Navigating Key Endpoints in Oncology Clinical Trials

Clinical trials are key to understanding the benefits and risks of new therapies. All clinical studies rely on endpoints — objective measures of how a therapy performs in groups of people over time. Below is a guide to navigating a dozen endpoints used in oncology clinical trials.

Overall Survival

One of the main aims of any cancer treatment is to prolong life. As such, overall survival remains the gold standard for assessing the effectiveness of a cancer therapy or treatment plan, which may involve a new drug or drug combination, radiation, or surgery.

In oncology studies, overall survival reflects how many people receiving a particular treatment were still alive at a certain timepoint or how long the typical person receiving the treatment lived. This study from last month’s American Thyroid Association meeting, for instance, found that almost 75% of patients with BRAF V600E-mutated anaplastic thyroid cancer were still alive at 2 years after receiving neoadjuvant pembrolizumab plus dabrafenib and trametinib. The median overall survival among these patients was 63 months.

Progression-free Survival (PFS)

PFS is defined as the length of time before a cancer progresses or a patient dies, whichever comes first. This measure is generally used to test treatments for advanced disease, in which physicians want to extend lifespan but cannot eliminate the cancer.

PFS has also become a popular surrogate for overall survival because fewer patients are needed in the trial setting and PFS can be measured more quickly. However, the use of PFS remains controversial because a growing body of evidence indicates it is often a poor surrogate for overall survival. For example, in this ovarian cancer study, rucaparib was associated with improved PFS compared with chemotherapy but worse overall survival.

Disease-free Survival

Disease-free survival is defined as the average length of time from the start of treatment until the cancer returns. Although disease-free survival and PFS seem quite similar, PFS is typically used in more advanced disease settings, while disease-free survival is typically used as a surrogate for cure. In the clinical trial setting, this endpoint helps assess whether a therapy reduced the risk that a patient’s cancer will return following definitive surgery or radiotherapy. In this adjuvant setting, research indicates that disease-free survival does appear to be a strong surrogate for overall survival in certain cancer types, including colon cancer and lung cancer.

Event-free Survival

Event-free survival measures how long people in a clinical trial remain free of certain major ‘events,’ such as disease progression, relapse, treatment discontinuation, or death.

Event-free survival is commonly used in studies of neoadjuvant treatments — therapies delivered before the main treatment to help shrink the tumor or eliminate any cancer cells that have spread — and as a primary trial endpoint for potentially curative therapies. At this early stage, avoiding harmful ‘events’ for as long as possible is key.

Time to Progression

In situations where a cancer has spread to new organs and eradicating the tumor cells is no longer possible, the goal of treatment may be to halt further growth or disease progression. Time to progression measures the length of time before a person’s cancer escapes the treatment and starts to grow again. In other words, it’s a measure of how long the disease remains stable.

Time to Treatment Failure

‘Time to treatment failure’ refers to the time from the start of a cancer treatment to its discontinuation. It is a catch-all measurement that covers all possible reasons a person might stop therapy, including disease progression, side effects, or patient choice. Unlike most measures, time to treatment failure does not aim to measure how well the therapy treats cancer. It is used to understand why patients stop treatment and may help clinicians devise strategies to mitigate those factors. Time to treatment failure is often measured alongside endpoints that do measure a therapy’s effectiveness.

Time to Next Treatment

‘Time to next treatment’ is defined as the time between starting one treatment and beginning the next. Time to next treatment is largely useful in studies of long-term, incurable cancers that need many drugs in sequence to prolong survival.

Time to next treatment has been used most often to measure the length of treatment benefit in cutaneous T-cell lymphoma. This endpoint helps capture a drug’s staying power as well as how tolerable the treatment is.

Duration of Clinical Benefit

This endpoint captures the time from the start of treatment until disease progression or death in people who responded partially or fully to treatment, or whose cancer remained stable for 24 weeks or longer. Duration of clinical benefit is usually reserved for settings where eliminating the cancer is no longer possible but stabilizing the disease could help prolong survival. As with PFS, it remains unclear whether duration of clinical benefit is a strong surrogate for overall survival for many cancers.

Objective Response Rate

Objective response rate is defined as the percentage of trial participants whose solid tumors respond either partially or fully to therapy. Objective response rate represents a solid measure of anti-tumor activity, which is typically assessed by tumor size and total tumor load, measured via imaging with CT or MRI. For consistency, researchers follow a set of rules called Response Evaluation Criteria in Solid Tumors (RECIST), in which the total diameter of up to five representative tumors are compared before and after treatment, assessed via imaging with CT or MRI. Because shrinking tumors is good but does not necessarily prolong life, studies may also assess overall survival.

Duration of Response

Duration of response is the next logical endpoint to measure after objective response rate. Duration of response is defined as the length of time tumors remain stable without growing or spreading among patients who responded to treatment, evaluated via CT or MRI. Unlike duration of clinical benefit, duration of response is used to evaluate treatments that promise long-lasting responses instead of treatments that aim to provide only temporary benefit.

Complete Response

A complete response occurs when a patient has no detectable cancer. It is used as a measure of treatment success in both solid and hematologic malignancies and evaluated with imaging. Although having a complete response to therapy sounds like great news for patients — and is much quicker to measure than overall survival — drugs that improve complete response do not necessarily prolong survival. So far, complete response seems to be a good surrogate for overall survival in multiple myeloma, but the relationship remains less clear for other cancer types.

Pathological Complete Response

A pathological complete response occurs when no cancer remains visible in the tissue removed during surgery. For this reason, this endpoint is generally reserved for studies of neoadjuvant chemotherapy — treatment given before surgery — and is typically studied in breast cancer. In breast cancer trials, patients who demonstrate a pathological complete response do seem to have better event-free survival and overall survival.

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