 18-month analysis was 28 percent with Opdivo versus 13 percent with docetaxel in previously treated patients with squamous NSCLC.

Another major development in lung cancer research has been an increased understanding of which chemotherapies and targeted treatments are most effective in subsets of patients at specific junctures in their treatment regimens. For example, the revised ASCO guidelines for treating NSCLC specify that, in second-line treatment settings, patients should be given docetaxel or, if they are EGFR-positive, Tarceva or Iressa.

The ASCO guidelines also specify that patients with non-squamous NSCLC are more likely to respond to treatment combinations that include the chemotherapy drug Alimta (pemetrexed), Masters says, while patients with squamous cancer are less likely to respond to that drug. “If you have non-squamous lung cancer but you don’t have a genetic mutation and you’re looking at chemotherapy, the combination of a platinum drug and pemetrexed is now the number-one choice,” Masters says.

Alimta is also now recommended as a standalone treatment for controlling non-squamous NSCLC after initial treatment, and though it has some of the side effects common in traditional chemotherapy, such as low blood counts, it has proven to be far less toxic than platinum-based chemotherapies. “It improves our ability to control those cancers,” Masters says. “It’s not curing the cancer, but we can treat those patients with maintenance chemotherapy and continue just the pemetrexed by itself and add to their quality of life.”

In small cell lung cancer (SCLC), which accounts for 15 percent of diagnoses and usually progresses very rapidly, there has been little progress in discovering and developing targeted treatments. The standard of care is chemotherapy and radiation, which is often used in a palliative setting. Although these treatments can be quite effective in the short term, most patients relapse within a few months.

That’s why oncologists are encouraged by early trials of immunotherapy treatments in small cell lung cancer. In one 2015 study, Keytruda was well tolerated in patients with PD-L1-positive SCLC and the response rate was 35 percent, though all the responses were partial. Another study testing a combination of Opdivo and Yervoy produced an overall response rate of 17 percent.

Some trials are now looking at the effectiveness of adding radiation to immunotherapy, in both small cell and non-small cell lung cancer. The idea is to use the radiation to release more tumor “antigens,” which are biological markers on tumor cells that trigger immune responses. “Radiation can also be a form of immunotherapy, so there has been a lot of interest in looking at combinations,” Rizvi says.

While oncology research is still a long way from a cure for late-stage lung cancer, the physicians treating the disease are optimistic that new treatments will help their patients to enjoy longer, more comfortable lives with the disease. “We have the potential to treat more people with lung cancer now,” Rizvi says, “and that’s really important.”