Into the Future

CUREImmunotherapy Special Issue
Volume 1
Issue 1

For some with lung cancer, immunotherapies are sparking long-lasting responses.

When she started treatment for allergies, Maureen O’Grady had no inkling that she was about to become a medical pioneer.

That journey began in 2008, when allergy treatment failed and she continued to battle congestion, cough and, especially, shortness of breath. The situation became more alarming when she coughed up blood. Soon thereafter, radiologic tests detected a large mass in her right lung.

“My first oncologist offered me no hope and told me I had 12 to 18 months to live,” says O’Grady, 62, of Milford, Conn., who was diagnosed with advanced-stage lung cancer at age 56 in January 2009. “I changed doctors. I knew I couldn’t change my diagnosis, but I could change the way I was treated.”

Despite a stage 4 diagnosis — with the metastatic cancer in her adrenal glands, liver and heart — she refused to give up. When one form of chemotherapy failed, she tried another and yet another, then enrolled in clinical trials. “I knew it was risky, but I was fighting for life,” O’Grady says.



Maureen O'Grady, who responded well to Opdivo after being diagnosed with advanced-stage lung cancer, stands with her husband, Tom O'Grady, and a banner depicting a graffiti-style wall that she and other cancer survivors painted.

Finally, she credits an early-phase immunotherapy study with her long-term survival. The drug Opdivo (nivolumab) — which works by taking the brakes off the immune system, allowing it to fight harder against cancer, and which had previously been approved for the treatment of melanoma — “has reduced and stabilized all areas of disease, with no new growths,” says O’Grady, who received the treatment from June 2010 through June 2012 at Yale Comprehensive Cancer Center in New Haven, Conn. “Physically, I’m feeling well and remain cautiously optimistic, as there is little, if any, history for this drug for lung cancer. I’m one of its pioneers.”

Based on promising results of a multi-center phase 3 trial known as CheckMate-017, the U.S. Food and Drug Administration in March approved Opdivo injection for the treatment of lung cancer, the first immunotherapy to be given the green light in this disease. Opdivo is indicated when metastatic squamous non-small cell lung cancer (NSCLC) has progressed during or after standard platinum-based chemotherapy.

A Quantum Leap Forward

Results of the trial were presented May 29 during the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. As one of the most common forms, NSCLC represents about 85 percent of cases. A subtype of this malignancy — squamous cell NSCLC — accounts for an estimated 25 percent to 30 percent of all lung cancers. For those with distant tumors caused by lung cancer that has spread to other organs, the five-year survival rate is only 4 percent, according to the National Institutes of Health.

While the earliest stages of lung cancer can often be treated with surgery alone with a reasonable chance of cure, they constitute only 15 percent of cases. In most instances, cancer has spread to the lymph nodes or the chest by the time it is detected. More than half of patients are diagnosed in stage 4, when the cancer has already metastasized to distant sites and surgical excision is no longer possible; these cases are not considered curable, though transient responses can be seen with chemotherapy, or when certain mutations are present in the tumor and biological therapies are given initially.

On a global scale, lung cancer claims more lives than any other type of malignancy, resulting in 1.59 million deaths each year, according to the World Health Organization’s latest statistics, released in February. Tobacco use is the most significant risk factor, causing about 70 percent of lung cancer deaths worldwide.

Hope has been offered via a number of immunotherapies recently approved, or being tested, in patients with the disease.

Like Opdivo, Keytruda (pembrolizumab) targets PD-1, an inhibitory T cell co-receptor, or PD-L1, a ligand expressed on the tumor. Interactions between PD-1 and the ligands PD-L1 or PD-L2 are believed to suppress the antitumor immune response. Immune checkpoint inhibitors are intended to impede those interactions, activating T cells — the white blood cells powerful enough to destroy cancer cells.

Keytruda is being tested in a phase 3 trial of patients with PD-L1-positive NSCLC; already approved for the treatment of melanoma, it’s being considered by the FDA under a breakthrough therapy designation, meaning the agency will expedite its review.

Yervoy (ipilimumab), too, is a checkpoint inhibitor approved for the treatment of melanoma, but it works a bit differently, by quieting the CTLA-4 checkpoint on T cells so that they can better fight cancer. It is being tested in phase 3 trials in both NSCLC and small cell lung cancer. Another CTLA-4 antibody, tremelimumab, is in phase 2 testing in patients with mesothelioma.

Immunotherapeutic vaccines include GV1001, which targets telomerase and is being tested in a phase 3 trial in patients with stage 3 NSCLC that can’t be removed surgically. Finally, adoptive T cell transfer is being considered in phase 2 lung cancer trials; this involves removing T cells from a patient, engineering them in a lab to be more active in the fight against cancer, and re-infusing them.

“Immunotherapy is a game-changer, a breakthrough that oncology desperately needs,” says Guneet Walia, director of research and medical affairs at the Bonnie J. Addario Lung Cancer Foundation in San Carlos, Calif. “For the first time, we can begin to talk about long-lasting effects and start thinking about using the ‘C word’ — for cure.”

A tumor doesn’t necessarily need to shrink for a patient to benefit from immunotherapy. “It’s a very important time for patients,” says Roy S. Herbst, a professor and chief of medical oncology at Yale Comprehensive Cancer Center. “Even if the tumor doesn’t change in size, it often stops progressing. Patients live longer because they have a slower progression of their disease.”

What’s unprecedented is, even after the patient stops the treatment, the immune system continues to police cancer cells and mount rigorous attacks. The discovery of immunotherapy is “a quantum leap forward, a moonshot,” Walia says, “adding to our arsenal of agents that are active against even the most intractable cancers for which patients didn’t have many options, especially after their disease progressed upon treatment with the current standard-of-care therapies.” So far, only 20 to 30 percent of cancer patients seem to respond to immunotherapies, and researchers are working to find out why, and how to make the most of the treatments.

PD-L1: An Important Biomarker

Determining which characteristics may predispose patients to derive the most positive outcomes from immunotherapy “is an area of intense investigation that could enable oncologists to deliver the treatment to more patients who could respond successfully and potentially live longer,” says Stephen V. Liu, an assistant professor of hematology/ oncology specializing in thoracic oncology at MedStar Georgetown University Hospital in Washington, D.C.In CheckMate-017, Opdivo demonstrated markedly improved overall survival compared with chemotherapy in previously treated metastatic squamous NSCLC. Due to the promising results, the study was terminated early, with the FDA deciding to approve the drug more than three months ahead of schedule. Among the 272 participants in the randomized trial, the median overall survival (OS) was 9.2 months in the group of 135 receiving Opdivo versus six months in the group of 137 using the chemotherapy drug docetaxel. Another measure, known as the hazard ratio, calculated a 41 percent decrease in the risk of death for those in the Opdivo group.

Based on the results of a separate phase 3 study, Opdivo is also showing promise in patients with non-squamous NSCLC, and is pending FDA approval for the treatment of that disease type.

In the two trials, investigators noticed differences in the groups of patients who benefited from the drug.

In non-squamous patients, stronger OS outcomes were observed in those who were PD-L1—positive, including a 60 percent reduction in the risk of death for those with the highest PD-L1 levels. But in patients with squamous NSCLC, outcomes favored nivolumab regardless of PD-L1 expression.

Also of note in those with squamous NSCLC was that “there is a subset of patients whose benefit lasts far greater than nine months,” says Liu. “We can’t identify those patients at the beginning, and that’s something that we need to be able to do.”

In the future, with a more reliable biomarker, the response rate may reach 80 percent among patients deemed eligible for the drug, “but we’re clearly not there yet,” says Renato G. Martins, medical director of thoracic, head and neck medical oncology at the Seattle Cancer Care Alliance and a professor of oncology at the University of Washington School of Medicine.

Might PD-L1 have played a role in the response of those excellent Opdivo responders in the squamous NSCLC group? Researchers aren’t yet sure.

“PD-L1 is not a perfect biomarker,” Liu says. “There are multiple ways to detect PD-L1 and different ways to do the test. We’re still learning how to use this marker.”

There is more evidence that the marker is a predictor of successful treatment when the investigational immunotherapy atezolizumab (MPDL3280A) is used in NSCLC.

When compared with docetaxel chemotherapy in the phase 2 POPLAR study, atezolizumab doubled the likelihood of survival in people whose immune cells or advanced NSCLC tumor cells expressed the highest levels of PD-L1. People who had lower levels of PD-L1 expression also benefited from atezolizumab with an improvement in survival; those without any PD-L1 expression had a similar survival with either atezolizumab or docetaxel.

In February, atezolizumab received breakthrough therapy designation from the FDA. Approval is being sought for the treatment of those whose NSCLC, either squamous or non-squamous, expresses PD-L1, and who progressed during or after standard treatments, such as platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease.

Robert “Bob” Schoenbauer, for one, has benefited greatly from the drug.

In late 2013, the now 80-year-old from Waldorf, Md. began coughing, then experiencing shortness of breath and feeling fatigued into the following year. Initial tests in Maryland weren’t definitive, and he and his wife of 60 years, Frances, suspected a winter cold as the culprit, yet were concerned that his worsening condition could be more serious. In March 2014, he was diagnosed with stage 3B NSCLC — a very aggressive form affecting the lungs and lymph nodes; long-term survival isn’t normally expected.



Robert Schoenbauer (second from the left) poses with his wife, Frances, and the bride and groom at a grandson’s wedding.

Schoenbauer entered a trial at Georgetown in which he received weekly infusions of atezolizumab in combination with two chemotherapies, carboplatin and nab-paclitaxel. After three months on this regimen, he has been receiving only atezolizumab every three weeks for about a year in the ongoing phase 1b trial. Investigators still don’t know whether his cancer expressed PD-L1, because that information was blinded as part of the trial.

Almost immediately, Schoenbauer began responding to the immunotherapy administered jointly with chemotherapy. Even his doctors couldn’t believe how quickly his tumor shrank, he says. As for side effects, there were hardly any except for hair loss on his head and body. “Once in a blue moon, I’d get a little tired, when I first started doing the chemo,” Schoenbauer recalls. For the time being, there is no evidence of cancer on his radiologic scans. “I feel absolutely great right now,” he says.

Beyond the expression of PD-L1, there are other biomarkers that indicate who might be a good candidate for immunotherapy.

While the treatment strategy works on both smokers and never-smokers with lung cancer, studies have shown that a higher presence of mutations in the genome — which is typically associated with smoking — correlates with a better response to treatment.

Timing and Other Concerns

“Smokers’ genomes are typically associated with higher mutational loads due to exposure to carcinogens in cigarette smoke and, therefore, may respond better than nonsmokers — an example being the promising effects of immunotherapies seen in squamous cell lung cancer and small cell lung cancer, both of which disproportionately affect smokers,” Walia says.Lung cancer isn’t one disease; it’s a constellation of many different diseases. Comprehensive genomic profiling or a specific molecular diagnostic test may pinpoint an underlying biomarker that, even before the evolution of immunotherapy, had meaning in determining how to treat the disease.

In some cases, a mutation means a patient’s lung cancer is likely to respond to a targeted drug, such as Tarceva (erlotinib), which treats NSCLCs with certain EGFR, or epidermal growth factor receptor, mutations. In those situations, it would typically make the most sense to use targeted treatments before considering immunotherapy, oncologists say. Logically, immunotherapy would come into play after resistance to a targeted drug develops — at least, that’s the thinking at the moment.

“For now, we reserve immunotherapy for use after the standard treatment is not working. But introducing immunotherapy earlier and earlier makes sense. We want to use our best drugs first,” says Georgetown’s Liu. “Targeted drugs have changed the landscape of non-small cell lung cancer, but while they’re very effective, they do not work forever. Eventually, these cancers develop resistance, so using these immunotherapy agents before resistance sets in is really appealing and may be able to provide longer periods of control. But the optimal sequencing of how to use these drugs? We simply don’t know yet.”

Immunotherapy doesn’t work for everyone. About 70 percent to 80 percent of cancer patients don’t respond. Others gain only modest benefits, while overall survival and longterm effects are still unknown. “But this must be considered in light of the fact that these patients don’t really have many options, so any positive effect is a good effect,” says Walia.

That’s only one of the concerns about the use of immunotherapy.

The drugs can cause side effects; with Opdivo, for example, they most commonly involve shortness of breath, fatigue, musculoskeletal pain, cough, decreased appetite, constipation and nausea. The most serious side effects are immune-related and affect healthy organs, potentially including the colon, liver, lung, kidneys and hormone-producing glands, according to the FDA.

Combination regimens of more than one immunotherapy are under evaluation. Administered either concurrently or sequentially, they are more likely to cause toxicities, in some cases severe enough to warrant hospitalization. Many patients also drop out of clinical trials due to serious or lifethreatening complications, Walia cautions.

Patients and their caregivers also should be prepared for a phenomenon called “pseudoprogression.” It’s a false alarm that the disease is progressing when it isn’t. This occurs when immune cells infiltrate tumors to mount an attack, inflating the tumor’s volume before causing it to shrink. The good news is, in most instances, patients with greater pseudoprogression tend to respond better to immunotherapy, she says.

Then there are the high costs of immunotherapy, compounded by the fact that it’s not yet clear how long patients should keep taking these drugs.

As combination regimens of immunotherapy and other standard-of-care regimens continue undergoing investigation, scientific data will increase, Walia says, helping to answer the question: “Are we delivering enough value for the cost? Do four-, five- or 10-month additions in progressionfree and overall survival justify six-figure costs?”

Despite those concerns, oncologists express continued optimism about immunotherapy’s untapped potential. “We do have patients in whom the disease hasn’t returned after they’ve stopped therapy,” Martins says. “Time will tell what that means, but that is not something we used to see with other treatment.”

Herbst, of Yale Cancer Center, adds: “For lung cancer, immunotherapy is really a new paradigm. Actually, for all tumors, immunotherapy is truly revolutionizing the way we care for cancer — using the body’s own immune system to target a tumor.”

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