June 13, 2019 -- Not long ago, only about five out of 100 people were expected to be alive 5 years after a diagnosis with an advanced form of lung cancer. Today, up to four times more live that long, thanks to treatments that help unleash the immune system to attack cancer.
These so-called immune checkpoint blockades have revolutionized cancer care, putting immune therapy on par with chemotherapy, radiation, surgery, and targeted therapies as a cornerstone of treatment for many tumor types.
“Without this, many, many, many more patients would have died,” says Allison Betof Warner, MD, PhD, an oncology fellow soon to be on the melanoma faculty at Memorial Sloan Kettering Cancer Center in New York City. “It’s a complete game changer for the diseases for which it works.”
But the success of these drugs has raised patient expectations about how much they will benefit. And if 20%-30% are given a long-term reprieve, that means 70%-80% still die of their disease.
Being a patient today is “certainly better than it was 5 years ago -- but definitely still a lot of work needs to be done and a lot of progress needs to be made,” says Mark Awad, MD, PhD, clinical director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School.
Providing patients with “realistic expectations is by far the most important thing that we can do as oncologists,” Betof Warner says. “Immune therapy is an incredible tool. But it’s not a magic bullet.”
For well over a century, doctors have dreamed of using the immune system to fight off cancer. If the immune system, once trained to recognize a virus like the measles, can protect against it for a lifetime, why can’t it do the same with cancer cells?
The answer, scientists realized after decades of research, is that cancers can manipulate the body’s immune system. Sometimes, tumors trick the immune system into stepping on the brakes instead of attacking when faced with cancer cells.
Checkpoint blockades may remove this brake, helping the body’s defenses mount a successful and long-lasting attack.
The FDA has approved seven checkpoint blockades that treat more than a dozen types of cancer, including melanoma, non-small-cell lung cancer, kidney cancer, and some types of colorectal cancer. Given alone, the drugs haven’t been shown to help many patients with advanced tumors of the pancreas, brain, and prostate, though they may eventually be part of a cocktail of treatments for these tumors.
Breast cancer had been looking even more promising. In March, the FDA approved checkpoint inhibitor Tecentriq, from biotech company Genentech, to treat metastatic triple-negative breast cancer, which is often lethal. But in one recent trial, treatment with Merck’s drug Keytruda failed to extend the lives of women with late-stage triple-negative breast cancer.
The checkpoint drugs took off in the early years of this decade, beginning with the approval of Yervoy for melanoma in 2011. The second type of blockade, including drugs like Keytruda and Opdivo, provided more than double the benefit of the first drug, Yervoy.
The assumption then was that improvements would keep on at that rate -- helping 20% of patients, then 40%, 60%, and 80%, says Drew Pardoll, MD, PhD, director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins Medicine in Baltimore.
Instead, improvements over the last 5 years have been more gradual.
In advanced melanoma, about 30% to 40% of patients still get no benefit at all from checkpoint inhibitors, say Keith Flaherty, MD, a melanoma specialist at Massachusetts General Hospital in Boston.
Roughly another third of melanoma patients get great early results, but then the drugs stop working, Flaherty says. The tumor apparently figures out how to take a different path to shutting down the immune system.
No one understands why. New research suggests this recurrence strikes patients whose tumors shrank at first on checkpoint inhibitors but didn’t disappear completely.
Regardless of their results on the therapy, patients and insurance companies are charged a lot of money for these immune therapies. According to one 2015 estimate, for instance, Opdivo costs just over $100,000 for a typical patient. With a 20% copay, that will run a patient $20,000. And side effects happen nearly as often in people who get little benefit from the drugs as those who benefit long-term, Awad says.
“We really have no way of predicting who’s going to develop which toxicity, but almost every organ has the potential to be involved,” he says, including the thyroid, nerves, skin, and digestive system. The vast majority of these side effects are reversible with early treatment or, in more serious cases, stopping the immune therapy, he notes.
Combinations Can Be Better, But Which Ones, and for Whom?
If a single checkpoint blockade drug doesn’t work, it may be because the cancer has stepped on more than one brake. To get around this, some patients are given two checkpoint blockades. The side effects are multiplied, though -- and often terrible -- while the combo doesn’t seem to do much for melanoma patients, Flaherty says. For them, each checkpoint blockade alone is better than the two together, though it’s hard to tell in advance who will benefit from which drug.
Other drugs and combinations may help deliver more gas to the immune system or push on its metaphoric gas pedal, revving it up to kill tumor cells. The so-called microenvironment right around the tumor seems to affect the immune system’s ability to fight, and researchers are still figuring out how to read and manipulate that ecosystem, Sloan Kettering’s Betof Warner says.
Padmanee Sharma, MD, PhD, a professor and researcher at the University of Texas MD Anderson Cancer Center in Houston, says scientists have so far focused on manipulating T cells, often described as the soldiers of the immune system. But the immune system is incredibly complex, with different routes for turning itself on to fight off invaders and off to prevent over-reactions that can lead to autoimmune disease.
“We shouldn’t assume that we’re done with understanding the basic science,” says Sharma, whose husband and colleague, James Allison, shared a Nobel Prize last year for work that led to the development of the first checkpoint inhibitor, Yervoy.
The immune system may also react differently, depending on where the tumor started, so a patient whose cancer started in the skin might need a different immune therapy than one whose cancer started in their bones, she says.
Yet another current hurdle: A lot of the research attention on checkpoint blockades has been redundant, proving the same basic findings again and again rather than pushing the science forward, Pardoll says. Other studies are simply pointless, he says.
What needs to happen, Flaherty says, is more careful research combining drugs like top sellers Keytruda and Opdivo with other treatments -- such as chemotherapy, targeted therapies, and other immune approaches like vaccines -- to see what works and how the approaches work at the molecular level. The results are likely to be different for different cancers -- and maybe different stages of cancer, he says, noting that most research so far has focused on end-stage cancer.
Gradual Improvements Are Better Than None at All
Pardoll says the scientific understanding of cancer and the immune system continues to improve and will eventually lead to better results for patients -- both in terms of longer life and fewer therapies that won't help.
“Science is creating a huge number of very promising new targets, new approaches, and also new insights in what I like to call precision immunotherapies,” he says, including indicators that will help doctors choose which patients are most likely to respond to a given combination of treatments.
But it isn’t easy to be a patient in the current climate, he and other doctors say, because it’s not known which drugs will help which patients and for how long. Hope can be crucial for someone getting cancer treatment, but irrational hope can be damaging.
If people are disappointed in immune therapy’s results now, it’s mainly because these checkpoint blockades “have been the most impactful [treatments] in the history of cancer therapy,” Pardoll says. “But you don’t hit a grand slam every time you come to bat.”