After the many success of immunotherapy in various cancer types over the last few years, recent news of failures has come as a bit of a shock.
It was a bad day for AstraZeneca in July when stock shares plummeted by more than 16% —the highly anticipated results of the phase 3 MYSTIC trial in lung cancer failed to show that combination immunotherapy was more effective than standard chemotherapy.
The study used two immunotherapies — the PD-L1 checkpoint inhibitor durvalumab (Imfinzi) and the investigational cytotoxic T lymphocyte-associated protein 4 (CTLA-4) drug tremelimumab. The study compared durvalumab alone and in combination with tremelimumab against platinum-based chemotherapy as a first-line treatment in metastatic non–small cell lung cancer, but it failed to meet its endpoint of improving progression-free survival.
AstraZeneca’s setback fell closely on the heels of another negative study, this time the Keynote-040 study of pembrolizumab (Ketyruda, Merck) in head and neck cancer. This was a pivotal phase 3 trial, and it failed to show superiority for immunotherapy over chemotherapy in recurrent head and neck squamous cell carcinoma (HNSCC): It did not meet its primary endpoint of improving overall survival.
And just 2 months earlier, a third phase 3 trial also was unable to demonstrate superiority for immunotherapy. This time, it was Roche/Genentech feeling the sting. In the IMvigor211 study, atezolizumab (Tecentriq) failed to meet its primary endpoint of overall survival for patients with locally advanced or metastatic urothelial cancer.
The failure of these three trials came as a shock — they had been expected to turn out positive, as previous trials with other immunotherapies in the same indications had been positive.
But these few disappointing results do not signal the end of immunotherapy, said Ryan Sullivan, MD, a member of the Center for Melanoma and Termeer Center for Targeted Therapy at Massachusetts General Hospital and a member of the Melanoma Program at the Dana-Farber Cancer Center, Boston.”There’s been tremendous progress, and the disappointment that people may be having over these recent results is a little bit like complaining about a clogged drain — -a first-world problem, basically,” he told Medscape Medical News. “For lack of a better way of describing it, what we’re seeing now is a ‘next level’ problem.”
Dr Sullivan noted that in melanoma, there really weren’t any therapies that were particularly useful. “We occasionally gave high-dose interleukin-2 to the patients who we thought could survive it, and sometimes people were cured,” he said. “But the great majority weren’t.”
“When the immunotherapies came on the market, we began to get greedy and think we could cure a substantial minority of patients,” Dr Sullivan explained. “But now we see that we need to look at different factors — who are the patients most likely to benefit, what combinations might work, or how should we give sequential therapy.”
In the oncology community, we now see that we are capable of activating the patient’s immune system to destroy the cancer.
Despite recent setbacks, data have emerged across several cancer types, including melanoma, showing that immunotherapy can work. “In the oncology community, we now see that we are capable of activating the patient’s immune system to destroy the cancer,” he said. “And that is an amazing statement because up until about 6 or 7 years ago, no one outside of those caring for melanoma patients or those with renal cell cancer believed that was true. Or even possible.”
“We have gotten over the most important hump, proof of principle,” Dr Sullivan added. “We can do it.”
Sizzling-Hot Field
Immunotherapy is a sizzling-hot field in oncology, and one that has scarcely been tapped. It has been referred to as a “miracle in the making” and a “game changer.” The media spotlight on immunotherapy also heightened considerably after pembrolizumab successfully treated melanoma in former president Jimmy Carter, who is currently completely free of cancer.
But all advances in medicine have their fair share of hits and misses, and immunotherapy is no exception. Along with the recent misses, which generated much coverage in mainstream media, there has been a degree of questioning among some experts regarding immunotherapy clinical trials and the race to produce more therapeutic agents.
Harnessing the Immune System
The idea that the body’s innate immune system could be harnessed to fight illness is not really a new one. Active immunotherapeutic approaches in the form of vaccines were introduced in 1796, when Edward Jenner used vaccination with cowpox to induce immunity to smallpox.
Using immunotherapy for cancer also dates back more than 125 years, when William Coley, MD, a surgeon working in New York City, advocated that the body’s response to infection could have an antitumor effect. (Iowa Orthop J. 2006;26:154-158). His work was primarily in bone and soft-tissue sarcomas, and during his tenure as head of the Bone Tumor Service at Memorial Hospital in New York, he injected more than 1000 cancer patients with bacteria or bacterial products.
Despite successes reported by Dr Coley and other physicians, his work was criticized by many who did not believe his results, and along with the advent of radiation therapy and chemotherapy, the use of bacterial agents gradually disappeared.
However, the paradigm of cancer care is rapidly changing because of recent advances in genomic technologies, and immunotherapy has become part of the drive for more personalized, more effective, and less toxic treatments. But while initial efforts of trying to use vaccines and other therapies to coax the immune system into destroying tumors was met with limited success, it does seem that the tide has finally changed.
Immunotherapy has been approved as a treatment for several cancer types, and current strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and the use of antibodies or recombinant proteins that costimulate cells or block the immune checkpoint pathways.
The checkpoint inhibitors have attracted the most attention. They include drugs that block CTLA-4, such as ipilimumab (Yervoy, Bristol-Myers Squibb) for melanoma, and drugs that block programmed cell death protein 1 (PD1), including nivolumab (Opdivo, Bristol-Myers Squibb), pembrolizumab, atezolizumab, avelumab (Bavencio, Pfizer), and durvalumab. These PD1 inhibitors have been approved for a variety of cancer types, including non–small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin’s lymphoma.
These checkpoint inhibitors are projected to generate as much as $50 billion per year.
Clinical trials for new agents and combinations are now taking place at an almost breathtaking pace. By some estimates, more than 1000 trials are ongoing, involving more than 100,000 patients. In 2015, for example, 1 of every 22 studies registered on ClinicalTrials.gov involved immunotherapy.
However, only a fraction of patients are benefitting. While some patients experience a dramatic response with these agents, the reality is still that only 20% to 40% will respond to immunotherapy, and responses are often not durable. Another issue is cost, as the new immunotherapies coming out of the pipeline are hugely expensive and will be unaffordable and out of reach for many patients.
Thus, it is not surprising that there has been some pushback and criticism, especially levied at the pace with which trials are being conducted.
Time Out for the “Gold Rush”?
A recent editorial in the Lancet Oncology has raised concerns over the seeming “gold rush” in immunotherapy. The editors point out that some opinion leaders are now calling for a halt in the number of studies being conducted.
“Many argue that this gold rush, which has seen most pharmaceutical companies aspiring for their own versions of immune-targeting drugs, is suffocating research, is leading to trials being done in haste without sufficient preclinical investigation, and is an inefficient use of funds spent on research and development,” they write.
Even though the interest in immunotherapy seems unprecedented, the Lancet editors remind readers that the same scenario took place with the advent of targeted agents, such as the epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors, and the potential they held as new drugs. This led to far too many “me too” versions of these drugs, the editors comment.
“Although competition is an effective means to reach a goal quickly, too much can lead to developments delivering diminishing returns and patients losing out through inefficient use of limited resources,” they write.
Are pharmaceutical companies moving too fast and therefore not putting enough time and research into investigating why a trial succeeds or fails?
Investor and analyst Brad Loncar, who also runs the Loncar Cancer Immunotherapy Index, which tracks the combined performance of a basket of companies that develop these therapies, told Medscape Medical News that companies may be moving faster than the scientific knowledge at hand.
“So I don’t know if they are moving too fast per se,” he said, “But some trials are being started with less preliminary information and scientific rationale than would normally be the case.”
Laura Q.M. Chow, MD, associate professor of medical oncology, University of Washington School of Medicine in Seattle, agrees that trials can be better designed.
“We could use biomarkers to better select patients,” Dr Chow said in an interview. “We also need to understand why patients become refractory or why they are not responding.”
The immune system is exceedingly complex, and immunity is influenced by tumor, host, and environmental factors that dictate the anticancer response to therapy. More investigation is needed to better coordinate patients with a therapy most likely to help them, “rather than just throwing everything into trials and hoping that something works.”
I suspect some of this is going to be wasted money.
“There are a huge number of trials going on and I think we’ve hit a plateau, and I suspect some of this is going to be wasted money,” Dr Chow noted. “We may see a lot of negative trials. There may be one or two winners, but I think it’s a long time coming before we see those results.”
“The key is to do really good early and phase 1 trials so as to understand all the dynamics,” she added, “And not hesitate to kill a drug and/or a combination if it doesn’t look good. It’s wrong to do a phase 3 study based on almost no phase 1 information.”
The “Me Too” Issue
The “me too” issue is one that has garnered attention both in oncology and for other medical conditions, but Loncar explained that this is part of the future for immunotherapy. “Cancer is going to be treated by a combination of drugs, and that will become the standard in a few years,” he said. “And this becomes a major cost issue because these therapies are very expensive, and that’s not sustainable.”
Instead of paying for each drug separately, they need to be offered in a combination package, much like the way it is done for hepatitis and the HIV cocktails. “These are marketed and priced as one package,” Loncar said. “But the only way this can be done is if you own all the components. Companies that are developing the PD-1/PD-L1 drugs realize that they will be in big trouble otherwise, as they can’t price a combination using someone else’s product.”
This is one reason for the so-called race to produce similar products, Loncar contends, and it has much to do with commercializing and designing their own combinations. “Whether this trend is good or bad I can’t say, but it makes sense for both patients and society, in that they will be able to sell their drugs in a more rational way.”
Another reason for tempering the frantic pace of trials is the associated adverse events. While different from those observed with cytotoxic drugs, immunotherapy-related events can also be serious. As the Lancet editorial notes, many of the oldest trials that now have at least 5 years of follow-up are seeing a wide range of unusual side effects that require different supportive interventions. Last year, for example, Juno Therapeutics permanently pulled the plug on a trial after five patients died of cerebral edema following treatment with JCAR015, an investigational chimeric antigen receptor T- cell agent.
“These findings emphasize the importance of accruing sufficient data before launching another trial, especially if the new study combines multiple immune-targeting drugs, each with unknown safety profiles,” says the editorial.
Finally, clinical trials cannot be run if there is a lack of patients to enroll. With over 1000 clinical trials and counting, the supply of eligible patients, and those who have access to even participate, falls short of the demand.
According to a recent article in the New York Times, many of the major medical centers have declined to enroll patients in the “me too” trials that are testing PD-1/PD-L1 inhibitors in the same cancers. The Yale Cancer Center in Connecticut is one example — it participates in fewer than 10% of the immunotherapy trials it is asked to join.
Roy Herbst, MD, chief of medical oncology at Yale, stated that these studies are uninteresting from a scientific view and that the “companies sponsoring these trials are not addressing new research questions. They are trying to get proprietary drugs approved.”
To test a combination therapy, GlaxoSmithKline spent more than a year searching the United States, Japan, South Korea, and Europe to find 59 patients whose tumors met their criteria. Similarly, Pfizer spent 3 years searching for 50 patients with lung cancer tumors that harbored ROS1 fusions.
Hits and Misses
Inconsistencies in trial results have demonstrated just how much remains unknown about immunotherapy.
Last year, Bristol-Myers Squibb suffered a fate similar to that of AstraZeneca, when its shares fell by 26% after nivolumab failed as a first-line monotherapy for lung cancer.
In contrast, Merck’s pembrolizumab was successful in producing results superior to those from chemotherapy, for the same indication.
But last year, nivolumab proved superior to standard chemotherapy in patients with platinum-refractory recurrent or metastatic HNSCC, while pembrolizumab failed to meet its endpoint in this setting.
In the lung cancer trials, Dr Sullivan sees these “disappointments” more as a failure of the trials than a failure of the drugs. “They did the wrong trial,” he said.
“Nivolumab and pembrolizumab are essentially the same drug,” Dr Sullivan said. “They have the same toxicity profile, and when you’re treating the same disease, they produce similar outcomes.”
Comparing two trials head to head does put a different spin on things. “In one trial, there was a very high bar of PD-L1 expression while the other trial had a much lower bar,” he said. “The one that used a high bar was a positive trial and changed how we view front-line therapy in lung cancer. The other trial used a lower bar, which, quite frankly, wasn’t very wise.”
In lung cancer, there are going to be patients who benefit from immunotherapy and those who don’t. Using a bar of high expression of PD-L1 (at least 50% of tumor cells) is a “pretty good discriminant of who’s going to benefit and who isn’t,” he noted.
Unlike melanoma, non–small cell lung cancer does have another effective therapy: chemotherapy. “It’s not awesome, but it’s pretty good,” he said. “It’s way better than anything we had for melanoma. So when we compared immunotherapy to chemotherapy in melanoma, we didn’t have to call out the patients who were most likely to benefit from PD-1 therapy across the whole population. But in lung cancer we do need to do that.”
Overall, it was a painful and expensive lesson for Bristol-Myers Squibb. “They ran the wrong trial and failed to understand who the best population was,” Dr Sullivan said. “So I would say that it wasn’t disappointing but rather expected.”
AstraZeneca’s recent failed MYSTIC trial of durvalumab and tremelimumab combination therapy could be considered a disappointment, but “truthfully, we should be going beyond the idea that we have two drugs so let’s put them together and see what happens,” he said. “And the silver lining on combination therapy trials not meeting their endpoint is that we should be figuring out ahead of time who is the best population. It requires a keen understanding of the immune system, understanding the mechanism of the PD-1 drives, and of the preclinical data.”
Moving Forward
Loncar noted that it is important to view this from the long-term perspective. “Drug development takes a long time, with many successes and failures,” he said. “Just think of where we were 6 years ago when there were no approved immunotherapies. This is something that will play out.”
The MYSTIC trial may also yet pan out, he said. “These are interim results, and there were very good responses,” he pointed out. “Sometimes it just takes time for the curves to separate.”
He also feels that this is probably the peak of trials, and the “next round” may be smaller and more precise.
Jeffrey Weber, MD, PhD, deputy director of the Perlmutter Cancer Center at New York University Langone Medical Center, feels that in the future, “we are going to be more in the era of biomarker and personalized immunotherapy. There’s no doubt about it.”
“I think we will finally be developing vaccine strategies that will work, which have not been very useful up until now,” Dr Weber told Medscape Medical News.
Drug development doesn’t seem to be an issue. “There are so many new drugs being developed now, and that will probably continue, but the real issues are better approaches and better biomarkers,” he said. “We are in need of better biomarkers so we can choose the patients who are most likely to benefit. We are not doing a great job of doing it now and we need to do better in the future.”
Dr Chow feels that there needs to be more dialogue among the pharmaceutical companies. “Combining tumor samples and having pharma companies collaborate and talk to each other would really be helpful in trying to figure out what is going on with the patients,” she said.
Because the current drugs work only in a small percentage of patients and have had success in only a few types of tumors, some research is now looking at ways to increase the applicability of these drugs. One is the promising concept of “hot” vs “cold” tumors.
Checkpoint inhibitors appear to be most effective in highly mutated tumors that are “hot” — highly infiltrated with immune cells. However, most human tumors are “cold,” so the challenge would be to convert cold tumors to hot ones.
Therefore, if the paradigm could be shifted, then checkpoint inhibitors would conceivably be effective in a dramatically larger patient population.
One small study now shows that a transition from cold to hot is feasible. An innovative vaccine known as HS-110 (viagenpumatucel-L), combined with nivolumab, produced objective responses in 5 of 15 patients with non–small cell lung cancer in a phase 1B trial.
“Three of the five patients went from cold to hot, so they had a clinical response, and a transition was also made,” said Jeff Hutchins, PhD, chief scientific officer and senior vice president of preclinical development at Heat Biologics, the developer of HS-110. “We now have an ongoing phase 2 trial.”
Dr Hutchins acknowledged that their results are in a very small population. But it means that 60% of the patients who responded to therapy have experienced significant tumor reduction, which is higher than the 10% response rate of patients with cold tumor, who generally respond to nivolumab alone.
“This approach lends itself to all tumor types,” he said. “We had an earlier program for bladder and prostate, and we are waiting for approval in the front-line setting before moving ahead with that.”
At this point, it is difficult to identify the patient population who may derive the most benefit from this strategy, “but probably those with low PD-1/PD-L1 expression and those who have cold tumors,” he said.
“If immunotherapy was a baseball game, we are in the second or third inning, and have a long way to go for a cure,” Dr Hutchins added. “Unfortunately, the majority of patients don’t have the luxury of waiting and need multiple and sustained strategies to get that cure.”
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