NKTR-214 combined with Nivolumab is also effective for PD-L1 ne

  • In recent years, immunological checkpoint inhibitors represented by anti-PD-1 monoclonal antibodies have revolutionized cancer treatment. However, there are still many patients who have no response to immune checkpoint inhibitors, especially those PD-L1 negative patients. Therefore, it is necessary to find a drug that can improve the efficacy and applicability of the immunological checkpoint inhibitor. Scientists have found a new drug, which can be combined with the PD-1 monoclonal antibody Opdivo (nivolumab) in cancer treatment.


    The PD-1 monoclonal antibody Opdivo (referred to as O drug) is an important anticancer drug developed by BMS. It was launched in July 2014 and has been approved by the US FDA for the treatment of melanoma, non-small cell lung cancer, liver cancer and gastric cancer. However, the effectiveness of O-drug when used alone is not high, especially in PD-L1-negative patients.


    What is NKTR-214?


    NKTR-214 is derived from an anticancer drug, interleukin 2 (IL-2), which was used more than 20 years ago. IL-2 is the first immunotherapeutic drug. As early as 1992 and 1998, the US FDA approved the IL-2 drug (Aldesleukin) for treating advanced kidney cancer and malignant melanoma. However, the half-life of this drug is as short as only a few minutes. In addition, the therapeutic window of this drug is very small; however, the side effects are very large. At that time, patients treated with IL-2 must be hospitalized and closely observed for 24 hours, otherwise, the patient may easily loss his or her life. Hence, the huge side effects limit its widespread use in the clinic.


    In order to overcome the side effects of IL-2, scientists have tried various methods. Finally, six polyethylene glycols (PEG) were added to the normal IL-2 molecule to modify the drug to form an inactive drug. However, after the injection of NKTR-214 in the patient, the added 6 PEG will gradually fall off, forming the form of active 2-PEG and 1-PEG, and the 2-PEG form of IL-2 can be combined with CD8+ T cells and bind to receptors on the surface of NK cells, which stimulates proliferation of immune cells. IL-2 in the form of 1-PEG does not bind to regulatory T cell proliferation receptors, thereby not increasing regulatory T cell proliferation. This is the basis for its use with PD1.


    Clinical Trials


    The PIVOT-02 dose-expanded group included 38 patients with advanced solid tumors, including 11 cases of melanomas, 22 cases of renal cell carcinomas, and 5 cases of non-small cell lung cancers. The result is amazing!


    Patients received NKTR-214 (0.003 mg/kg or 0.006 mg/kg once every two weeks or once every three weeks) in combination with Opdivo (Nivolumab 240 mg every two weeks or 360 mg every three weeks). The second phase clinical dose was determined to be NKTR-214 (0.006 mg/kg once every three weeks) in combination with Opdivo (360 mg every three weeks).


    The objective rate of 11 cases of melanoma was 64%, of which 1 patient was completely relieved. The disease control rate was 91%, and the median onset time was 1.7 months. As of November 2, 2017, all patients who were relieved were still in the clinical group.


    In 13 cases of newly diagnosed renal cell carcinoma, the objective response rate was 46% (n=13), the disease control rate was 85%, and the objective efficiency was 60% in the second imaging evaluation (n=10). The disease control rate was 80%, and the median onset time was 1.9 months. As of November 2, 2017, all patients with remission were still in the clinical group. Seven cases of renal cell carcinoma were treated with an objective rate of 14% and a disease control rate of 100%.


    In 4 cases of non-small cell lung cancer, the expression of PD-L1 was negative, and the objective efficiency and disease control rate were 75%. The median onset time was 1.7 months.


    The FDA awarded NKTR-214 in combination with Opdivo's combination therapy breakthrough therapy for the treatment of patients with newly diagnosed unresectable or metastatic melanoma. In terms of safety, the incidence of AE of 3-4 grades is only 14.6%, which is very safe compared to some of the currently mature combination therapies, such as PD1 combined chemotherapy, PD1 combined with ipi or even PD1+.


    NKTR-214, a revolutionary anticancer drug, when combined with PD-1 inhibitors, can greatly increase the effectiveness of PD-1 inhibitors, even for PD-L1 negative patients. Small molecule inhibitors are a well-established drugs whose therapeutic potentials are widely exploited for curing various diseases such as cancer, cardiovascular disease, infection, metabolic disease, inflammation, and immunology. BOC Sciences offers a comprehensive collection of inhibitors for researchers’ use, including c-FMS Inhibitor, DAPK Inhibitor, Dynamin Inhibitor, GIP Receptor Inhibitor, and many more.