CSF1R/PD-1 immunotherapy combination is not effective
Release date: 2017-11-09
[News]: Today, Five Prime announced partial clinical results of its CSF1R antibody cabilalizumab (FPA008) in combination with Opdivo. This combination produced a 10% objective response in patients with second-line pancreatic cancer and a 13-month disease control rate of 13%. However, 43% of patients had grade 3-5 adverse reactions, which made investors disappointed. Today FPRX shares fell 40%. Detailed results will be announced at the ongoing SITC Annual Meeting, and the results of Array's small molecule CSF1R inhibitors will also be announced at this annual meeting.
[Drug source analysis]: PD-1 antibody produces a durable response in some patients of many types of tumors, and Keytruda is even approved for all tumor patients carrying repair mismatch defects. However, usually only about 20% of patients respond to PD-1 therapy, so the population of PD-1 responders has become the hottest research direction of anticancer drugs. Combination therapy is the absolute mainstream because there is no evidence that any other monotherapy can cover and expand the PD-1 response population. IDO is the leading PD-1 partner, but has not shown synergy in controlled clinical trials. Some of the mechanisms showing superimposition/synergy in preclinical conditions have not been repeated in clinical trials, such as the A2A receptor antagonist CPI-444.
CSF1R is a broadly expressed receptor and is a co-receptor of CSF1 and IL34. CSF1R is also a kinase, so antibodies such as cabilalizumab can also be regulated with small molecule kinase inhibitors. CSF1R inhibitors are mainly used for the development of immune diseases because CSF1 can recruit macrophages expressing CSF1R to produce inflammation. CSF1R inhibitors are also effective in a class of macrophage-driven benign tumors called PNVS, but current data on the treatment of advanced malignancies is limited. There are some so-called tumor-associated macrophages (TAMs) in the microenvironment of malignant tumors, which are now considered to have immunosuppressive activity, and one of the PD-1 resistances may be the presence of immunosuppressive mechanisms similar to TAM in the tumor microenvironment. Therefore, there is a certain theoretical basis for further abolishing tumor immunosuppression by inhibiting CSF1R.
However, macrophages and tumor microenvironment are dynamic. Different signals have different effects on macrophage differentiation and tumor environment. The widespread expression of CSF1R also makes adverse reactions a hidden danger. A 10% response rate in second-line pancreatic cancer should not be considered bad. This is, after all, a type of stubborn tumor that responds poorly to all therapies, including immunotherapy, but the toxicity is so likely to limit the prospects of this combination. In addition, there are several other solid tumor patients in this phase of clinical trials. Today, only the pancreatic cancer group has been published. The effect is generally general, which makes investors worry that the combination of tumors with relatively more treatments is more toxic than the efficacy.
Predicting clinical efficacy/toxicity from basic research results is not reliable for any mechanism, but it is more difficult to remove the highly complex mechanism of tumor immunosuppression by inhibiting TAM. There must be some relatively reliable models between the results of the basic research and the clinic to enrich the treatments that are more likely to show clinical efficacy. It is unrealistic to expect that an animal model is 100% reliable, but all the treatments are clinically validated and not sustainable. We need an optimization system, similar to the test of Yang Zirong. It is not that you are self-reported, but you believe that you are really a Hu. Although he does not have a reliable way to distinguish between true and false, he can ask a series of whispers and slang, and which one is wrong may be found to kill. There is a similar system for the development of new drugs, but the temptation of immunotherapy is too big. Now everyone has no patience to wait for the establishment of this system. Comrade Zirong is more witty than a mountain sculpture, and the tumor is probably less than wit than our existing optimization system. It is blindly believed that more Weihushan should be prepared.
Source: US and Chinese medicine source
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