Question 1: Is there a reason to believe that these drugs are different from each other?
Abrams & Sharon: From our estimate, there are more than 700 trials on ClinicalTrials.gov, with the bulk of those trials (approximately 700) involving agents from the five leading PD-1/PD-L1 companies (Merck, BMS, AZ, Genentech, and EMD Serono/Pfizer). 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.
This may be subtly different with some of the agents. Avelumab from EMD Serono has a native-Fc receptor allowing for normal ADCC for its anti-PD-L1 antibody, whereas atezolizumab from Genentech has a modification which reduces ADCC. Since the mechanism of interference with the PD-1/PD-L1 axis may be slightly different, the efficacy may be different as well. This is as of yet unknown, however. At present, both the NCI and the companies generally pay attention to the literature and public announcements of trial results at major conferences. If one agent is shown to work in a particular disease, the competing companies will frequently take that as a signal that responses may be seen with their agents as well.
Allen: Early evidence certainly suggests that there is similarity between the efficacy and toxicity profiles of these agents. Perhaps there could be a baseline of key analytical or clinical characteristics identified for PD-1/PD-L1 drugs that, if met, could constitute a level of similarity that clinicians and patients would be comfortable with and, if different, could help indicate that the drug is not as similar to its competitors.
Bach: Lacking formal comparisons within studies or at least very convincing characterization of similarity each of these drugs will be presented as a unique product with its own advantages.
If the issue you are asking about is payment, insurers, including Medicare, will have challenges in treating them as interchangeable. If this is a clinical question, the prediction would be that the small differences in efficacy and toxicity might be below a scale that could be easily detected in cross study comparisons.
I want to flag a statistical issue for you here that could I think go unnoticed, but may end up being very important.
We usually think about multiple comparisons and multiple looks at sub-groups within a trial as scientific steps that increase the risk of false-positive results (the chance of finding an association or ‘effect’ that is a product of chance).
But anything that drives up the number of ‘looks’ can increase the risk of false positive findings, and that includes running hundreds of trials all at the same time. If you run hundreds of trials, some just due to chance will be positive even if there are no true effects.
The number is about one in 20 if the P value is <0.05.
In oncology, both approval and NCCN compendium listing can easily be triggered by a single positive trial, confirmatory trials are not the norm. So we run the very serious risk that compendia listings and approvals may be associated with false positive results that once codified, will never be re-tested because randomization after the result will be considered unethical and/or risk without benefit for the sponsors.
This problem is actually heightened by early stopping rules in trials, because it affects the timing, a false positive result early will result in unmasking, while a true negative result is just continued after an early look, so temporally the false positives, I would predict, would come out before the negative trials that might counteract it.
Of course, this problem is widely appreciated, but it is not obvious to me how even you could correct for the problem when the scale of studies numbers in the hundreds.
Jaffee: 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. There may be small differences, but these have not been determined as of yet. They all work by blocking the same pathway. It is possible that there are small differences in binding properties, for example, but these have not been identified based on response rates. There are differences between humanized and fully human antibodies—mostly toxicity differences. Fully human antibodies are expected to have less toxicity. Humanized antibodies will cause “allergic” type reactions that would not be expected from fully human antibodies. It is also possible that some of these have different isotypes (I am not aware of the isotypes of all of the antibodies in the clinic so I cannot specifically speak to this), which can alter their activity.
Ratain: There are biological reasons why there may be differences between PD-1 and PD-L1 inhibitors, since PD-L1 inhibitors should also inhibit the binding of ligands other than PD-1. Whether or not this will translate into differences in efficacy or toxicity is unknown.
Wolchok: Many of these are likely to be very similar. What we have seen in the admittedly imperfect context of cross-trial comparisons is that at least nivolumab, pembrolizumab, MDX-1105, and atezolizumab have generally similar profiles of toxicity and efficacy. It seems as if avelumab will also be in that same category. AMP-224 seemed to have more limited activity as a monotherapy. The VISTA antibody is likely to be different and the engineered cell products are also likely to be different biologically.
Question 2: Will this number of trials produce data showing how these drugs compare to each other and how they should be used?
Abrams & Sharon: In particular histologies that are being pursued by the major companies, such as non-small cell lung cancer, it may be possible to compare superficially across a number of trials to determine relative efficacy. However, it would be important to ensure that the patient populations are generally similar when comparing the agents. Subtle differences in populations may account for differences in overall survival rates or responses. Regardless, it would make sense to consider such an analysis only for large phase III trials in similar diseases and settings. Smaller trials are more subject to selection bias, which would make such comparisons difficult.
Allen: Not precisely, unless the trials begin to involve head to head comparisons and that seems unlikely in the short term.
Bach: I don’t see a lot of comparative designs in this list of trials, which is no surprise, really.
Competitors face huge risks and expenses running such comparative trials and the current system allows monopoly pricing without proving superiority, so why do it? 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.
Blanke: Indirectly at best, through cross-trial comparisons. There is little incentive for companies to pit their drug against a rival in a formal clinical comparison.
Jaffee: I do not believe these studies will be helpful in showing how the different PD-1 blocking antibodies compare. However, the different studies may help determine the best patient population and also the best combinations (for example, the best drugs or other antibodies to combine with PD-1 blocking antibodies).
Ratain: Cross-trial comparisons should not be used to make conclusions about differences between drugs. At most, they can generate hypotheses.
Wolchok: Since these trials are not formally comparative, any such conclusions will be subject to criticism as being cross-trial efforts. Nonetheless, the early result mentioned above suggest some learnings.
Question 3: In your opinion, which of these PD-1 and PD-L1 drugs are going to be the best? How could companies or other individuals tell whether their drug will be better than another drug? Is there a way to tell whether some of these drugs should not go past phase I?
Abrams & Sharon: It is possible that we will see one agent emerge as superior in a particular type of cancer, but to date, there has not been an overwhelming signal of this. For the five leading agents, there was no maximum tolerated dose found during the phase I trials.
Dosing for Merck’s pembrolizumab is instructive. The phase I trial expanded at the 2 mg/kg dose every 3 weeks, the 10 mg/kg dose every 3 weeks, and the 10 mg/kg dose every 2 weeks.
Merck’s internal analysis (presented at ASCO) showed no significant differences in safety, tolerability, or efficacy amongst those dosing strategies. Effectively, that suggests that a dose of 2 mg/kg every three 3 weeks was equivalent to a dose of 10 mg/kg every 2 weeks.
At steady-state, that would be a seven-fold difference in drug exposure. The affinities and dosing are different for the various agents, but there is a wide therapeutic window for PD-1 agents in general.
All of the leading companies have been moving to flat dosing with their more recent trials. The other companies that are still in early testing will likely have a wide therapeutic window to work with as well, and potentially similar efficacy and safety. Minor differences may turn out to have different results for those other agents, but thus far, these drugs have not been failing in the phase I setting, which is likely the reason for the continued investment in this area.
Currently, there are approvals for both pembrolizumab and nivolumab in metastatic non-small cell lung cancer and melanoma. Nivolumab has additional approvals for Hodgkin Lymphoma and renal cell cancer, but the pembrolizumab trials are not far behind.
Atezolizumab has an approval in metastatic bladder cancer, and other companies will follow suit soon enough. The preliminary data is not showing an overwhelming difference amongst these agents, but as the phase III data become available, we will get a chance to evaluate responses, toxicities, and overall survival.
For the papers and abstracts published thus far, differences have not been very significant.
Allen: I don’t think there is any way to know until they have actually undergone some clinical testing. It may be that rather than any drug being superior to the others, minor differences (perhaps in the spectrum of low-grade toxicities) could make one drug more tolerable/preferable to one patient, while another patient might do better with another agent in this class. Like any drug, if there’s a significant toxicity issue or no sign of activity, development should probably be discontinued after phase I.
Bach: I am not the best person to answer this question, but I am skeptical that this immense scientific effort is actually designed to answer that question, which is the most important one for patients.
Jaffee: I do not know which are best. So far the data suggests that they are comparable with the caveats mentioned in your question number two. Right now there are not great biomarkers to show who is responding and who will respond. Companies are looking for biomarkers to measure extent and duration of response to these agents. Biomarkers that are specific will help companies and others determine which are best and how best to use each. There is not a good way to tell if some should not go past phase I unless they do not show the same clinical activity in the diseases that are known to respond [245 trials are in phase I].
Ratain: There are insufficient data to draw reliable conclusions about differences between drugs. Conceptually, all PD-1 inhibitors are effectively biosimilar to each other—at least until there is reliable evidence to the contrary. The potential differences between PD-1 and PD-L1 inhibitors warrant a comparative trial, which could potentially be mandated by the payers (but funded by the companies) given the costs of these drugs.
Wolchok: As above, some of the more well studied ones seem similar. Unless there are changes to the Fc isotype of the mAb then it is not likely that anti-PD1 drugs that bind the receptor well will be markedly different.
Question 4: Should there be national leadership in command or in control that determines which of these drugs will not be viable? Why doesn’t anybody do that?
Abrams & Sharon: 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. Competitive pressures tend to determine which histologies will be pursued by the various stakeholders.
For example, there are phase III trials for all of the leading PD-1/PD-L1-targeting agents in non-small cell lung cancer. However, AstraZeneca, Genentech, and EMD Serono/Pfizer are not pursuing any indications in melanoma.
It is partially due to the fact that melanoma is a smaller indication, and partially because BMS and Merck are already well-established, but logic suggests that other similar agents could show some efficacy in melanoma.
The key here is that the PD-1/PD-L1 pathway is not just another target that happens to show some activity.
The broader oncology community is going to become an immunotherapy community.
Immunotherapy in cancer has a 100-year history, but in recent decades, it has been mostly at the fringes of drug development. The intramural program at the NCI was instrumental at sustaining investment in immunotherapy for most of the recent past when pharmaceutical companies were focused on other strategies.
The broad activity seen with PD-1/PD-L1 agents is changing all of that. This is a wave that needs to occur in order to benefit the broadest array of patients possible. The fact that industry is taking on this task frees up the NCI to focus on the most important questions that industry is either unwilling or unable to address on its own.
Currently, the NCI Cancer Therapy Evaluation Program has collaborative research and development agreements with AstraZeneca, BMS, Merck, and Genentech.
The NCI intramural program was also instrumental in the early trials with EMD Serono. These efforts are beginning to bear fruit. At AACR 2016, NCI-funded investigators from the Cancer Immunotherapy Trials Network presented the findings of our trial with pembrolizumab in Merkel cell cancer.
That small trial showed the highest rate of response to any PD-1/PD-L1 agent thus far seen in a solid tumor. At ASCO 2016, our anal cell cancer trial in the Experimental Therapeutics Clinical Trials Network showed a significant response rate for a disease that hasn’t seen progress in years.
We are conducting a sequencing trial through the National Clinical Trials Network trying to find out if BRAF-mutant melanoma patients should be treated first with BRAF/MEK inhibitors or with nivolumab/ipilimumab. These are all trials that industry was not approaching on its own for a variety of reasons, but the NCI has taken on those efforts and many more.
Immunotherapy is now seen as the most significant advance in cancer care in decades because we see that the immune system was an under-recognized player involved in a broad swathe of cancers. Cancer is enormously complex, but the easy work is screening all of these different settings and histologies and seeing where immunotherapy can be inserted.
The harder part is broadening the efficacy of these new therapies. Even if PD-1/PD-L1 therapies show efficacy in many different cancer types, for the overwhelming majority of those cancers, only a minority of patients benefit. Combinations seem like a worthy approach, and there are now efforts looking at combinations with other immune-related agents, such as immune stimulators, as well as combinations with other targeted therapies. Time will tell if those strategies will pay off.
In short, there isn’t currently a central control mechanism for oncology drug development, and central control is probably not desirable or beneficial in the long-term. The fact that more patients in more histologies may be tested is a good thing. Our focus at the NCI is on how we can serve as a catalyst and move the field forward through unique leveraging of our networks of academic investigators and our focus on high impact studies that complement the efforts of industry. We pay close attention to developments in the field and attempt to minimize duplicative efforts in indications already being pursued by similar agents, unless there are novel scientific objectives being pursued. Our goal is to push forward advances in the science that improve patient care and outcomes.
Allen: It could be helpful for a broad national strategy and key priorities to be developed. While this might be informative as to where to prioritize public and private resources, it would be difficult and perhaps inappropriate to actively enforce. As it relates to PD-1/PD-L1 drugs, the presence of so many products in the pipeline directed toward the same target is shifting toward supporting research of combinations, rather than just numerous monotherapies attempting to solely compete with each other.
Bach: The NIH director is calling for this kind of portfolio focus on clinical research funded by the federal government. It would, of course, be desirable to have some overarching plan here, although I am not certain it should either be centralized or overseen by the government.
Blanke: There are simply so many mechanisms for drugs to get to trial-pharma, IIT (say through a cancer center), publicly funded (cooperative groups). There is no overarching strategy nor agency in charge.
Jaffee: Very complicated question. We are still early in development. Each company has a different development plan that will provide important information concerning different cancers that respond to these agents, different combinations, etc. 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.
Pentz: That is not realistic, given the way the funding of the development pharmaceuticals in the U.S. is done. Pharma is the only one with money and resources to do this so every pharma company will want to be in the game. NIH cannot handle this in the current political climate.
Ratain: There should not be controls on the development of drugs because of concerns regarding duplication. In theory, having multiple similar drugs should lead to lower costs, particularly if the payers demand studies that provide reliable information regarding optimal dosing, optimal duration, and potential cheaper alternatives (i.e., if there are price differences). However, such studies should be funded by industry, and we should resist the temptation to utilize scarce NCI funds to support such comparative studies, unless the results would potentially lead to lower treatment costs.
Wolchok: Why doesn’t anybody do that? 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.
Question 5: Is there a common biomarker assay? Do these companies have uniform toxicity management? How will these drugs be studied in combination? How will they be studied in the adjuvant setting?
Abrams & Sharon: There are now three separate assays that have been FDA-approved as companion diagnostics for the three approved PD-1/PD-L1 agents thus far. At AACR 2016, four of the leading pharmaceutical companies along with two diagnostics companies, Dako and Ventana, compared their assays on non-small cell lung cancer tissue.
The results were broadly similar for the assays being developed by Merck, BMS, and AZ, but Genentech’s assay is slightly different and seems to highlight more of the PD-L1 expression in immune subsets of the tumor microenviroment as well as in the tumor itself.
This was only tested in non-small cell lung cancer, and there are no current plans to compare the assays in a formal matter in other histologies. However, it is important to remember that PD-L1 is not similar to BRAF mutations or RAS mutations, in terms of being present or absent.
PD-L1 may be somewhat prognostic, but it exists in a dynamic equilibrium as a ligand that is expressed in response to gamma-interferon production. When cancers are termed PD-L1-positive, they are subject to sampling bias and temporal bias. As a result, there are patients with PD-L1-negative tumors (by various cutoffs) that clearly benefit with PD-1 or PD-L1-inhibiting agents.
Even if the companies do find a concordance for their PD-L1 assays, as a field, we should be seeking other, better biomarkers that may be predictive of response.
While toxicity management is not uniform, it is clear that these agents have broadly similar toxicity profiles and management strategies are correspondingly similar as well. Pembrolizumab, nivolumab, and atezolizumab are now approved and in the community, and steroids are the mainstay of management of severe toxicity with other anti-inflammatory agents being deployed in severe cases of significant toxicity.
The companies on their own and in collaboration with the NCI are conducting a number of combination trials. The most obvious combinations include CTLA4 inhibitors, ipilimumab (BMS) and tremelimumab (AZ), but there are other combinations being conducted. In NCI networks, we are examining immunotherapy-angiogenesis strategies and combinations with other targeted agents, such as the CD30-targeting antibody-drug-conjugate, brentuximab vedotin in Hodgkin Lymphoma. In addition, the NCTN is evaluating a promising combination of nivolumab and ipilimumab and GMCSF, based on some early results with Steve Hodi, which showed synergy of GMCSF with ipilimumab. We are utilizing our earlier and extensive experience with ipilimumab to guide us, along with preclinical data where available.
The NCI is currently conducting or in the process of approving adjuvant trials in renal cell cancer, non-small cell lung cancer, melanoma, and others. The NCTN is uniquely suited to conducting adjuvant trials in collaboration with global partners, such as our colleagues in Europe through the EORTC.
Allen: In general, the potential for variability between tests that currently claim to measure the same alteration is something that the cancer community needs to address in terms of the appropriate level of regulatory oversight for diagnostic tests. This is likely to be a subject of debate for lawmakers in the year to come. The current PD-1 landscape demonstrates the complexity of multiple diagnostic tests, since different tests are being developed with different drugs. In addition to different tests, the role of measuring PD-1 expression is still not exactly clear.
With regards to differences in the toxicity management guidelines, our preliminary assessment shows that of the 11 common immune-related toxicities identified with currently approved PD-1 inhibitors, there is only 42 percent concordance among the recommended approaches for managing these toxicities. This is the subject of a new collaboration Friends of Cancer Research has developed with the Parker Institute for Cancer Immunotherapy to attempt to streamline the different toxicity management guidelines.
Jaffee: Toxicity management is very similar between companies. As [in my answers] above, no great biomarker. There is an immunohistochemistry assay, but it is not close to being perfect. We need a serum biomarker, preferably, that can be used during therapy to best optimize the agents and to determine how best to combine with other agents. These drugs are already being studied in combination and tumor biopsies are being taken pretreatment and during treatment to assess how these agents are working alone and in combination. Because PD-1 blockade has clinical activity, we look for enhanced clinical activity from the combinations. They are being studied in the neo-adjuvant setting, because we can see how the treatment changes the tumor before surgery. The only way to study in the adjuvant setting is to have an endpoint of disease-free survival.
Ratain: There are a variety of biomarkers being studied, some of which are highly exploratory. The general principles of toxicity management are similar across this class of drugs, but the specifics are appropriately variable, and will depend on the specific clinical context.
Studies of combinations of PD-1/PD-L1 inhibitors with other immune modulators are proliferating, but the challenge will be to demonstrate that the value of the combination will justify the expected financial toxicity. Again, the use of scarce NCI funds to support the development of unaffordable drug combinations should be questioned.
Wolchok: There are several PD-L1 expression assays, some available as companion diagnostics. However, none are binary predictors of outcome. Toxicity management seems to be similar, but there could be a central effort to harmonize that with experienced academic investigators leading it. Combinations are widely being explored, in varying ways. Again, some central philosophy to instill a precision approach to use combinations would be helpful. This requires knowledge of an individual patient/tumor’s immunologic ‘needs’ and a means to dynamically address those over time, such as when adaptive resistance occurs. Adjuvant studies are starting now. I believe the use of these medicines in the adjuvant setting is a strong ‘call-out’ to develop better and more sensitive measurements of minimal residual disease. This is starting, but not optimal yet. Ideally, adjuvant use of these medicines would be limited to patients with detectable residual disease, in an effort to spare others from potential toxicity and enhance value.[/su_spoiler]
[su_spoiler title=”6. How can these drugs be approved? Can FDA handle the onslaught of drugs?” style=”simple”]
Abrams & Sharon: If the drugs show a significant overall survival benefit and safety profile, then they will be approved if the data are available.
Allen: I don’t think that there is reason to believe that FDA will be a rate limiting step for availability of these drugs. Numerous Breakthrough Therapy Designations have been granted for drugs in this class and the development strategies and review periods have been rapid.
Bach: Yes, the FDA will have no problem keeping up, all the evidence suggests that, even with the rise in approvals we have seen in the past few years, the agency has gotten faster.
Blanke: There is no doubt the criteria for approval will continue to evolve.
Jaffee: The FDA seems to be handling it, but I am not the best person to really address this question. These drugs are already approved for a number of indications based on survival advantage.
Ratain: Given the similarities of these drugs, the FDA will have abundant information with which to make regulatory decisions. Sponsors should be aware, however, that adverse events occurring with any drug in the class will likely be imputed across the class. Thus, the large number of companies developing these drugs (some of which may have less experience than others) is a risk factor for the larger more experienced companies.
Wolchok: I don’t have a simple answer. The question will be complex and centered on how to prioritize their use based on efficacy, safety and value.
Question 6: How can these drugs be approved? Can FDA handle the onslaught of drugs?
Abrams & Sharon: This estimate is only a small fraction of the patients with cancer in the U.S. and the world who may benefit from checkpoint inhibitors.
If the trials show benefit, then this may not be too large a number. The NCI is actively working on new strategies for immunotherapy and other targeted agent trials. If PD-1/PDL-1 inhibitors become part of the standard of care and raise the bar on therapy, then we will continue to search for newer and better ways to help patients.
Allen: Patients are enrolling in these trials because they want access to the experimental agent, not the standard of care. This should be taken into consideration. There are legitimate reasons that randomized trials are still part of the development for these drugs, but with so much interest in the PD-1 space and the activity of these agents, creative approaches, like use of common control arms without direct comparisons, could help facilitate patient access and still support rapid development.
Blanke: This is a real concern. 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.
Jaffee: These agents are showing significant survival advantage with less toxicity than most other types of therapy (chemotherapy, radiation). These agents are showing durable responses – survival lasting years in metastatic disease. PD-1 pathway is just the beginning. We need to better understand all of the immune pathways involved in preventing the immune system from recognizing cancers. Patients want these agents because of the responses and the durability without bad complications. I do not think these agents are getting in the way of other treatments from being developed.
Pentz: Our biggest concern is the low number of adult cancer patients enrolled in clinical trials. If the immunotherapy drug trials are attracting participants, this is a plus. Clearly this is the hot area, but if the trials are well designed (I have no way of knowing if they are), all will contribute to our knowledge.
Ratain: We continue to have many more patients seeking novel immunotherapies than available studies. 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.
Wolchok: Quite possibly, yes. We do need to ‘fan out’ widely to seek biologically important subsets of patients who may respond to these medicines. 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?
Question 7: 166,736 patients are enrolled or will be enrolled in these clinical trials as of Sept. 9. Is that too many? Is the push towards PD-1 and PD-L1 drugs getting in the way of other trials or the possible development of other types of treatment?
Abrams & Sharon: No. Almost all the trials are coming from the five leading companies. The other companies are much further behind in their development. However, this is a good and useful therapeutic class of agents.
Cardiologists don’t complain that there are too many statins, and oncologists can likely manage a choice of PD-1/PD-L1 inhibitors. Over time, comparative effectiveness approaches with aggregated data from electronic medical records may help determine which agents may be the best overall, but these are early days for immunotherapy as a part of the standard of care in oncology.
The NCI recently faced a related issue with the Lung-MAP investigators. The approval of nivolumab in non-small cell lung cancer led the NCI and the Lung-MAP team to redesign their trial. They had to adapt, quickly, to avoid wasting patients’ time and NCI resources. If PD-1/PD-L1 agents show significant benefit, then other drugs have to be developed with that in mind. There is no reason to lower the bar. All other drug development efforts will need to take account of this new reality.
Allen: This doesn’t appear to be the case thus far, but it will likely add to the complexity as the field moves toward testing PD-1/PD-L1s in combination with other therapies.
Blanke: Hard to say. Depends on whether these are the best drugs or not!
Jaffee: Again, not my area of expertise. But I would guess that there are still not enough drugs that cause survival benefits with long duration to slow the process.
Pentz: There is no way to know which drug is best until we test them.
Ratain: It is not clear that any of the drugs in this class are superior to any of the others.
Wolchok: I’m not certain. My question would be whether the exploration of combinations would be expedited if individual companies did not have to spend resources and time generating their own foundational anti-PD-1 or PD-L1 as a combinatorial partner.[/su_spoiler]
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