Checkpoint inhibitors can be extremely effective for the right patients, but identifying who will benefit remains an imprecise science.
BY MEERI KIM, PH.D.
T.J. and JEN SHARPE searched for immunotherapy clinical trials to treat his stage 4 melanoma. - Photo by KIM RUOFF
One weekend in August 2012, while his wife and two children visited family out of town, T.J. Sharpe was stuck at home nursing a high fever that just wouldn’t quit. He tried every trick in the book to lower his body temperature — Advil, Gatorade, soup — but it continued to spike up to 103.8 degrees Fahrenheit.
Sharpe reluctantly went to his local hospital’s emergency department, where a doctor told him an X-ray showed spots on his lungs that were likely cancerous. Over the next few days, tests confirmed the presence of tumors in his lungs, spleen, liver and abdomen. What Sharpe assumed would be a quick trip to the emergency department led to a diagnosis of stage 4 melanoma and a 16-day hospital stay.
“I was originally diagnosed with stage 1b melanoma that I had removed when I was 25 years old, and then 12 years later I get diagnosed with stage 4,” says Sharpe, a resident of Fort Lauderdale, Florida. “It was a difficult diagnosis, since my son was only 4 weeks old at the time.”
Sharpe lost 30 pounds in two weeks, had the large tumor in his abdomen removed and started researching the best course of treatment. His initial oncologist offered chemotherapy, which was then a standard, but said he’d be surprised if Sharpe survived two years. For the 37-year-old husband and father of two young children, that prognosis simply wasn’t good enough.
“My wife and I had a couple of friends who were familiar with the pharmaceutical space, and they knew that there was a ton of good research being done on immunotherapy, especially with checkpoint inhibitors,” Sharpe says. “We continued to look for something better than chemotherapy and eventually found two clinical trials that could give us the response that we were hoping for.”
Unlike traditional treatments such as chemotherapy or radiation therapy, immunotherapy helps stimulate a patient’s own immune system to fight cancer. Many types exist, but the most promising options for patients across a wide array of cancers today include immune checkpoint inhibitors. The job of proteins called immune checkpoints, such as PD-1 and CTLA-4, is to prevent the immune system from being overly aggressive in attacking invaders, but cancer cells can also use them to hide. When checkpoints are blocked with inhibitors, the immune system becomes more aggressive and can do more to kill cancer cells.
Many experts believe that checkpoint inhibitors have the potential to fight cancer more effectively and with fewer side effects than traditional therapies. “Immune checkpoint blockade was initially thought to be a narrow therapy confined to melanoma, and it wasn’t even completely clear if it worked in melanoma, so why should the average oncologist care about it?” recalls Jeffrey S. Weber, M.D., Ph.D., deputy director of Perlmutter Cancer Center at NYU Langone Health in New York City. “But then PD-1 and PD-L1 blockade worked well in melanoma and in other cancers, and so now it finally has respect. It’s a major sea change in the way people with cancer are treated.”
Sharpe was initially treated by Weber in a clinical trial at Moffitt Cancer Center, in Tampa, Florida, that combined the CTLA-4 inhibitor Yervoy (ipilimumab) with tumorinfiltrating lymphocyte therapy. The latter immunotherapy type involves multiplying a patient’s own tumor-fighting T cells in a lab and then infusing them into the body so they can work as an army to fight cancer.
Unfortunately, the trial didn’t work out for Sharpe as he had hoped. Four months in, CT scans revealed that three out of his five tumors had grown, and some new tumors had appeared. But Sharpe is not alone — in fact, just 20 percent of patients with advanced melanoma achieve long-term overall survival with Yervoy.
Research has found that better responses generally occur with checkpoint drugs that inhibit PD-1 or PD-L1 (another protein) as opposed to CTLA-4. But even with these drugs, the rate of response varies from 15 to 65 percent, depending on the cancer type and treatment setting (first-line versus later-line therapy for metastatic disease).
An active area of cancer research involves finding out why these often very effective drugs work for just a minority of patients. So far, there are a lot of questions and not very many answers.
For instance, ideally, patients would get tested for various biomarkers before treatment to predict their individual clinical response to many different checkpoint inhibitors. While a couple of biomarkers have been identified, an extensive test does not yet exist, so how should doctors assess patients’ eligibility for these novel therapies? And what does the future hold for checkpoint inhibitors and finding related biomarkers?
“By studying tumors from patients who are treated and by studying events ongoing in their blood, we hope to be able to find more highly predictive biomarkers,” says Suzanne Topalian, M.D., associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University in Baltimore. “A combination of factors may need to be tested in order to give us a better idea of which patients are likely to respond.”
CONSIDERING PATIENT SELECTION
Doctors do have at least some information to go on. Whether and when an oncologist decides to use a checkpoint inhibitor for treatment depends largely on the kind of cancer involved. Some types, such as head and neck cancer, stomach cancer and Hodgkin lymphoma, have effective therapies that do not include immunotherapy, so checkpoint blockade would typically not be employed as first-line treatment, although that’s being explored in clinical trials.
For instance, one trial is testing chemoradiation with and without the PD-1 inhibitor Keytruda (pembrolizumab) in patients with locally advanced head and neck squamous cell carcinoma. Other subtypes of the disease — for instance, prostate cancer and pancreatic cancer — have not so far responded to checkpoint inhibitors.
On the other hand, advanced melanoma lacked good treatment options in the past, so when checkpoint inhibitor immunotherapy began to show efficacy, physicians jumped on it. Even in melanoma, where immunotherapy has shown great promise, a large number of factors come into play when deciding on a particular treatment plan: What stage is the cancer? Has it been surgically removed?
Has it spread throughout the body? Is there evidence that it is rapidly growing? Does the cancer express a BRAF mutation, making it likely to respond to a targeted drug? Does the patient have time to try a second or third option? All those considerations must be taken into account.
As with many cancer therapies, trying these treatments without knowing if they will work comes with risks in the areas of both health and financial cost. Immunerelated side effects of PD-1 and PD-L1 inhibitors include fatigue, nausea, rash, diarrhea, cough, itching, decreased appetite and musculoskeletal pain. And although physicians want these drugs to be available to all patients who need them, treatment regimens with checkpoint inhibitors can cost hundreds of thousands of dollars. One doctor estimated that a combination treatment involving two drugs would total $300,000, with the patient’s out-of-pocket cost being upward of $60,000.
Combining checkpoint inhibitors with other immunotherapies or traditional treatments may be the key to improving the probability and quality of response. A recent analysis of eight studies found that higher values of response, survival and time until disease progression were observed in combination therapy compared with single-agent therapy. Already, the FDA has approved Keytruda in combination with chemotherapy for previously untreated metastatic nonsquamous non-small cell lung cancer, as well as the PD-1 inhibitor Opdivo (nivolumab) plus Yervoy for adults with metastatic melanoma.
And studies are being conducted on a variety of combinations across cancer types. For example, a reduced dose of Yervoy combined with Keytruda, has demonstrated promising results in patients with melanoma and renal cell carcinoma. Other trials are examining checkpoint inhibitors used in different combinations or together with cancer vaccines, chemotherapy, radiation and T-cell therapies.
“Right now, most of our clinical trials involve giving new drugs in combination with one of the PD-1 inhibitors,” says Beth Buchbinder, M.D., a medical oncologist at Dana-Farber Cancer Institute in Boston. “We have a really exciting trial in lung cancer and melanoma that takes a piece of the tumor to the lab, where we create a vaccine out of it. If the patient isn’t getting a good response after surgery and Opdivo, then we can add the vaccine as a backup plan.”
Meanwhile, Topalian and others continue to research ways to deliver precision immunotherapy that is tailored to individual patients. Physicians hope that the discovery of robust biomarkers will pave the way for this type of treatment in the future. “Today, we sometimes make a seat-of-the-pants assessment in terms of trying a checkpoint inhibitor, but I think in the future, there will be less art and more science,” Weber says. “If we had biomarkers to predict outcome with great accuracy, we could take a blood sample and then (be able to tell) our patients who will do well and who won’t.”
Two biomarker tests now exist to guide doctors about a patient’s response: PD-L1 and a genetic fingerprint called microsatellite instability (MSI). A PD-L1 test requires sending a piece of tumor tissue to a lab that measures how much of the protein it expresses. Patients with tumors high in PD-L1 are more likely to respond to checkpoint blockade, although those lower in PD-L1 could still see a response. MSI is a biomarker that signifies whether the cancer has many or few gene mutations, and those with many — MSI-high cancers — seem to have a greater likelihood of response to checkpoint inhibitors. In fact, the FDA has approved Opdivo for metastatic colorectal cancers that are MSI-high and have progressed after other treatments, as well as Keytruda to treat any metastatic, MSI-high solid tumor that progressed on previous treatments. Now, scientists are exploring the use of drugs that might cause cancers to express more mutations, thus making them more responsive to immunotherapies.
Neither biomarker test is perfect, however, and there doesn’t always seem to be a direct correlation between the result and an individual patient’s response to anti-PD-1.
Also, test results could change over the lifetime of a tumor or even based on the location from which the tissue sample is taken.
“I think a lot of these tests are helpful but not yet to the point where you would make a patient decision based off of them,” Buchbinder says. “Eventually, there might be some algorithm where you combine all of these factors to help pick immune therapies, but we’re not quite there yet.”
Meanwhile, researchers are in the midst of discovering and testing immune checkpoint proteins beyond CLTA-4 and PD-1/PD-L1. Other targets with drugs in development include IDO, LAG3, KIR and TIM-3. “There are probably two or three dozen different checkpoint pathways, and they are all unique. Some of them act early in the immune response against cancer; some of them act later; some of them act together,” Topalian says. “There is a lot of very interesting scientific research going on and much we still need to learn about how these pathways work.”
Sharpe, who discovered that his cancer responded to one type of checkpoint inhibitor but not another, is a case in point.
Although disappointed with his results in the clinical trial of Yervoy, Sharpe wasted little time feeling sorry for himself and began looking into a plan B. In April 2013, he joined a clinical trial of then-experimental Keytruda. By July, his follow-up CT scans showed that the overall tumor size had shrunk 30 percent, and more than half of the tumors from his last scan were no longer seen. After remaining on Keytruda for years, Sharpe received his last dose in August 2017 and is now considered cancer-free.
Sharpe, who doesn’t recall his tumor ever being tested for PD-L1 expression, is not certain why Keytruda worked for him when Yervoy didn’t. One possibility he discussed with doctors is that Keytruda reinforced the tumor-infiltrating lymphocytes that remained in his system from the first trial.
He may never have a definitive understanding of why, but Sharpe credits his survival to the Keytruda clinical trial and feels extremely fortunate that he was eligible to participate. Still, his journey isn’t over, and he now dedicates much of his life to helping other patients educate themselves about cancer. He has written 200 posts detailing his battle with melanoma for a Philly.com blog called Patient #1 and serves as a patient expert consultant to the biopharma and clinical research industries.
“When my first oncologist told me I had less than two years to live, it really gave me the motivation to look at the pictures of my two young children and say, ‘That’s not good enough for me,’” Sharpe says. “People are going to live long, happy, healthy lives because immunotherapy and checkpoint inhibitors were able to activate their immune systems to fight cancers that would have otherwise killed them.”