How to choose 8 immune drugs exactly? I. PD-1/PD-L1 immunologics are the hottest topic in the anti-cancer field these years. These drugs have attracted much attention because of the wide range of people they benefit and the potential to bring about clinically curable super survivors. So far, eight new drugs in this category have been marketed in China, with exactly half imported and half domestic. Imported drugs: Ondivolol, Corydal, Infivolvan, Taishengqi Domestic drugs: Topeka, Daboxu, Erika, Bazedan Four imported ones have two PD-1 antibodies and two PD-L1 antibodies, while four domestic ones are all PD-1 antibodies. In the face of 8 listed immune drugs, how in the end to choose, has become a very headache. Almost every day someone asks me, “Pineapple, which immune drug is the best?” This is a very realistic and good question, but there is no easy answer. On the one hand, these 8 immune drugs are not exactly the same, and each has its own characteristics, both in terms of efficacy and side effects, so they certainly cannot just be interchanged; just because drug A works well in lung cancer does not necessarily mean that drug B will also work well. On the other hand, although they have differences, they basically belong to the same class of drugs. Quite a lot of their clinical data are very close. For example, the objective remission rates in clinical studies for the three immune drugs approved in China for third-line treatment of classical Hodgkin’s lymphoma were 80.4% for Daboxu, 77.3% for Erika, and 76.9% for Bazedan, which are very similar. In short, these 8 drugs are both similar and not exactly the same. No one has an answer as to which one is best, because there are no studies that compare these drugs directly. Then the reality is that the patient must make a choice. What to do? In addition to the word “compliance”, my personal advice is to look at two key points: first, the clinical data and second, the price. When choosing an immune drug, the first thing to look at is the approved indications and clinical data, especially for Chinese people; then the price of the drug and one’s financial ability. Scientifically speaking, the first step in choosing an anti-cancer drug is to look at the approved indications and give priority to the varieties that have been approved in China. I have compiled a list of approved indications of immune drugs listed in China so far. As you can see, the scope of the eight approved drugs varies greatly. Being approved for marketing means that the drug has achieved significant success in clinical trials against this cancer and has received official recognition. Choosing such a drug carries the least risk. If there are some indications for which only one drug is currently approved, priority should be given. For example, second-line treatment for non-small cell lung cancer (Ondivol); first-line treatment for non-small cell squamous lung cancer (Corydal); consolidation maintenance therapy for stage III non-small cell lung cancer (Infiban); first-line treatment for small cell lung cancer (Tesenoside); second-line treatment for hepatocellular carcinoma (Ereka); second-line treatment for uroepithelial carcinoma (Bazedan), etc. It is important to note that this table is always being updated, as each PD-1 drug has additional indications pending approval and a large number of clinical trials underway. Last month alone, three new indications were approved in China for Corydal and Ereka. I will give you regular updates later. Second, if a drug is not approved for an indication in China, does it necessarily mean that it cannot be used? Not necessarily. Using a drug without approval is called “over-indication use”. This is a very complex topic that involves not only science, but also economics, social ethics, and many other aspects. Strictly speaking, experts cannot recommend the use of a drug for a super-indication, and pharmaceutical companies cannot promote it. However, in reality, due to various reasons, it is very common for Chinese oncology patients to use drugs beyond their indications. In my personal opinion, “over-indication” should not be the norm. If oncology patients have no other choice and there is clear evidence to support the effectiveness of the drug in Chinese patients, it can be considered with caution, but it must be emphasized that it must be supported by data, otherwise it can easily become abusive. What evidence would suggest that a new drug would be effective in Chinese patients? This includes the following: Large-scale clinical studies in Chinese patients have been successful, and marketing applications have even been submitted. Official clinical guidelines in China have recommended it. The indication is already approved in other countries and there are no significant ethnic differences. Multiple cases of significantly benefited patients have been seen in early clinical studies in Chinese patients. In line with this principle, for colorectal cancer patients with high microsatellite instability (MSI-H)/defective mismatch repair (dMMR), although there are no immunologic agents approved in China, immunologic agents can be considered as they are already approved in Europe and the US and have been recommended in Chinese clinical guidelines. As early as 2017, Corydal or Ondivol has been approved in the United States for this indication, respectively. Several studies have found that about 40% of colorectal cancer patients with MSI-H/dMMR have significant tumor shrinkage with the use of immune drugs, and some of them even disappear completely. It is important to emphasize that there are data from Chinese (or at least East Asian) patients that are very important. Just because it is approved abroad does not mean that it is necessarily suitable for Chinese patients. Why? Because some tumors that look similar on the surface may not have the same pathogenesis in Chinese and European and American patients. This can cause them to respond differently to immunotherapy. For example, melanoma. Most melanomas in Europe and the United States are associated with excessive sun exposure and belong to the sun-damaged subtype, whereas melanomas in China are rarely sun-damaged and have other causes, mainly the mucosal or limbic subtype, which accounts for more than 70% of the cases. The different mechanisms bring about very different immune escape mechanisms and drug efficacy. The European and American sun-damaged melanoma types respond better to immunotherapy overall. Whether the different melanoma patient populations in China can benefit from immunotherapy is a very important scientific question. The fact that Topeka was approved for a melanoma indication in China is because it directly demonstrates that Chinese patients can also benefit from it. Another example is gastric cancer. Gastric cancer can be divided into distal and proximal, and also into different subtypes such as intestinal, diffuse, and mixed types. Distal gastric cancer is more common in China and intestinal type is more common, while proximal gastric cancer is more common in Europe and America. Therefore, after the approval of immune drugs for gastric cancer indications in Europe and the United States, it cannot be assumed that Chinese patients are also suitable, and separate studies for Chinese patients must be done. Ondivo was the first one approved for gastric cancer in China mainly because it was the first one to do a large phase III clinical trial for Asian patients. Overall, the biggest advantage of imported drugs is that they have more clinical data and wide global indication coverage. In particular, Ondivol (O drug) and Corydal (K drug), the so-called OK combination, have been marketed abroad as early as 2014, and have been approved for more than 10 indications, accumulating a large amount of clinical studies and real-world data. Both the efficacy and side effects are very well known. Before it was launched in China, many people had already gone to Hong Kong and other places to buy and use it, and doctors were more familiar with it. In comparison, domestic drugs are more “young” and require more learning process for both doctors and patients. Third, in addition to clinical efficacy, cost is also a very important consideration in reality. This is the biggest competitive advantage of domestic drugs. China is still a developing country and the per capita disposable income is not high, the recently published data is 600 million people have a monthly income of only about 1000 yuan. Coupled with the fact that many people do not have insurance, the cost of oncology treatment, especially for new drugs, is largely out of one’s own pocket, so money is an issue that has to be considered. Although the pricing of imported immune drugs in China is already basically the lowest in the world, domestic drugs usually still have some price advantage. Non-small cell lung cancer is one of the most competitive areas of immunotherapy. With multiple imported immunologics and domestic immunologics approved, this is bound to be a big battle. For example, with the recent approval of Ereka, there are now two very similar combinations of imported regimens (Corydal + chemotherapy) and domestic regimens (Ereka + chemotherapy) for first-line treatment of non-squamous non-small cell lung cancer. What will doctors and patients choose? We’ll see. But there is no doubt that, in addition to clinical data, price will be a very important factor. For patients, it’s good to have competition for drugs, because it often means better prices and complimentary drug policies. Another frequently asked question is: When will oncology immune drugs be introduced into health insurance? So far, only one indication of an immune drug has made it into Medicare. In 2019, Dapoxetine for classic Hodgkin’s lymphoma became the only PD-1 monoclonal antibody drug included in the national health insurance list. The market price of a bottle was reduced from RMB 7,838 to RMB 2,843, a reduction of more than 60%. If the policy is implemented, Daboxu will certainly become a priority choice for many patients with classic Hodgkin’s lymphoma. Will more immune drugs enter the health insurance in the future? Definitely, but I personally feel that the pace is likely to be slower and narrower than we all think. One of the reasons why Daboxu was successfully negotiated is that it was declared for the indication of third-line treatment of classic Hodgkin’s lymphoma. On the one hand, immunotherapy is very effective in classic Hodgkin’s lymphoma, with an objective remission rate close to 80%, which is a miracle drug. With good efficacy and few patients, coupled with a significant price reduction, the cost effectiveness for health insurance is very high and the chance of successful negotiation is very high. Unfortunately, there are not many such tumor types. The biggest problem facing PD-1 class immune drugs at present is the overall low efficiency. If patients are not screened, the objective remission rate for a single drug is often only 15% to 20% in common cancer types such as lung, liver, and gastric cancers, and the patient population is often in the high hundreds of thousands. If facing a cancer type with low treatment efficiency and a large number of patients, it is quite difficult to get into medical insurance, whether imported or domestic drugs, with limited medical insurance fund pool. If we want to promote immune drugs into medical insurance, I am afraid we need to do more research and rely on biomarkers to further subdivide the patient population and improve the probability of benefiting patients. For example, the overall response rate of non-small cell lung cancer is not high, but patients with strong PD-L1 positivity are not bad; the overall response rate of gastric cancer is not high, but patients with MSI-H/dMMR are not bad. Subgroups of patients like these may have a better chance of being paid by Medicare. The concept of precision medicine also has significant implications for health insurance. Fourth, to summarize, the eight immune drugs currently on the market belong to the same class of drugs as a whole, with many similarities, but not exactly the same. When you choose, the main thing to look at should be the strength of the evidence supporting its effectiveness in Chinese patients and not to use it blindly across indications. If multiple drugs are eligible, then the choice will largely depend on the price of the drug and your own economic conditions. Personally, I feel that immune drugs are not realistic or reasonable to be included in health insurance on a large scale at this time due to their overall lack of efficiency. Promoting philanthropic drug grant programs by drug companies or actively participating in reliable clinical trials with free drugs may be a better way to save money for now. However, with further research on tumor immunity and further segmentation of patients, it is hoped that patient groups that truly benefit from immune drugs (e.g., classical Hodgkin’s lymphoma, MSI-H subtype tumors, etc.) will soon receive support from health insurance and other sources to significantly reduce the financial burden. We still have many oncology patients who cannot benefit from existing immunologic drugs, so research and new drug development definitely cannot stop, and we all still have to work together.