During summer 2015, Teri Kennedy was at a yoga festival in Squaw Valley, California, when she started to wheeze and had trouble breathing. The inhaler her doctor gave her didn’t help. When the then 51-year-old from Sacramento returned home, she went for an X-ray that showed a cloudy right lung. Antibiotics didn’t work, and her doctor called for more tests: a CT scan revealed a tumor the size of a fist in her right lung.
“I felt really good otherwise,” says Kennedy, now 54, a tennis player who enjoys power yoga, too. “I was very fit and active, never smoked, and am very conscientious about diet and exercise. But I do have some family history.” Kennedy explains that her father, aunt and uncle (all siblings) died of lung cancer and were never tested for any genetic mutations.
A few more tests showed the tumor was stage 4 non-small cell lung cancer (NSCLC) that had metastasized to her lymph nodes, bones and back vertebrae. Kennedy’s cancer had spread too far for surgery, so she began chemotherapy while waiting for DNA testing results.
Lung cancer is the second most common cancer among men and women in the United States, but it causes the most cancer-related deaths — more than colon, breast and prostate cancers combined. Although disease rates have declined alongside smoking rates, lung cancer is still responsible for 1 in 4 cancer deaths in the U.S.
NSCLC makes up about 85 percent of all lung cancers. The leading risk factor remains tobacco smoking, which accounts for approximately 80 to 90 percent of lung cancers. In addition, the risk of lung cancer or death from the disease is 15 to 30 times greater for those who smoke than those who don’t, according to the Centers for Disease Control and Prevention. The other major risk factors include exposure to radon gas and asbestos; cancercausing agents in the workplace, such as uranium and nickel compounds; secondhand smoke; air pollution, even indoor smoke from cooking oil; and family history. The five-year survival rate for stage 1 NSCLC ranges from 68 to 92 percent, but drops to 1 to 10 percent for stage 4.
Still, in the last decade new therapies have proven to be effective. Patients now have an ever-expanding range of options for treatment, including emerging therapies that combine chemotherapy with drugs that kick the immune system into action against the cancer.
EXPLORING COMBINATION IMMUNOTHERAPY
When cancer attacks the body, it switches off many of the immune system’s mechanisms for fighting it at certain so-called checkpoints.
“The human body has a system of checks and balances to regulate the immune response and prevent damage to healthy tissues,” explains Rafael Santana-Davila, M.D., an assistant professor at the University of Washington School of Medicine in Seattle. “Cancers take advantage of many of those checkpoints to evade the immune system.”
Immunotherapy attempts to switch those mechanisms back on to bring the body’s immune system back on board. In 2011, the Food and Drug Administration (FDA) approved Yervoy (ipilimumab), the first checkpoint inhibitor to target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which is a protein receptor that holds back immune response. Approved for unresectable or metastatic melanoma, Yervoy is being studied in patients with NSCLC. However, CTLA-4 isn’t the only pathway to explore. Programmed cell death protein 1 (PD-1) also plays a role.
“One of the main mechanisms by which the tumors evade the immune system is activation of the PD-1 pathway, which causes exhaustion of the T cells that are responsible for killing cancer cells,” explains Suresh S. Ramalingam, M.D., assistant dean for cancer research and deputy director of the Winship Cancer Institute at Emory University School of Medicine in Atlanta. “By blocking PD-1, now we know that we can turn on the anti-cancer immunity, which can cause tumor shrinkage.”
A protein called programmed death-ligand 1 (PD-L1) connects to the PD-1 receptor and puts the brakes on the immune system. Immunotherapy drugs called checkpoint inhibitors inhibit either the PD-1 checkpoint or PD-L1 to lift those brakes so the immune system can go after the tumor. One of the standard tests after a cancer diagnosis looks for the level of PD-L1 expression in the tumor. “If it’s really rich, then that provides the milieu where an immune checkpoint inhibitor will be very effective,” says Ramalingam.
Keytruda (pembrolizumab) was the first PD-1 checkpoint inhibitor approved by the FDA for first-line treatment of lung cancer in patients whose tumors have high expression of PD-L1, which is approximately 25 to 30 percent of patients with NSCLC. Now researchers are exploring whether the combination of immunotherapy with chemotherapy, or with other immunotherapy drugs, might lead to an even better response in patients with cancer.
“Combining checkpoint inhibition with chemotherapy has yielded positive results for patients,” says Daniel Haggstrom, M.D., an oncologist for Levine Cancer Institute within Carolinas HealthCare System. “For patients without a driver mutation and PD-L1 expression of less than 50 percent, the standard is to provide combination chemotherapy and immunotherapy, and if expression is greater than 50 percent, then immunotherapy alone. For patients who possess low or minimal PD-L1 expression, additional combination regimens are certainly on the horizon.”
New optimism came out of the phase 3 KEYNOTE-189 trial which showed a more than 50 percent reduced risk of death in patients with nonsquamous NSCLC without EGFR or ALK mutations when Keytruda was added to a chemotherapy combination of Alimta (pemetrexed) and either cisplatin or carboplatin in the frontline setting. At a median follow-up of 10.5 months, the estimated 12-month overall survival (OS) rate was 69.2 percent in the Keytruda group compared with 49.4 percent in the control group.
In the KEYNOTE-024 phase 3 clinical trial, two-year results presented late last year found that Keytruda more than doubled the median OS in patients with high PD-L1- expressing NSCLC compared with chemotherapy (30.2 vs 14.2 months). Keytruda also showed a better overall response rate, 45.5 percent compared with 29.8 percent in the chemotherapy group. Fewer side effects were also seen in the Keytruda group.
The KEYNOTE-021 trial’s cohort G found that combining Keytruda with chemotherapy led to a 55 percent objective response rate in patients with nonsquamous NSCLC, regardless of PD-L1 expression, compared with 29 percent who received chemotherapy alone.
“What we’re learning now is that PD-L1 status may not be the most accurate way to gauge a person’s response to immunotherapy, either in terms of the magnitude or the duration of response,” says Haggstrom.
Another biomarker gaining attention is tumor mutation burden (TMB). “Mutation burden is looking at the whole genetic makeup of the tumor and seeing how many total mutations are there, seeing if their tumor is high or low in mutation burden” says Ramalingam. “If the mutation burden is high, there is indication that immunotherapy might work well.”
A higher burden often means there are more neoantigens. These are altered proteins that may be more recognizable by the immune system, allowing it to identify tumors and produce specific T cells to fight the cancer. The CheckMate-227 trial, which involved more than 2,500 patients and examined the combination of Opdivo plus Yervoy versus chemotherapy, reported positive frontline treatment results for patients with a high TMB. Phase 3 data show the one-year progression-free survival (PFS) rate was more than triple with the combination versus chemotherapy (43 percent vs 13 percent). The overall response rate was nearly double and patients had fewer treatment-related side effects.
GOING BEYOND FRONTLINE TREATMENT
The fact that TMB is emerging as a helpful biomarker in immunotherapy also suggests alternatives for patients who don’t respond to prior therapies or who develop resistance to prior therapies. In Kennedy’s case, doctors found she had the EGFR gene mutation, which occurs in 15 to 20 percent of NSCLCs. She began Gilotrif (afatinib), a targeted therapy for EGFR mutations, which stops tumors from activating the gene and related growth factor receptors. Other mutations in NSCLC that have existing targeted therapies include ALK, MET, ROS1, T790M and BRAF.
Over the next nine months, Kennedy’s bone tumors calcified and disappeared and the primary lung tumor gradually shrunk to the size of a nickel. But then a scan showed more scattered small nodules in her lungs. That led to trying one therapy after another until Kennedy decided to try a combination immunotherapy on trial early this year. She qualified for the one remaining spot in an early clinical trial in Los Angeles that was testing investigational drugs INCAGN01876, a type of immunotherapy known as a GITR agonist, and epacadostat, an IDO1 inhibitor, with Keytruda.
“It was a ‘do it or the opportunity is gone’ situation, so I decided to try it,” says Kennedy. “With EGFR, immunotherapy is typically the last straw when you’re dying and your back is up against the wall. I was advised a toxic chemo combination had a much higher chance of being effective. I was feeling strong and my symptoms were manageable, so I thought, ‘OK, I’m going to go for it.’ If it didn’t work, I would know quickly enough and move on.”
Kennedy’s decision was scary because of past failures of immunotherapy with EGFR mutations, the risk of rapid progression of her cancer and the possibility of serious side effects. In February, she received her first infusion and dealt with flu-like symptoms — fever, extreme fatigue and achiness — but is now feeling better and recently learned from her doctor that she appears to be responding. Her trial is one of hundreds exploring various combinations of immunotherapy and other drugs.
Kennedy experienced extreme toxicity with some of her earlier regimens, requiring hospitalization for low heart rate and a severe rash. “My skin reacted like a chemical peel,” she recalls. She has been fortunate on her current trial. Toxicities can vary widely by drug, combination and patient. “By taking the brakes off the immune system, you unleash the ability of the immune system to be more effective against the cancer, but the downside to any immunotherapy is you run the risk of having the immune system attack healthy tissues, such as the colon, skin or the lung,” says Santana-Davila.
Rates of colitis or pneumonitis remain below 10 percent with a single agent, he adds, but combining agents brings those complications’ rates closer to 25 percent. Damage to the endocrine system and thyroid is another common risk, and combining chemotherapy adds its usual side effects, such as fatigue, nausea and blood count issues, to sometimes less predictable immunotherapy ones.
“Any organ you can think of can be affected if the immune system goes haywire,” says Sukhmani Padda, M.D., an assistant professor of medicine at Stanford University in California. “We need to be mindful of that, and we always counsel our patients to call us sooner than later if they’re having an unusual side effect, because it is important to catch these autoimmune toxicities early.”
Taking a very detailed medical history, especially for autoimmune conditions, is especially important for patients considering immunotherapy, says Padda. “At times of treatment decisions, we try to objectively evaluate what we think our patients can tolerate,” says Padda. “It’s always important to do no harm. We know our therapies have promise for activity and making patients feel better, but we also know that there are side effects for all of our therapies, including immunotherapy.”
Fortunately, doctors are learning more about what to monitor and how to treat it. “As these immunotherapy agents are being more commonly used, we’re learning the right questions to ask patients and knowing when to tell patients to contact their doctors,” says Haggstrom. “We’re much more deft at catching higher toxicities now.”
RESEARCH ADVANCING QUICKLY
About a half dozen clinical trials exploring combination immunotherapy in the frontline setting have started reporting promising results, most involving combinations with chemotherapy.
“We’re moving rapidly into an era of combination therapy for this disease and tailoring the chemotherapy to squamous and nonsquamous carcinomas,” Haggstrom says. “There’s still going to be enthusiasm for the combination immunotherapies, but currently there is a bit of an uphill climb to make those more efficacious than combos with chemo or a single agent.”
In late 2017, IMpower150, a phase 3 trial involving the immunotherapy drug Tecentriq (atezolizumab) and the tumor blood vessel-inhibiting drug Avastin (bevacizumab) with two chemotherapy drugs, became the first to show longer PFS for advanced nonsquamous NSCLC with frontline combination immunotherapy in patients without ALK or EGFR mutations.
“I’m really optimistic about how immunotherapy is going to help patients with cancer beyond where it is today,” says Ramalingam. “PD-1 inhibitors are clearly a breakthrough, and now we’re testing them not just in advanced stage cancers but in earlier stages and developing combination approaches.”
But there have been setbacks, too. The phase 3 MYSTIC trial tested Imfinzi (durvalumab) with or without tremelimumab — an immunotherapy drug not yet approved by the FDA for any treatment — against chemotherapy standard of care. Researchers found no PFS benefit to combining Imfinzi and tremelimumab compared with chemotherapy.
However, the PACIFIC trial found that Imfinzi monotherapy extended PFS by nearly a year in those with inoperable stage 3 cancer that had not progressed with chemoradiation. These findings led to the FDA’s expanded approval of Imfinzi for the treatment of patients with locally advanced unresectable stage 3 NSCLC. PACIFIC’s findings underscore how much there is to learn about immunotherapy alone or in combination with other treatments.
“It’s important for patients to understand that lung cancer is not one disease and that their physicians are going to be looking at all of these various biomarkers to tailor the right treatment for them,” says Padda. “Lung cancer has moved from a treat-all-patients-the-same-way to a very nuanced approach. Even though immunotherapy is a fantastic advance for NSCLC, it may not be the right step for a specific patient. It’s a very personalized approach.”
Ideally, findings from the KEYNOTE, CheckMate and other clinical trials will help doctors determine how to do that personalization.
“Developing biomarkers to determine who will benefit from which approach will be critical to how we use these clinical drugs in practice,” says Ramalingam. “Timing and sequences are critical questions that upcoming trials will answer.” Many questions remain too: How much does a tumor’s PD-L1 expression influence the level of response to combining one or more immunotherapy drugs with chemotherapy? Are there better biomarkers? What order of immunotherapy, chemotherapy and radiation therapy, or a combination of these, will lead to the best response rates? How does that answer change according to a patient’s biomarkers?
“There’s a lot more for us to understand,” says Padda. “Even though better biomarker-guided strategies are going to be much more prominent and identify more subsets of patients who will benefit from treatments, I do think chemotherapy is going to continue to play an important role, because we need to use as many tools in our toolbox as we can.”