New drugs for gene immunotherapy are "escorted" to fight the drug resistance problem of oxitinib

It is a difficult problem to avoid that EGFR target therapy is resistant, especially after the third generation of drug resistance, oxitinib (azd9291) is very difficult, which has become the focus and difficulty of the majority of lung cancer patients Recently, with the "escort" of a new drug, this problem has finally ushered in a new solution The FDA granted oncoplex and oxitinib fast track approval qualification for the treatment of EGFR mutant advanced non-small cell lung cancer (NSCLC) after oxitinib resistance, which means that oncoplex has been "escorted" to obtain the priority entry without a long approval process This will fight for more treatment opportunities for NSCLC patients who are stuck in the bottleneck of drug resistance Oncoprex is a combination of gene therapy and immunotherapy, which is developed by genprex, a new American biopharmaceutical company Its main active component is a tumor suppressor gene named tusc2 Previous studies have shown that 80% of cancer cells, including NSCLC, lack of tumor suppressor gene tusc2 In vivo tests also show that related kinase inhibitors can affect cell proliferation and programmed death Oncoprex encapsulates the optimized tusc2 gene in lipid and positively charged nanocapsules After intravenous administration, it is attracted by negatively charged tumor cells Tusc2 gene will generate a protein in tumor cells, which will help to restore some functional defects in tumor cells and cut off the pathway of tumor cell replication and proliferation In addition, because it upregulates tumor suppressor gene tusc2, increases the number of anti-tumor immune cells, downregulates PD1 and PD-L1 receptors, thereby enhancing the immune response to cancer Phase II clinical study of oncoplex combined with erlotinib in the treatment of drug-resistant non-small cell lung cancer has been carried out The following three types were included in the study: EGFR sensitive mutations but targeted drug resistance (mutations that can be treated by existing targeted drugs); EGFR non sensitive mutations (mutations that are ineffective by existing targeted drugs); and wild-type patients (no mutations) Patients were scheduled to receive the following treatment: oncoplex + erlotinib, once every three weeks intravenous drip of oncoplex, once a day oral administration of 150 mg of erlotinib Among them, 9 patients can evaluate the efficacy: The results showed that 4 patients had tumor reduction, the median dor (duration of remission) was 3 months, and the DCR (disease control rate) was 78% Among them, one patient achieved complete remission of Cr, which was a rare mutation of EGFR; one patient with negative EGFR reduced the target focus by 24%; one patient with negative EGFR reduced the target focus by 30%, and all the lesions were reduced by 18%; one patient with negative T790M, which was a sensitive mutation of EGFR, achieved disease stability, and the tumor was reduced Oncoplex was well tolerated, and there was no dose limiting toxicity Most of the adverse reactions were related to erlotinib Oncoplex has been awarded the fast review qualification by FDA, indicating that it has the potential to meet the treatment needs of serious or life-threatening diseases in the current medical market This not only speeds up the drug development process, but also the drug market The drug-resistant treatment of oxitinib, which is favored by FDA, will speed up its clinical application In addition to this new program, there is another effective drug that can solve the problem of drug resistance of oxitinib HER3 antibody coupling drug u3-1402 About 57-67% of the EGFR mutant NSCLC patients carry a certain degree of HER3 protein expression Therefore, Japan's first three pharmaceutical companies have developed the HER3 antibody coupling drug u3-1402 As of May 3, 2019, 30 NSCLC patients were included in the first phase clinical trial nct03260491, including 10 males and 20 females, with a median age of 63 years, a PS score of 0-1, 17 EGFR 19del, 12 EGFR L858R, and 1 l861q All patients had received EGFR TKI treatment before, 15 had received chemotherapy before, and 28 had used oxitinib All patients were in stage IV, in which 15 (50%) had brain metastasis and 25 (100%) had HER3 expression Four dose levels (3.2, 4.8, 5.6, 6.4 mg / kg) of u3-1402 were received in groups, and the median follow-up was 4.5 months 1 The disease control rate of u3-1402 is close to 100% Of the 23 assessable patients, 22 had a reduced tumor size and a disease control rate of more than 95% 17 cases are still under treatment 2 U3-1402 was effective in patients with different resistance mechanisms of EGFR-TKI Among them, u3-1402 was still effective in 2 patients with L858R / T790M / c797s triple gene mutation 6 of 23 patients had partial remission, and the objective remission rate was more than one quarter 3 The disease control rate of brain metastasis patients reached 85.7% For 14 NSCLC patients with brain metastases that can be evaluated, 4 patients had partial remission, and the objective remission rate was more than one quarter Another 8 cases were stable and the duration of treatment was satisfactory, 5 of them were still in treatment, 3 of them had been over 6 months Another 2 patients progressed unhappily, 1 patient died The problem of drug resistance of oxitinib has been a worldwide problem for patients and academia The above treatment plan is expected to provide a solution for EGFR-TKI in the treatment of drug-resistant patients, especially those with oxitinib resistance.