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The appearance of PD-1/L1 inhibitors about five or six years ago has triggered a frantic fever in the field of cancer treatment. This class of drugs can use the immune system to fight cancer by relieving the tumor’s suppression of the human immune system.

For a small percentage of patients, the efficacy of checkpoint inhibitors, including PD-1/L1 inhibitors, is excellent. It is likely that many oncologists will find it difficult to forget the first time that PD-1 inhibitors have been used to successfully treat patients who are in critical condition.

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

 

At present, six checkpoint inhibitors have been approved for the market, for melanoma and other types of cancer treatment. For some patients and doctors, the efficacy of this type of drug is indeed very good, which can make many patients’ tumors completely disappear.

However, despite this, checkpoint inhibitors are still only effective in a small number of patients. However, many researchers in the field of oncology have long realized that PD-1 inhibitors will become the cornerstone of cancer immunotherapy, so pharmaceutical companies are also looking for combination therapy 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 of pharmaceutical companies to enter cancer immunocombination therapy is also very 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, even if the biotech companies have only very preliminary data confirming that their immunotherapy can improve the efficacy of checkpoint inhibitors, they can also make their stock prices soar. Some very small companies engaged in R&D of cancer immunological drugs may even be acquired by other pharmaceutical companies at a staggering price even if they do not have sufficient data.

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

According to data from the National Cancer Center, as of September last year, more than 250 tumor-immune-related drugs have entered clinical studies. At the same time, there are more than 1100 clinical trials of PD-1/L1 combination therapy, and among these, a combination of tumor immunotherapy drugs, targeted drugs, and chemotherapy drugs account for a large part.

Starting from 2014, the number of clinical trials of combinatorial therapy with joint checkpoint inhibitors has increased dramatically

However, the path for exploring tumor immunocombination therapy is not smooth. In fact, there have been some failed cases in this area. The most influential of these is the combination therapy of Keytruda and Incyte, an experimental drug.

IDO frustrated

 

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

 

In this series of tumor immunotherapy targets, there are few popular targets like IDO. Previous studies have shown that IDO inhibitors are ineffective and do not inhibit tumor growth (see the story behind IDO inhibitors (above), the story behind IDO inhibitors (bottom))

However, with the emergence of checkpoint inhibitor R&D booms, many people believe that the use of another drug that can suppress immunosuppression can improve the efficacy of checkpoint inhibitors. Therefore, researchers also pinned their hopes on IDO inhibitors.

 

Between 2014 and 2015, large pharmaceutical companies spent more than $1 billion to acquire IDO inhibitor related rights. In the following years, the number of pharmaceutical companies conducting IDO R&D was 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. Of these, 9 of them are related to Incyte’s epacadostat.

 

These studies are largely based on data from a phase I/II clinical study with fewer than 60 participants in epacadostat and Keytruda.

However, some pharmaceutical companies have expressed doubts about the mechanism of IDO inhibitors in this process and have therefore opted out of the field. The first is that Genentech returned the rights to a drug from Newlink to Newlink, and Pfizer also stopped its cooperation with iTeos.

 

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

Although epacadostat is not the first failed drug in the field of tumor immunotherapy, it does make the tumor immune combination therapy a major setback for the first time.

Although phase III of Keytruda’s combination chemotherapy regimen in April this year has demonstrated the obvious superiority of this combination regimen, the combination of checkpoint inhibitors and other immunotherapeutic drugs has yet to see any signs of success.

The frustration of IDO inhibitors is also very important for those who want to rapidly advance the research of combination therapy. There is also a boom and bubble in the financing of other combinatorial therapies, including oncolytic viruses, cytokine-related drugs, and drugs that activate the innate immune system, such as STING agonists. Many people worry that these areas will also Frustrated by clinical trials.

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

Of course, there are also many people who make hindsight, saying that the failure of some clinical trials of IDO inhibitors can actually be avoided. However, if you want to avoid these failures, you must also try 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 is how to evaluate the efficacy of drugs before entering clinical trials; second is to find suitable biomarkers; and finally, how to design clinical trials more rationally.

Animal model

 

The preclinical studies of cancer immunotherapy drugs are difficult to carry out, largely because of the nature of these therapies. Unlike chemotherapeutics or targeted drugs, these drugs can act on the immune system, not the tumor itself.

 

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

The mice’s cancer 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 mouse’s tumor shrinks, it does not mean that the drug is really effective.

Although the quality of animal models has increased in recent years, the predictive value of animal models for cancer immunotherapeutics has not been predicted by other therapeutic animal models.

 

Basically, people are pushing medicine into the clinic based on conceptual theory and hypothesis. These hypotheses can only be verified by clinical trials. It is easy to imagine that if drugs are developed in this way, the failure rate of drugs will not be low.

 

The immune system is very complex, which we have long been very clear about, but the current progress of clinical research has clearly exceeded our understanding of tumor immunity.

Biomarkers

In addition to the relevant research on animal models, many researchers also hope to quickly understand whether a certain combination can produce efficacy by optimizing clinical trial design, and this depends to a large extent on the rapid and efficient identification of responses to tumor immunotherapy. group.

We are already familiar with the development of targeted drugs. Targeted drugs need to be screened for appropriate patient populations prior to use. 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. He actually spent a long time looking for relevant CTLA-4 markers, but he never found any valid 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 PD-L1 expression, but the performance of the PD-L1 biomarker can only be considered to be unsatisfactory. Some patients whose tumors do not express PD-L1 can also benefit from this type of drug, and patients with high PD-L1 expression may not necessarily be able to respond to drugs.

With the increased use of checkpoint inhibitors, designers of clinical trials must also pay attention to how biomarkers are selected. Because in many cases clinical trials can actually use biomarkers to screen patients, few pharmaceutical companies choose to do so.

Taking IDO inhibitors as an example, in the early clinical trials there was no test to test the expression of patients’ IDO1, such as whether the patient’s tumor expressed IDO1, or whether the expression level was sufficiently high.

Early in the development of CTLA-4 inhibitors, researchers now appear to have many problems with drug efficacy evaluation methods, such as when researchers assessed the degree of T-cell activation in the blood, but the problem is that most of the tumor patients Immune cells do not have anti-tumor effects. Therefore, evaluating the degree of activation of T cells in blood is also of limited predictive value for anti-tumor effects.

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

Clinical trial design

The failure of Epacadostat/Keytruda clinical trials has also had a very important impact on the field of tumor immunotherapy, because the failure of this clinical trial has also led people to rethink the requirements of combination therapy for the quality of the drug itself.

Does the drug used in combination with Keytruda or Opdivo need to prove its effectiveness as a single drug? I think this is a problem that has long lingered in the heart of practitioners in the field of tumor immunity.

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

This problem is probably the same as the amyloid hypothesis, and everyone’s point of view is different. Some experts believe that the lack of single-agent effectiveness requires sufficient vigilance. If a single drug does not produce a significant effect, synergistic effects through checkpoint inhibitors are also difficult. The additive or synergistic effect of pharmacodynamics can only be produced by combination therapy if the drug can produce 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 drugs do not shrink the tumor, then we can consider whether it can make the patient stable.

 

Every medical advance will bring more pressure for later drug research. For example, Keytruda’s latest data show that keytruda combined with chemotherapy can significantly reduce patient mortality, which in fact also raises barriers for other drugs to enter the field.

If we say that 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. Prior to stage III clinical trials, rationally designed, randomized clinical trials are necessary.

However, in spite of this, many drug company executives are unwilling to adopt such a strategy. Drug development in the field of cancer immunology is now very fanatical, and the executives of these drug companies and the people involved in clinical trials are also under tremendous pressure. Therefore, many pharmaceutical companies have chosen to look for possible directions for success and invested huge sums of money in this project. They are not willing to spend a lot of time to do preparatory work.

This is largely a helpless move. The high risk of new drug development means that failure is inevitable. But Keytruda took only less than four years from clinical trials to market, and the unparalleled efficacy of these checkpoint inhibitors does not require us to advance the drug to a phase III clinical trial after conducting very detailed early clinical studies. . 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 cancer immunotherapy, and there are countless unknowns waiting for us to explore.

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