Tumor Trial Endpoints: Understanding OS PFS DFS and 8 Key Measures

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Tumor Trial Endpoints: Understanding OS PFS DFS and 8 Key Measures

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Tumor Trial Endpoints: Understanding OS PFS DFS and 8 Key Measures

In recent years, it’s evident that clinical research and the introduction of new anti-tumor drugs have been in a constant surge. Deciphering the clinical studies of these new drugs has become an essential skill for oncologists, especially those in the field of oncology.

The most commonly used efficacy endpoints in clinical trials for anti-tumor drugs include Overall Survival (OS), Objective Response Rate (ORR), and Progression-Free Survival (PFS).

Similar to ORR, another endpoint is Disease Control Rate (DCR).

Endpoints like Disease-Free Survival (DFS), Event-Free Survival (EFS), Time To Progression (TTP), and Time To Treatment Failure (TTF) are also related to PFS.

Overall Survival (OS):

Definition:

The time from randomization (or the start of treatment in a single-arm trial) to death from any cause.

Positioning:

OS is considered the gold standard in evaluating the clinical benefits of anti-tumor drugs in randomized controlled clinical trials. It is widely accepted and recognized, providing a statistically significant and clinically meaningful improvement. OS improvement supports the standard application for new drug approvals.

Advantages:

Widely recognized as a clinical benefit endpoint, based on objective and quantitative measures, precise and easy to assess.

Disadvantages:

Often involves a 5-year survival rate, requiring large samples and longer follow-up. Results may be influenced by crossover and subsequent treatments, and the inclusion of non-tumor deaths can impact accuracy.

In some promotional events by drug manufacturers, OS efficacy is sometimes compared horizontally with results from other manufacturers to highlight their own drug’s effectiveness. However, comparing OS from different trials is unreliable due to potential heterogeneity in patient selection, standard of care (SOC), and best supportive care (BSC).

Objective Response Rate (ORR):

Definition:

The proportion of patients achieving a predefined reduction in tumor volume according to recognized response evaluation criteria (such as RECIST 1.1).

Positioning:

ORR is a direct measure of a drug’s anti-tumor activity and is commonly evaluated in single-arm trials. While ORR alone generally cannot be a basis for drug approval, for drugs with significant or breakthrough efficacy, especially those urgently needed clinically, temporary accelerated approval can be obtained based on ORR results. However, subsequent supplementation with PFS or OS results is usually required.

Advantages:

Typically requires smaller sample sizes and shorter follow-up times. Attributed to the drug, excluding the natural progression of the disease, and is based on objective and quantitative evaluation, making it suitable for population enrichment trials.

Disadvantages:

The main drawback is that ORR efficacy may not translate into survival benefits. Frequent imaging assessments are needed during the evaluation, and ORR is not a direct measure of clinical benefit. Additionally, using ORR alone may not fully describe the drug’s anti-tumor activity, necessitating descriptive analyses of response duration (from initial tumor response to disease progression or death for any reason, whichever occurs first) and time to response.

Disease Control Rate (DCR):

Definition:

The proportion of patients achieving relief (PR+CR) and disease stabilization (SD) based on recognized response evaluation criteria (such as RECIST 1.1).

Positioning/Advantages and Disadvantages:

Equivalent to Objective Response Rate (ORR). DCR and ORR have similar clinical research significance. The difference lies in that DCR includes patients with stable disease (SD), i.e., DCR = CR+PR+SD, while ORR = CR+PR. The ability to maintain a tumor in SD for an extended period is also an indication of the drug’s efficacy. For drugs that clinically benefit patients through disease stabilization, DCR can also be analyzed.

Progression-Free Survival (PFS):

Definition:

The time from randomization (or the start of treatment in a single-arm trial) to tumor progression or death from any cause (whichever occurs first).

Positioning:

PFS is an endpoint based on tumor measurements, primarily assessing the anti-tumor activity of a drug, to some extent balancing drug safety and patient survival (unexpected death). In some clinical studies, PFS is closely related to OS outcomes. Certain immune combination therapies in first-line non-small cell lung cancer studies and drugs like sunitinib and sorafenib in advanced renal cell carcinoma have been approved based on PFS. However, in recent years, the FDA has not highly recognized PFS results, and drug approvals generally rely on OS outcomes.

Advantages:

Usually involves smaller sample sizes and shorter follow-up times. Studies are typically based on objective and quantitative evaluations, unaffected by crossover and subsequent treatments, providing higher credibility.

Disadvantages:

Although PFS is highly correlated with OS, it may not always translate into survival benefits. PFS assessment requires frequent imaging evaluations, and evaluation biases may exist. Importantly, PFS results are influenced by assessment intervals, and definitions and deletion rules for PFS may vary between different trials, requiring clear definitions beforehand.

Disease-Free Survival (DFS) & Event-Free Survival (EFS):

Definition:

DFS is the time from randomization (or the start of treatment in a single-arm trial) to disease recurrence or death from any cause (whichever occurs first).

EFS is the time from randomization (or the start of treatment in a single-arm trial) to the first occurrence of any of the following events: progression of the disease to a point where surgery is not possible, local or distant recurrence, or death from any cause.

Positioning/Advantages and Disadvantages:

Equivalent to Progression-Free Survival (PFS). DFS, EFS, and PFS are similar endpoints.

DFS primarily evaluates disease recurrence and is often used to evaluate adjuvant therapy after surgery or radiotherapy.

EFS, compared to DFS, expands the indications for surgical treatment and is often used to evaluate neoadjuvant therapy before surgery or radiotherapy.

When extending survival makes it difficult to use OS as the primary endpoint, DFS and EFS can serve as important endpoints. For example, adjuvant therapy for breast cancer and colorectal cancer may use DFS as the primary endpoint, and neoadjuvant therapy before radical surgery for breast cancer may use EFS as the primary endpoint.

DFS and EFS include non-tumor deaths, and deaths from early or locally advanced tumors not progressing may introduce more bias than deaths from late-stage tumors. Defining all deaths occurring after long-term loss to follow-up as disease recurrence may overestimate efficacy. Distinguishing between tumor/non-tumor deaths and excluding non-tumor deaths may introduce bias in determining the cause of death.

Time To Progression (TTP) & Time To Treatment Failure (TTF):

Definition:

Time To Progression (TTP) is the time from randomization to the occurrence of objective tumor progression, excluding deaths.

Time To Treatment Failure (TTF) is the time from randomization to treatment failure or withdrawal from the trial, with reasons for withdrawal including patient request, disease progression, death, or adverse events.

Positioning/Advantages and Disadvantages:

Equivalent to Progression-Free Survival (PFS). Both are positioned similarly to PFS, and the analysis of these two endpoints is usually considered a sensitivity analysis. The results cannot be the main evidence for confirmatory study conclusions but can be used to support the main PFS results.

Differences between Time To Progression (TTP), Time To Treatment Failure (TTF), and Progression-Free Survival (PFS):

TTP, compared to PFS, excludes deaths. Although it more objectively reflects the anti-tumor effects of drugs, its correlation with OS is lower than PFS because it does not include deaths.

TTF, compared to PFS, combines the effectiveness and safety characteristics of the drug, including all-cause treatment failure and deaths. However, the judgment of treatment failure may be subjectively influenced and is less objective than imaging assessments.

In summary, understanding the nuances of endpoints such as OS, PFS, and DFS is crucial for accurately interpreting the efficacy of anti-tumor drugs in clinical trials.

Each endpoint has its advantages and limitations, and their appropriate use depends on the specific context and goals of the study.

Tumor Trial Endpoints: Understanding OS PFS DFS and 8 Key Measures

(source:internet, reference only)

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