Interpretation of Endpoint Data for Clinical Trials on Tumors

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

Similar to the endpoint of ORR is the Disease Control Rate (DCR). 

Endpoints similar to PFS also include Disease Free Survival (DFS), Event Free Survival (EFS), Time To Progression (TTP), and Time To Treatment Failure (TTF).

Overall Survival (OS) 

Refers to the time from randomization (or initiation of treatment in single-arm trials) to death from any cause.

Overall Survival (OS) is the only endpoint solely based on survival events, fairly objective, and precisely measurable. Therefore, it is recognized as the most reliable endpoint in randomized controlled clinical trials to measure the clinical benefits of anti-tumor drugs, known as the gold standard in clinical trials endpoints for anti-tumor drugs. The improvements in OS have statistical significance and clinical meaning, which can be used to support the routine application for the market approval of trial drugs.

It is a widely accepted endpoint for clinical benefits, based on objectivity and quantification, and easy to measure and assess accurately.

In clinical trials, the 5-year survival rate is often used, which usually requires a larger sample size and longer follow-up period. The study results could be affected by crossover phenomena and subsequent treatment. The inclusion of non-tumor deaths in the study outcomes also might influence the accuracy of the results. 

It's worth noting that comparing OS from different trials is not reliable. There can be heterogeneity among different trials in the areas of patient selection, standard care (SOC), and best supportive care (BSC). Therefore, it is recommended to use and interpret OS data with caution in single-arm trials.

Objective Response Rate (ORR) 

This refers to the proportion of patients who, according to the universally accepted criteria for tumor mitigation, have achieved a pre-established reduction in tumor volume (CR/PR) and can maintain the minimum time requirement. The remission of solid tumors can be complete (Complete Response, CR) or partial (Partial Response, PR), while the assessment of non-solid tumors has some other evaluation criteria.

ORR is an index directly measuring the anti-tumor activity of a drug and is the most common endpoint based on tumor measurements, evaluated in single-arm trials. ORR usually cannot serve as the basis for drug approval, but for some drugs with significant ORR effects or breakthrough drugs, especially those urgently needed in clinical practice, can obtain temporary rapid approval from drug approval authorities through ORR results. Nevertheless, subsequent supplements of PFS or OS results are still required.

Typically smaller sample size, shorter follow-up time. The therapeutic effect is attributed to the drug, excluding the natural course of the disease and is usually based on objective and quantitative assessments, making it more suitable for enriched population trials.

The major downside of ORR is that the ORR effect may not translate into survival benefits. Frequent imaging evaluations are required in the process of assessing ORR, and ORR is not a direct measure of the clinical benefits of the drugs. Further, the use of ORR alone may not adequately describe the anti-tumor activity of the trial drug, hence the need for a concurrent descriptive analysis of the duration of response (i.e., the time from the initial tumor response to disease progression or death from any cause, whichever occurs first) and time to response.

Progression Free Survival (PFS)

Refers to the time from randomization (or the initiation of treatment in a single-arm trial) to tumor progression or death from any cause, whichever comes first.

PFS is a tumor measurement-based endpoint that primarily evaluates the anti-tumor activity of a drug and, to a certain extent, considers the drug's safety and patient survival (accidental death). It is generally closely related to OS results. Some immunotherapies combined with chemotherapy in first-line non-small cell lung cancer clinical trials, as well as drugs like Sunitinib and Sorafenib in advanced renal cell carcinoma, have all been approved using PFS as the primary endpoint. However, FDA approval of PFS results has not been high in recent years, and drug approvals are usually based on OS results.

Compared to OS, PFS generally requires fewer samples and shorter follow-up time. Studies are usually based on objective and quantitative assessments, and are not affected by cross-over and subsequent treatments, making them more reliable.

Although PFS is highly correlated with OS, it may not necessarily translate into survival benefits. The evaluation of PFS requires frequent imaging assessments which may introduce assessment bias. More importantly, PFS results are influenced by the assessment interval. Different studies might have different definitions and censoring rules for PFS, so a clear definition is needed in advance.

Disease Control Rate (DCR)

This refers to the proportion of patients who, according to internationally recognized criteria for alleviating evaluation, achieve tumor relief (PR+CR) and stable disease (SD) after treatment and can maintain for the minimum duration requirement.

The clinical research significance of Disease Control Rate (DCR) and Objective Response Rate (ORR) are generally the same, the difference between them is that: Disease Control Rate (DCR) includes patients with tumor maintained at SD (Stable), i.e., DCR = CR+PR+SD; ORR = CR+PR. The ability of a tumor to be controlled at SD (Stable) for a long time is also one of the effective performances of drug treatment. For drugs that benefit patients clinically by stabilizing the disease, the Disease Control Rate (DCR) can also be analyzed.

Disease Free Survival (DFS) and Event Free Survival (EFS)

Disease-Free Survival (DFS) refers to the time from randomization (or initiation of treatment in single-arm trials) to the recurrence of the disease or death due to any cause (whichever occurs first).

Event-Free Survival (EFS) refers to the time from randomization (or initiation of treatment in single-arm trials) to the first occurrence of any of the following events: progression of disease preventing surgical treatment, local or distant relapse, or death from any cause, etc.

equivalent to Progression-Free Survival (PFS). Progression-Free Survival (PFS), Disease-Free Survival (DFS), Event-Free Survival (EFS) are similar in meaning as endpoints.

Disease-Free Survival (DFS) primarily assesses disease recurrence and is frequently used to evaluate adjuvant therapy post-surgery or radiotherapy.

Event-Free Survival (EFS), compared to Disease-Free Survival (DFS), adds a surgical intervention criterion and is often used to evaluate neoadjuvant therapy pre-surgery, or radiotherapy.

When survival duration makes Overall Survival (OS) difficult to maintain as the primary endpoint, DFS, EFS can serve as important endpoint indicators. Such as in breast cancer, colorectal cancer adjuvant therapy where DFS can be the main endpoint, and EFS as the main endpoint in neoadjuvant therapy before radical mastectomy for breast cancer, etc.

Both DFS and EFS include non-tumor deaths, with non-progression deaths in early or locally advanced tumors potentially creating more bias compared to late-stage tumors. If deaths occurring after long-term loss to follow-up are all defined as disease recurrence, it might overestimate the treatment effect. But distinguishing between tumor/non-tumor deaths, and omitting non-tumor deaths, could result in bias when determining the cause of death.

Time To Progression (TTP) and Time To Treatment Failure (TTF)

Time to progression (TTP) refers to the period from randomization to the manifestation of objective tumor progression, but excluding occurrences of death. 

Time to treatment failure (TTF) indicates the duration from randomization to the failure of treatment or withdrawal from the trial. The reasons for trial withdrawal could include patient's request, disease progression, death, or adverse events.

Equivalent to Progression-Free Survival (PFS). Both TTP and TTF are positioned similarly to PFS endpoints. The analysis of these two endpoints is often considered as sensitivity analyses, with their findings not serving as primary evidences for confirmatory research conclusions but can be utilized in supporting the main endpoint PFS results.

The distinctions among Time to Progression (TTP), Time to Treatment Failure (TTF), and Progression-Free Survival (PFS)

TTP, when compared to PFS, excludes death. While it can reflect the anticancer effects of the drug more objectively, its correlation with OS (Overall Survival) is lower than that of PFS since it does not include death. 

TTF, in comparison to PFS, synthesizes the effectiveness and safety characteristics of the drug, encompasses treatment failure for any reason and includes death. However, the judgement of therapy cessation might be subjective and not as objective as radiological assessments.