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About five or six years ago, the emergence of PD-1/L1 inhibitors triggered a burst of fanaticism in the field of cancer treatment, which can use the immune system to fight cancer by relieving tumor suppression of the human immune system.

For a small number of patients, checkpoint inhibitors, including PD-1/L1 inhibitors, are extremely effective. Probably many oncologists will have a hard time forgetting the first time they used PD-1 inhibitors to successfully treat patients with dying lives.

“I still clearly remember the appearance of the patient and remember the name of the first patient responding to the PD-1 inhibitor, which was more than six years ago,” Kim Blackwell said. Blackwell, a former breast cancer doctor at Duke University Medical Center, is currently working on Lilly’s early drug development and tumor immunity research.

 

Six checkpoint inhibitors have been approved for use in the treatment of melanoma and many other types of cancer. For some patients and doctors, the efficacy of this class of drugs is indeed very good, can make the tumor disappear completely in many patients.

But despite this, checkpoint inhibitors are still only effective for a small number of patients. However, many researchers in the field of cancer have long recognized that PD-1 inhibitors will become the cornerstone of tumor immunotherapy, so pharmaceutical companies are also looking for combination therapies that can be combined with such drugs to improve checkpoint inhibitors. Efficacy and response rate.

After that, the field has also fallen into a state of madness. The motivation for pharmaceutical companies to enter the tumor immunocombination therapy is also easy to understand, because Keytruda and Opdivo have a wide range of indications, and the market for combination therapy is also very large.

At the same time, biotech companies can make their share price soar even if they have very preliminary data confirming that their immunotherapy can improve the efficacy of checkpoint inhibitors. Some small companies that are engaged in the development of oncology drugs may be acquired by other pharmaceutical companies at an appalling price even without sufficient data.

The upsurge in the field of tumor immunity has made the drug research and development pipelines in this field extremely crowded, which has led to a sudden increase in the number of clinical trials, and has also made drug development in this field extremely complicated.

According to data from the National Cancer Center, more than 250 tumor-immune-related drugs have entered clinical research as of September last year. At the same time, there have been more than 1,100 clinical trials of PD-1/L1 combination therapy, and among them, the combination of tumor immunotherapy drugs, targeted drugs and chemotherapy drugs accounted for a large part.

Since 2014, the number of combined therapy clinical trials for joint checkpoint inhibitors has increased dramatically

However, the exploration of tumor immunocombination therapy is not smooth. In fact, some failed cases have emerged in this field. The most influential of these is the failure of a combination of experimental drugs from Keytruda and Incyte.

 

Setback of IDO

 

Over the past few years, large pharmaceutical companies such as BMS have spent billions of dollars looking for drugs that have the potential to improve the efficacy of checkpoint inhibitors. These drugs can be roughly divided into three categories: drugs that can further relieve immunosuppression; drugs that activate the immune system; drugs that can regulate the microenvironment near the tumor, making it more conducive to T cell attack.

 

Among the targets of this series of tumor immunotherapy, there are few popular targets like IDO. Previous studies have shown that IDO inhibitors are ineffective and do not inhibit tumor growth.

However, with the advent of checkpoint inhibitor development, many people believe that the use of another drug that can relieve immunosuppression enhances the efficacy of checkpoint inhibitors. Therefore, researchers are also pinning their hopes on IDO inhibitors.

 

Between 2014 and 2015, large pharmaceutical companies spent more than $1 billion to acquire stakes in IDO inhibitors. The number of pharmaceutical companies that have been developing IDOs in the next few years is also growing rapidly. By the beginning of this year, there have been more than 10 clinical studies evaluating the efficacy of the combination of Keytruda or Opdivo with IDO inhibitors. Nine of these are related to Incyte’s epacadostat.

 

These studies are largely based on data from Phase I/II clinical studies of epacadostat and Keytruda with fewer than 60 participants.

While some pharmaceutical companies have doubts about the mechanism of IDO inhibitors in this process, they have opted out of the field. First, Genentech returned the benefits of a drug from Newlink to Newlink, and Pfizer stopped working with iTeos.

 

In April of this year, Merck and Incyte announced that a phase III clinical trial of epacadostat in combination with keytruda for the treatment of melanoma failed. It is also because the melanoma involved in this study is the most responsive cancer to tumor immunotherapy, and the failure of this clinical trial has also frustrated confidence in IDO inhibitors across the field. Many large pharmaceutical companies quickly stopped research and development projects related to drugs.

Although epacadostat is not the first drug to fail in the field of tumor immunotherapy, it has indeed caused a major setback for tumor immunocombination therapy for the first time.

Although the Phase III clinical trial of the combination of chemotherapy with Chemtruda in April this year has demonstrated significant advantages in this combination, the combination of checkpoint inhibitors with other immunotherapeutics has not yet seen signs of success.

The frustration of IDO inhibitors is also important for those who want to advance the research of combination therapy. Because of the combination of oncolytic viruses, cytokine-related drugs, and other combination therapy therapies such as STING agonists that activate the innate immune system, there are also booms and bubbles in financing. Many people worry that these areas will also Frustrated by clinical trials.

At the ASCO meeting a few days ago, Nektar Therapeutics/BMS published data on Phase I/II clinical trials of combination therapy with NKTR-214 and Opdivo. Compared to previously published data, the response rate for melanoma decreased from 64% to 33%. %, RCC’s response rate dropped from 71% to 20%. Although still early clinical trial data, the number of patients enrolled is small, but the results still cast a shadow over the future of NKTR-214/Opdivo combination therapy and even cytokine combination therapy.

Of course, there are a lot of people after the incident, saying that some clinical trial failures of IDO inhibitors can actually be avoided. But to avoid these failures, you need to climb over three mountains as much as possible.

 

Three mountains

At present, there are three major problems in the field of tumor immunotherapy: first, how to evaluate the efficacy of drugs before entering clinical trials; secondly, to find suitable biomarkers; and finally how to design clinical trials more rationally.

Animal model

Preclinical studies of tumor immunotherapy drugs are difficult to determine, largely due to the nature of such therapies themselves. Unlike chemotherapeutic drugs or targeted drugs, these drugs can act on the immune system, not the tumor itself.

 

The problem is that the predictive value of current animal models of tumor immunotherapy for drug efficacy is unknown. In many cases, researchers do not know how to effectively evaluate whether a drug can work before conducting a clinical study.

Cancer in mice is easy to treat because it seems that all drugs can work in a mouse model, and it is not difficult to treat cancer in mice. The problem is that even if the tumor shrinks in the mouse, it does not mean that the drug is really effective.

Although the quality of animal models has improved in recent years, the predictive value of animal models for tumor immunotherapy drugs is still not as high as that of other therapeutic animal models.

 

Basically, people are pushing drugs into the clinic based on conceptual theories and hypotheses. These hypotheses can only be verified after waiting for clinical trials. It is easy to imagine that in this way, the drug development rate will not be low.

 

The immune system is very complex, and everyone has long been very clear, but the progress of clinical research has clearly exceeded our understanding of tumor immunity.

Biomarkers

In addition to research related to animal models, many researchers also hope to quickly understand whether a combination can produce efficacy by optimizing clinical trial design, which relies heavily on rapid and efficient identification of tumor immunotherapy responses. group.

We are already familiar with the development of targeted drugs, and targeted drugs need to be genetically screened to select the right patient population. In the field of tumor immunotherapy, researchers are also looking for similar biomarkers of tumor immunity.

 

Berman worked at BMS. He also participated in the development of the first checkpoint inhibitor, Yervoy. In fact, he spent a long time looking for CTLA-4 related markers, but he never found any effective markers.

For PD-1 inhibitors, Merck, BMS and other pharmaceutical companies have achieved some success in biomarkers. It is now possible to predict the response of this class of drugs by detecting the degree of expression of PD-L1, but the performance of PD-L1, a biomarker, can only be considered to be unsatisfactory. Some patients whose tumors do not express PD-L1 can also benefit from this class of drugs, and patients with high PD-L1 expression may not be able to respond to drugs.

As the combination of checkpoint inhibitors increases, designers of clinical trials must also pay attention to how biomarkers are selected. Because in many cases, biomarkers can be used to screen patients in some clinical trials, but few pharmaceutical companies choose to do so.

Taking IDO inhibitors as an example, none of the early clinical trials tested the expression of IDO1 in patients, such as detecting whether a patient’s tumor expresses IDO1, or whether the expression level is sufficiently high.

In the early days of the development of CTLA-4 inhibitors, researchers now seem to have many problems with the evaluation of drug efficacy. For example, researchers at the time evaluated the degree of T cell activation in the blood, but the problem lies in the majority of tumor patients. Immune cells do not have anti-tumor effects, so the evaluation of the degree of activation of T cells in the blood is also of limited predictive value for anti-tumor effects.

But now researchers have developed better tools to track the traces of specific types of immune cells in the body and analyze the effects of drugs against tumor-associated immune cells. For IDO inhibitors, few people at the time were investigating whether IDO1 inhibitors could promote T cell infiltration into tumors.

Clinical trial design

The failure of the Epacadostat/Keytruda clinical trial has a very important impact on the field of oncology immunotherapy, as the failure of this clinical trial has also led to a renewed thinking about the quality of the combination itself.

Do the drugs used with Keytruda or Opdivo need to prove the effectiveness of their single drug? I think this is a problem that has long lingered in the minds of practitioners in the field of cancer immunity.

Epacadostat alone is not enough to inhibit tumor growth, which we knew very well long ago. Many people believe that epacadostat can synergize with checkpoint inhibitors despite the ineffectiveness of single drugs.

This problem is probably the same as the amyloid hypothesis, and everyone’s views are different. Some experts believe that the lack of single-agent effectiveness requires sufficient vigilance. If a single drug does not produce significant effects, it is difficult to produce synergistic effects by checkpoint inhibitors. The combination or synergy of the effects can be produced by combination therapy only if the drug is capable of producing a significant therapeutic effect.

However, this situation is not absolute, and the effectiveness of a single drug can also be considered from many levels. For example, if the drug cannot shrink the tumor, then it can be considered whether the patient’s condition can be stabilized.

 

Every advance in medicine will put more pressure on later drug research. For example, Keytruda’s recent data suggests that keytruda combined with chemotherapy can significantly reduce patient mortality, which in fact increases barriers to entry of other drugs into the field.

If the development of IDO inhibitors can bring us lessons, it is probably to make everyone aware of the importance of high-quality phase II clinical research. Randomized clinical trials are necessary before a phase III clinical trial.

But despite this, many executives of pharmaceutical companies are reluctant to adopt such a strategy. Drug development in the field of tumor immunity is now very frenetic, and the executives of these companies and the people involved in clinical trials are also under tremendous pressure. As a result, many pharmaceutical companies choose to look for possible successes and invest huge sums of money in this project, and they are not willing to spend a lot of time preparing for the early stage.

This is largely a helpless move. The high risk of new drug development means that failure is inevitable. However, Keytruda took less than four years from clinical trials to market launches, and the unparalleled efficacy of such checkpoint inhibitors does not require us to conduct a very detailed early clinical study of the drug before advancing it to Phase III clinical trials. . But the question is whether this model is suitable for the development of other drugs?

There is no doubt that it is still in the early stages of tumor immunotherapy, and there are countless unknowns waiting for us to explore.

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