Quetiapine Fumarate

On August 30, HUTCHMED officially announced that it had voluntarily withdrawn its marketing application for fuquinitinib for second-line gastric cancer. This decision was made on the basis that, after in-depth communication with the Center for Drug Evaluation (CDE) of the State Drug Administration and members of its external expert committee, the Company realized that the information submitted so far is not sufficient to meet the approval requirements of the marketing application for the new indication, and therefore further research and data support are needed. Industry observers say this is not surprising. The marketing application for the new indication for fuquintinib was based on data from FRUTIGA's Phase III study, in which only progression-free survival (PFS) achieved the desired effect, while overall survival (OS) improved but was not statistically significant among the two primary endpoints. This shows that CDE is gradually integrating with FDA and paying increasing attention to OS, a key standard.   It is well known that the central goal of demonstrating the efficacy of oncology drugs in development is to extend overall survival (OS) of patients. Although multiple alternative endpoints, including PFS, have been used in the past to help bring numerous oncology drugs to market for a variety of reasons, alternative endpoints cannot replace OS as the gold standard. In the past two years, with the tightening of FDA review standards, those drugs that have greater side effects and fail to meet the OS gold standard have been gradually withdrawn from the market, and the approval of new drugs has become more stringent. The current withdrawal of Fuquinitinib appears to signal a new move by domestic regulators, a change that could have far-reaching implications for all oncology drugs.   Previously, Fuquinitinib was seen as a potentially effective treatment option for patients with stomach cancer. Gastric cancer is the fifth most common cancer in the world, with a high incidence in China and a large patient population. With the continuous progress of precision medicine, PD-1 combined chemotherapy has become a new standard of first-line treatment for advanced gastric cancer. However, both nationally and globally, the treatment options available for patients with second-line and above treatment options remain limited.   The world's major pharmaceutical companies have invested a lot of research resources in this field, promoting a variety of drugs, including PD-1, ADC, VEGFR inhibitors, etc., to enter clinical trials. VEGFR inhibitors play a key role in inhibiting tumor angiogenesis, and previous studies have shown that there are often high levels of VEGF expression in gastric cancer tissues, which is associated with advanced stages of the disease and poor prognosis. Lilly's VEGFR2 monoclonal antibody Ramoxiumab combined with paclitaxel has become the standard second-line chemotherapy regimen for advanced gastric cancer (AGC). Fuquinitinib has shown promising potential as a highly selective oral inhibitor of VEGFR-1, 2, and 3 in Phase III studies.   In the FRUTIGA Phase III study, Fuquinitinib combined with paclitaxel was used as a second-line treatment in 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma. The results showed that the median progression-free survival (PFS) was 5.6 months in patients treated with fuquintinib plus paclitaxel, compared with 2.7 months in patients treated with paclitaxel alone (HR=0.569, p < 0.0001). Overall survival (OS) also improved, at 9.6 versus 8.4 months, although the difference was not statistically significant. In terms of safety, the safety characteristics of fuquinitinib were consistent with previous studies, and no new safety problems were found. Clearly, the FRUTIGA Phase III study confirmed that the combination of fuquintinib and paclitaxel significantly prolonged PFS in patients compared to paclitaxel monotherapy. In addition, the objective response rate (ORR, 42.5% vs. 22.4%), disease control rate (DCR, 77.2% vs. 56.3%) and median duration of response (mDoR, 5.5 months vs. 3.7 months) in the combination treatment group were significantly better than those in the paclitaxel monotherapy group.   At the ASCO Congress, HUTCHMED presented further analysis of key subgroups in FRUTIGA's Phase III study, showing that PFS and OS results were consistent with those of the intended treatment population. The combination of fuquinitinib and paclitaxel showed a clear PFS benefit in most subgroups, especially in the enteric subgroup and the lymph node metastasis subgroup, where the benefits of PFS and OS were particularly significant. In clinical design, PFS and OS are used as double primary endpoints, alpha resolution and circulation. Studies are considered positive when at least one endpoint reaches statistical significance. Nevertheless, HUTCHMED believes that despite not meeting the OS endpoint, the available clinical data and findings are sufficient to support the combination of fuquinitinib and paclitaxel as a new treatment option for second-line patients with gastric cancer, and had filed a marketing application last year. However, the CDE rejected the application for fuquitinib.   HUTCHMED noted that although the higher and uneven proportion of patients receiving subsequent antitumor therapy (20% higher in the paclitaxel monotherapy group than in the combination group) may have influenced OS results, fuquinitinib combined with paclitaxel demonstrated meaningful clinical benefits and favorable OS trends across a range of models. However, the CDE does not agree with this understanding of the OS results, arguing that the available data are not yet sufficient to support marketing applications for new indications and that further research is needed. In other words, CDE expects to see more and more favorable OS data. The CDE's rigorous scrutiny of OS data is justified because overall survival data is critical for evaluating the clinical effectiveness of cancer treatments, and it directly reflects how long patients survive after receiving treatment. Based on international experience, the FDA has in the past allowed progression-free survival as a primary endpoint to provide a path to accelerated approval for drugs to market. But in the past two years, there has been a marked shift in the FDA's regulatory attitude. A batch of drugs, including ibrutinib, are voluntarily withdrawn from the market or the indication is withdrawn under the guidance of the FDA due to confirmatory clinical data failing to meet expectations, or large side effects, or limited overall survival benefits; For some new drug/new indication applications, the FDA has also begun to review OS data.   At the heart of the FDA's change of heart is the fact that while some oncology drugs are marketed with alternative endpoints such as progression-free survival or objective response rates, they ultimately fail to equate these alternative endpoints with the gold standard of OS. As a result, the FDA is increasingly looking to companies to provide reliable OS data to prove that new therapies really help patients live longer. The FDA's change did not come in the form of draft guidance, but was communicated to drug companies through meetings, articles and comments from the agency's top oncologists. The CDE of cefuroxime quetiapine for the "stop", may be the beginning of a new trend. What impact this will have on cancer drug development is worth further observation.