Moboxetinib and sotoraxib have suffered setbacks one after another. What are the primary endpoints and secondary endpoints of clinical trials of anti-

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On October 2, 2023, Japan's Takeda Pharmaceutical announced on its official website that after discussions with the U.S. FDA, the company will cooperate with the FDA to actively withdraw EXKIVITY? (mobocertinib) in the United States for adult diseases that progress during or after platinum-based chemotherapy. Patients with EGFR exon20 ins mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). This decision was based on results from the Phase 3 EXCLAIM-2 trial, which did not meet its primary endpoint and therefore did not meet the relevant confirmation requirements for accelerated approval by the U.S. FDA, nor did it meet the requirements for conditional marketing approval approved in other countries. The EXCLAIM-2 trial is a phase 3, multicenter, open-label study investigating the safety and efficacy of EXKIVITY as monotherapy versus platinum-based chemotherapy in first-line EGFR exon20 ins mutated locally advanced or metastatic non-small cell lung cancer effectiveness.

On October 5, 2023, the FDA held a nearly 6-hour meeting to discuss the supplementary information submitted by Amgen about sotorasib. In the voting session, the first question is: Do you think the PFS evaluated by CodeBreaK 200's BICR can be reliably explained? 10 out of 12 experts (83%) voted against it. The reason for a serious vote on PFS is that in the Phase III study of CodeBreaK 200, not only PFS was set as the primary research endpoint, but also key secondary endpoints including OS were set, that is to say, the OS result It is also statistically valid. Although the difference in the primary study endpoint of PFS (5.6 vs 4.5, HR 0.66 (0.51, 0.86)), unfortunately there was no statistical difference in OS (10.6 vs 11.3, HR 1.01), even in the sotorasib group The absolute value of OS was slightly lower than that of the docetaxel chemotherapy group.

Evaluation of the efficacy of anti-tumor treatment

Regarding the evaluation of tumor treatment efficacy, the RECIST evaluation standard is currently commonly used in clinical practice, which is used to evaluate the overall condition of the patient's disease. The longest diameter of the tumor (needs ≧20mm) is used as the measurement baseline; it is only applicable to solid tumors, excluding blood system and lymphoma. After treatment, a reduction of ≧30% in the longest diameter of the tumor is considered partial response, and an increase of ≧20% is considered disease progression. For details, see: How to evaluate the progression, stability, or remission of tumor disease?

Antineoplastic drug clinical trial endpoints

Clinical trial endpoints serve different research purposes. In traditional oncology drug development, the purpose of early clinical trials is to evaluate the safety and biological activity of the drug, such as tumor shrinkage. Later-stage effectiveness studies typically evaluate whether a drug provides a clinical benefit, such as prolonged survival or improvement in symptoms.

In 1988, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use issued the "Statistical Guidelines for Clinical Trials" (ICH E9), proposing an overall recommendation to set the primary endpoint of clinical trials to one [1]. In 2007, the U.S. Food and Drug Administration (FDA) issued its first anti-tumor drug clinical trial endpoint guidelines, and revised the guidelines in 2018. In 2012, the former State Food and Drug Administration of China also issued the "Technical Guiding Principles for Anti-tumor Drug Clinical Trial Endpoints", which provided recommendations on the type, comparison and statistical analysis of the main efficacy endpoints of anti-tumor drug clinical trials for the purpose of supporting the launch of new drugs [ 2-4].

In view of the multi-endpoint design and the resulting multiplicity problems, the European Medicines Agency, the FDA and the China Medical Products Administration have successively issued various guidance documents to systematically elaborate on common multiplicity problem scenarios, multiplicity adjustment strategies and procedures in clinical trials. Analytical methods, etc. [5-6]. In 2019, in response to common concomitant events in clinical trials, the ICH Steering Committee issued ICH E9 (R1) to clarify issues such as the definition of estimated targets, including the primary endpoint, and its sensitivity analysis methods. This series of guidelines has important guiding significance for the design and statistical analysis of primary endpoints of oncology drugs.

The "Technical Guiding Principles for Endpoints of Anti-Tumor Drug Clinical Trials" issued by China states that clinical trial endpoints include overall survival (OS), endpoints based on tumor measurement such as disease-free survival (DFS), ORR, complete response (CR), time to progression (TTP), progression-free survival (PFS), and endpoints based on symptom evaluation. A comparison of important clinical trial endpoints used in the approval of anti-cancer drugs is shown in the table below

In clinical trials of anti-tumor drugs, the scientific design of primary and secondary endpoints is very important. They are used to evaluate the safety and efficacy of drugs and provide objective data to support drug approval and use. The following are generally the scientific design principles for primary and secondary endpoints in clinical trials:

Primary endpoint: The primary endpoint is usually the most critical endpoint used to assess efficacy. For example, clinical trials can use patient survival as the primary endpoint to evaluate whether a drug can prolong patient survival. The selection of the primary endpoint should have the following characteristics: be relevant to drug treatment, be clinically important, measurable, and have a clear outcome.

Secondary endpoints: Secondary endpoints are used to provide additional information to more fully assess the efficacy and safety of the drug. Secondary endpoints may include survival, delay in disease progression, clinical response rate, etc. The selection of secondary endpoints should be related to the primary endpoint and should also take into account that some secondary endpoints may be easily misunderstood or uncertain.

Statistical design: Properly designed statistical methods are critical to ensuring the reliability and validity of clinical trials. The size and grouping of trial samples, randomization procedures, double-blind design, etc. all need to be designed according to scientific principles to ensure the credibility and generalizability of the results.

Endpoint measurement: Primary and secondary endpoints often require rigorous measurement procedures to ensure data accuracy and consistency. Measurement methods must be reliable and valid and must undergo predetermined, standardized procedures.

The primary goal of scientific design is to ensure that the results of clinical trials are reliable, valid, and clinically meaningful. This requires full consideration of the drug's mechanism of action, pharmacokinetics, disease characteristics and other factors during the design stage, and weighing them in combination with clinical practice experience and ethical principles. The design process often requires a combination of multidisciplinary expertise and clinical experience to ensure scientific and interpretable results.

References

[1]Stat Med, 2001, 20(17-18):2549-2560. ??

[2]JAMA Oncol, 2018, 4(6):849-856.?

[3]Am J Cancer Res, 2021, 11(4):1121-1131. ? ?

[4]Lancet Oncol, 2015, 16(1):e32-e42.?

[5]N Engl J Med, 2018, 378(22):2115-2122. ? ?

[6]Stat Med, 2014, 33(4):693-713.??