Before this, furiquintinib was regarded as another effective treatment option for gastric cancer patients.
After all, gastric cancer is the fifth most common cancer in the world, and my country is a country with a high incidence of gastric cancer, with a large number of patients. With the continuous development of precision medicine, PD-1 combined with chemotherapy has become a new standard for first-line treatment of advanced gastric cancer. However, both in China and around the world, there is still a lack of treatment options available for second-line and above patients.

Global pharmaceutical companies have deployed a large number of research in this field to promote clinical trials including PD-1, ADC, and VEGFR inhibitors.
Among them, VEGFR inhibitors play a vital role in inhibiting tumor angiogenesis, and studies have shown that gastric cancer tissues often express high levels of VEGF, which is associated with more advanced disease and poor prognosis. Eli Lilly's VEGFR2 monoclonal antibody ramucirumab combined with paclitaxel has also become a standard second-line chemotherapy regimen for advanced gastric cancer (AGC).

As a highly selective oral VEGFR-1, 2 and 3 inhibitor, furiquintinib has shown good potential in Phase III studies.
According to the FRUTIGA Phase III study, fruquintinib combined with paclitaxel monotherapy was used as a second-line treatment for 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma. The results showed that the median PFS of patients receiving fruquintinib plus paclitaxel was 5.6 months, while that of patients receiving paclitaxel monotherapy was 2.7 months (HR= 0.569, p < 0.0001); OS was also observed to improve, 9.6 months VS 8.4 months, but this was not statistically significant.

In terms of safety, the safety characteristics of fruquintinib are consistent with previous studies, and no new safety signals were found.
Obviously, in the FRUTIGA Phase III study, fruquintinib has confirmed that its combination with paclitaxel significantly prolonged the patient's PFS compared with 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 vs. 3.7 m) of the combination group were significantly higher than those of the paclitaxel monotherapy group.

Further analysis of key subgroups announced by Hutchison Medicine at the ASCO conference showed that the PFS and OS results were consistent with those of the intended treatment population. Clear PFS benefits were observed in most subgroups with the combination of furiquintinib and paclitaxel, and the benefits of PFS and OS were particularly evident in the intestinal subgroup and lymph node metastasis subgroup.
In the clinical design, PFS and OS are dual primary endpoints, alpha split and cycle. When at least one endpoint reaches statistical significance, the study is considered positive. Originally, it might not be difficult to get listed with such clinical data.
Hutchison Medicine also believes that although the OS endpoint has not been reached, the existing clinical data and findings are sufficient to support the combination therapy of fruquintinib and paclitaxel as a new treatment option for second-line gastric cancer patients, and submitted a marketing application last year.
However, this time the CDE rejected fruquintinib.

According to Hutchison Medicine, a large number of subsequent analyses showed that although the proportion of patients receiving subsequent anti-tumor treatment was high and unbalanced (the proportion of subsequent anti-tumor treatment in the paclitaxel monotherapy group was 20% higher than that in the combination therapy group), which had an impact on the OS results, fruquintinib combined with paclitaxel showed meaningful clinical benefits and favorable OS trends in a series of models. However, the CDE does not recognize this understanding and interpretation of the OS results, and believes that the existing data is not sufficient to support the approval of the new indication marketing application, and more work needs to be done.

In other words, the CDE hopes to see more and more favorable OS data.
It is not difficult to understand that the CDE's review of OS data has become stricter. Overall survival data is crucial to evaluating the clinical effect of cancer treatment because it directly reflects the survival time of patients after treatment.
Referring to overseas experience, for many years, the FDA has allowed progression-free survival to replace the primary endpoint, allowing drugs to obtain accelerated approval and marketing.
However, in the past two years, the FDA's regulatory attitude has changed significantly. A number of drugs that were launched through the accelerated approval channel, including ibrutinib, were either voluntarily withdrawn from the market or their indications were withdrawn under the guidance of the FDA because the data of the confirmatory clinical trial failed to meet the deadline, the side effects were greater, or the overall survival benefit was not great;

For the marketing applications of some new drugs/new indications, the FDA has also begun to review OS data.
The core reason for the FDA's change in attitude is that although many tumor drugs rely on alternative endpoints such as progression-free survival or objective response rate to be launched, in the end, many drugs failed to equate these alternative endpoints with the gold standard of OS.
Therefore, the FDA increasingly hopes that pharmaceutical companies can provide reliable OS data to prove that new therapies can really help patients prolong their lives.
The FDA's change did not appear in the form of a draft guideline, but conveyed this central idea to pharmaceutical companies through meetings, articles, and comments from top FDA oncology experts.
Perhaps, this "persuasion to withdraw" of furiquintinib is also the beginning of CDE's transmission of a new regulatory trend. And what impact will this have on the development of tumor drugs?

If innovative pharmaceutical companies are aiming to go overseas or are already on the road to going overseas, they must be familiar with the change in regulatory attitudes regarding OS. Judging from the actions of the FDA in recent years, it is not only intended to clean up the drugs that have been approved for accelerated approval, but also to tighten the approval of drugs that will be applied for listing in the future.

Novartis CEO Vas Narasimhan also said in a conference call that the FDA has made a major change in the expectations of OS data when submitting applications using PFS, which may affect all cancer drugs.
This change means that accelerated approval for listing may not be as strongly predictive of full approval as before. A batch of drugs that have been delisted and their indications withdrawn have already illustrated this point.

For biotech, which is relatively tight on funds, this is undoubtedly a huge blow. In the past, the fast track was seen as a "shortcut" that could minimize capital expenditures. But now, pharmaceutical companies may not be able to rely on guaranteed continued profits when the drug goes through the full approval process, which undoubtedly increases the difficulty of funding confirmatory studies.
In contrast, large pharmaceutical companies have greater financial flexibility and will not be greatly affected.
For new drugs that have not yet been launched, the FDA's change of attitude may mean that the road to listing with PFS as an alternative endpoint may not be easy. In areas where patient needs are not so urgent, the FDA may want to see pharmaceutical companies provide more mature overall survival data before supporting drug listing. This requires pharmaceutical companies to invest more time and money, and uncertainty will increase accordingly.
This may have a significant impact on the development process of cancer drugs because it will force pharmaceutical companies to collect and analyze more comprehensive patient outcome data, which includes not only overall survival but also quality of life related indicators. This requires pharmaceutical companies to invest more time, money, and increase the complexity of clinical trials, and uncertainty will increase accordingly.
Of course, at present, the FDA should not require OS data for all drugs.
In an interview with foreign media, an FDA spokesperson said that the FDA usually needs to see mature data when there is preliminary evidence of potential damage to OS in clinical trials. For those tumor indications that urgently need new treatments, the FDA may not immediately strengthen its review.
Back to China, with the regulatory level fully aligned with international standards, the trend of future clinical endpoint selection does not seem difficult to predict.
Of course, we still need to continue to observe the next trend and impact. Hutchison Medicine also stated that despite the disappointing results, it remains optimistic about the use of furiquintinib in the treatment of gastric cancer, and the company is also interested in exploring its possibilities in depth.
In any case, changes have already occurred. All pharmaceutical companies must pay attention to it.

https://mp.weixin.qq.com/s/LljDpfg-94p-UwM0HaIHMA