Pharmaceutical companies are betting big on cancer immunotherapies that rely on the PD-1 protein and its ligands, PD-L1 and PD-L2, to initiate an immune response.
The rush to develop these agents is likely unprecedented in scale and scope, insiders say. A federal database lists 803 registered clinical trials testing 20 of these drugs. The trials, in various stages of completion, have slots for 166,736 patients.
To chart the full extent of this massive clinical development push, The Cancer Letter has compiled a table listing clinical trials of all the drugs in this category. The compilation includes information about all the trials reported in the government-run ClinicalTrials.gov database.
To understand the context, The Cancer Letter asked nine drug development experts to respond to a uniform set of questions about the science, regulation, economics, andethical considerations inherent in this push.
Some insiders question the wisdom of committing such vast resources—especially so many cancer patients—to trials that they say could be asking duplicative questions.
The studies focus on PD-1, PD-L1, and PD-L2 drugs as single agents and in combination with other immunotherapies, biologics, radiation, chemotherapy, vaccines, and surgery.
The agents act through the same pathway and have similar efficacy and toxicity profiles—enough so that distinguishing them from each other and determining sequences in which they should be administered will be a challenge.
The risks for sponsors are high.
Patent disputes over two of the three approved drugs have sparked lawsuits in the U.S. and around the globe. Litigants include competing drug companies Bristol-Myers Squibb and Merck, as well as Dana-Farber Cancer Institute, which is seeking partial ownership of Bristol’s patent.
Moreover, the similarity of the drugs in the pipeline could make the path to regulatory approval unpredictable.
Success is not guaranteed in these trials.
In August, Bristol-Myers Squibb announced that its PD-1 immunotherapy nivolumab (Opdivo) didn’t meet the primary endpoint of progression-free survival in patients with previously untreated advanced non-small cell lung cancer. The trial, called CheckMAte-026, investigated nivolumab as a single agent in unselected patients. The drug is approved for metastatic disease. The front-line results could have been different had patients been preselected based on biomarker status or had the drug been used in combination with chemotherapy.
PD-1 is a transmembrane protein on the surface of T-cells that controls the response T-cells have to other cells in the body. Cancers produce ligands that bind to the protein, which tell T-cells not to attack cancer cells. PD-1, PD-L1, and PD-L2 drugs typically stop ligands from binding to PD-1 proteins, allowing T-cells to attack cancers.
FDA has approved three agents—Bristol’s nivolumab, Merck’s pembrolizumab (Keytruda), and Genentech’s atezolizumab (Tecentriq). Other major pharmaceutical companies, including AstraZeneca, Pfizer, and Eli Lilly & Co., also have PD-1, PD-L1, and PD-L2 drugs in development.
Who Has the Most PD-1 Clinical Trials?
Bristol and Merck have secured many of the biggest indications.
Merck’s pembrolizumab is being tested in 337 trials and Bristol’s nivolumab in 222 trials. Merck’s drug accounts for 41.6 percent of trials, Bristol’s for 27.5 percent. AstraZeneca has 14.8 percent of trials, and Genentech has 9.6 percent. Other sponsors account for the remaining 6.5 percent of trials.
Of the 803 trials underway, two are in phase IV, 101 in phase III (including phase II/III trials), 426 in phase II (including phase I/II trials), 245 in phase I, and 29 in phase 0 or without a phase. The database was last accessed on Sept. 9.
Only eight trials compare two of the 20 PD-1, PD-L1, and PD-L2 drugs, nivolumab, and pembrolizumab, directly. One trial compares durvalumab and MEDI0680, both owned by AstraZeneca.
No government agency has the authority to regulate the allocation of patients to clinical trials.
“Our system does not allow for the government or any particular party to restrict or control the development of these agents, but the broad interest is significant,” said Jeff Abrams, NCI acting director for clinical research and associate director of the NCI Cancer Therapy Evaluation Program, and Elad Sharon, senior investigator in the CTEP Investigational Drug Branch. “Competitive pressures tend to determine which histologies will be pursued by the various stakeholders.”
The issue of the lack of coordination and obstacles to data-sharing—or “siloes”—figures broadly in Vice President Joe Biden’s moonshot initiative. On Sept. 7, the Blue Ribbon Panel, an NCI-run working group advising the White House initiative, presented a report to the National Cancer Advisory Board, recommending the creation of a national clinical trials network specifically focused on immunotherapy.
“I have never seen this before, where you have so much [development] activity in the same class of drugs,” Richard Pazdur, acting director of the FDA Oncology Center of Excellence, said to Newsmax, an online health publication. “Do we need all of these drugs in the same class? And should these resources—and I’m not only talking about financial resources, but I’m also talking about patient resources—be devoted to exploration of new targets and new therapeutic approaches?”
On another occasion, speaking with Reuters, Pazdur, who is also director of the FDA Office of Hematology and Oncology Products, said: “People should ask themselves, ‘Would we be better off spending those resources into looking at more novel drugs?’”
In another interview, with Peter Garrett, director of the Office of Communications and Public Liaison at NCI, Pazdur said that these therapies aren’t a sure thing. The interview was intended to be distributed internally at NCI.
“We’re early in the development of these treatments,” Pazdur said. “There are many questions that still need answers. Although many of the immunotherapy trials have shown impressive effects on overall survival in difficult-to-treat diseases, such as lung cancer and melanoma, we still don’t know which patients may optimally respond to a given drug.
“It’s estimated that approximately five percent of American patients accrue to clinical trials. A question we should ask is the reasons why patients are not entering clinical trials.
“I would like to see a greater degree of collaboration in the pharmaceutical industry with the development of these drugs, especially in biomarker development.”
Pazdur’s interview with Garrett is posted here.
Pazdur, who made these statements earlier this year, declined The Cancer Letter’s request for an interview. Pazdur isn’t alone in expressing unease about the high number of patient slots in ongoing trials.
“This is a real concern,” agreed Charles Blanke, chair of SWOG, a clinical trials group, and professor of medicine at Oregon Health and Science University. “As popular as the drugs are, it is hard to imagine accrual will be brisk to all trials, based on the number required alone. These are the hot drugs and seem to be currently favored over other agents.”
NCI’s Abrams and Sharon acknowledge that the PD-1 drugs appear to be similar.
“There are obviously some subtle differences in terms of agents that target PD-1 versus PD-L1, but by and large, if there is efficacy with one agent seen, then we have generally seen a similar range of efficacy with the other agents,” they said.
These trials are competing for some of the same patients, said Mark Ratain, the Leon O. Jacobson professor of Medicine, director of the Center for Personalized Therapeutics, and associate director for Clinical Sciences at the Comprehensive Cancer Center at the University of Chicago.
“We continue to have many more patients seeking novel immunotherapies than available studies,” Ratain said. “A concern, however, is that many of the studies are seeking the same population of patients, which does inhibit opportunities for discovery of novel indications.
“Competition is great when it results in price competition and savings for patients. In this context, many of the ongoing studies may be wasteful from the perspective of shareholders. On the other hand, if there is no impact on pricing, we will have systemic financial toxicity that will have unpredictable consequences to patients and employers.”
ClinicalTrials.gov lists NCI as a sponsor or collaborator on 94 trials.
“The use of scarce NCI funds to support the development of unaffordable drug combinations should be questioned,” Ratain said.
The promise of these treatments warrants an NCI role, counters Abrams and Sharon.
“The key here is that the PD-1/PD-L1 pathway is not just another target that happens to show some activity,” Abrams and Sharon said in their joint response to questions from The Cancer Letter. “The broader oncology community is going to become an immunotherapy community.”
Some researchers point out that the large number of trial participants that drug companies expect to accrue could help the patients get access to investigational drugs at no cost.
“It is clear that our most precious resource is our patients and that [we] should do whatever we can to accelerate new and better treatments to improve outcomes,” said Brian Druker, director of the OHSU Knight Cancer Institute. “But, if a side effect of the current number of immune checkpoint inhibitors in trials is that over 160,000 people will have access to these drugs in potentially promising combinations, with the cost of the medications borne by the companies, that might actually be of some benefit too.”
NCI experts say that the number of trials reflects the importance of these therapies.
“The estimate is only a small fraction of the patients with cancer in the U.S. and the world who may benefit from checkpoint inhibitors,” Abrams and Sharon said. “If the trials show benefit, then this may not be too large a number.
“It’s important to note that these agents are working, and we need to get them into routine care,” Abrams said.
The task of prioritizing these trials would be anything but straightforward, said Robert Cook-Deegan, a health policy expert and professor at Arizona State University.
“Everyone would be better off if there were some capacity for triage of the most important trials, although it’s an open question whether there’s a procedure to get enough consensus to design and select trials to address the most pressing questions quickly, while respecting the rights and interests of stakeholders,” Cook-Deegan said.
It may never be possible—and perhaps not interesting—to compare the safety and efficacy profiles of all the agents.
“Although there has not been a study that compares the different PD-1 blocking antibodies directly, the data so far show similar responses in patients with the same cancers,” said Elizabeth Jaffee, professor and deputy director of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. “There may be small differences but these have not been determined as of yet. They all work by blocking the same pathway.”
Has the number of ongoing trials and the number of patients slots become excessive?
Jaffee sees it as reasonable.
“Each company has a different development plan that will provide important information concerning different cancers that respond to these agents, different combinations, etc.,” she said. “There is a lot of room right now in the field to learn from these agents. They are active and work similarly, but are being tested in different ways. If we limited this approach, it will take longer to determine all of the indications for these drugs and all of the combinations.”
Coordination is necessary, said Jedd Wolchok, director of the Parker Institute at Memorial Sloan Kettering Cancer Center, chief of the MSKCC Melanoma and Immunotherapeutic Service, associate director of the Ludwig Cancer Center at MSKCC and the Lloyd J. Old/Virginia and Daniel K. Ludwig chair in clinical investigation.
“Why doesn’t anybody do that?” Wolchok said. “I think a summit amongst industry colleagues to discuss why there is a compelling need to develop so many similar products would be a first step. There could also be discussion of prioritization and impact of such redundant efforts when permission to test a new essentially bio-similar or fast-follower is proposed to a regulatory agency.”
Duplication in these trials could very well be occuring, he said.
“We do need to ‘fan out’ widely to seek biologically important subsets of patients who may respond to these medicines,” Wolchok said. “This is exemplified by the studies done in patients with mismatch repair deficiency. The question is what value is being brought to patients and the drug development research community at large by so many very similar agents entering trials?”
Linda House, president of Cancer Support Community, said the understanding of these drugs hasn’t evolved to a point where any of them could be described as “me too” agents, which makes it impossible for her to comment on whether the number of ongoing trials and patient slots is reasonable.
Sponsors need to broaden the range of data collected as part of trials, she said.
“Cancer Support Community continues to feel that patient-centered drug development should include patient reported outcomes beyond the traditional disease symptoms, treatment side effects and physical functioning,” House said.
Trials should include metrics that “matter most to patients.” Psychosocial metrics “would inform the community in a different way and could also provide an early signal which, when interventions are applied, could improve patient outcomes and improve trial retention,” House said.
“Given the current conversation on value and the development of value frameworks that do not include many elements of the patient experience (e.g., chronic, long-term side effects, out of pocket costs for travel to clinic, etc.), we should be utilizing data collection with over 160,000 patients to secure information appropriate to include in the frameworks and conversations,” House said. “Currently, the feedback on the frameworks is that the information is not included because it is not collected. We must change the current clinical trials process to ensure that relevant and meaningful information is included in the clinical trial.”
A few years ago, when a company wanted to study someone else’s drug in combination, it could either reach a cross-licensing agreement or simply buy the drug. With prices of new drugs at astronomical levels, the latter path—simply buying someone else’s agents—has become more difficult.
“One of the difficulties is that for combination therapy to occur, many companies feel that having their own drug will save them money in the long run, although other companies have developed broad partnership agreements,” said Druker. “There is little incentive for companies to pit their drug against a rival in a formal clinical comparison.”
According to industry figures, nivolumab, atezolizumab, and pembrolizumab are priced at around $150,000 per year. Nivolumab in combination with ipilimumab (Yervoy) is priced at $252,000.
Drug companies are generally reluctant to compare their drugs with those of their competitors, said Peter Bach, director of the Center for Health Policy and Outcomes at Memorial Sloan Kettering Center
“Competitors face huge risks and expenses running such comparative trials, and the current system allows monopoly pricing without proving superiority, so why do it,” Bach said. “The opportunity here to do cross-trial comparisons might come in doing individual level patient data analyses across the studies. Generally, the data in these studies is not made available by the sponsors for such analyses, but the trend appears to be, in part spearheaded by the journals, to make this type of data-sharing more the expectation than the exception. Regardless, it is doubtful the FDA would take regulatory action based on such analyses.”
Number of Trials Conducted in Common Indications
Nivolumab is approved by FDA for treating classical Hodgkin’s lymphoma, metastatic renal cell carcinoma, metastatic non-squamous non-small cell lung cancer, advanced metastatic squamous non-small cell lung cancer, and unresectable or metastatic melanoma. Nivolumab is also approved to be used with ipilimumab in melanoma.
Genentech has the only other FDA-approved PD-1 drug, atezolizumab. Atezolizumab is approved by FDA for treating urothelial carcinoma.