Chordoma Foundation

Clinical trials roundtable clarifies path to get drugs approved for chordoma

2014 ASCO Roundtable

A global panel of 37 experts has suggested that establishing new clinical trial endpoints—measurements to determine whether a cancer drug works —would allow much-needed new drugs for chordoma to be evaluated more efficiently and effectively and potentially brought to patients faster.

The panel, representing chordoma clinicians and scientists, biotech firms, and officials from the US Food and Drug Administration (FDA), was brought together by the Chordoma Foundation during the latest annual meeting of the American Society of Clinical Oncology (ASCO) in an effort to gain clarity on how to determine whether a drug is beneficial to chordoma patients.

A drug is generally deemed beneficial when it prolongs survival and/or improves a patient’s quality of life. For many years, the most common endpoint used in developing new cancer drugs has been overall survival — that is, whether the drug helps people live longer.

However, using overall survival as an endpoint is problematic for chordoma because it would take many years to measure the impact a drug has on survival—time that patients cannot afford to wait for answers. Measuring survival benefit also requires many patients to be part of the trial — an often insurmountable challenge in rare cancers, such as chordoma, where there are fewer numbers of patients to enroll in clinical trials.

To accommodate situations for which overall survival is not an ideal endpoint, there are other ways to tell if a drug is working. In fact, drugs are increasingly approved for cancer and other serious disease based on what’s called a “surrogate end-point,” an alternative measure that “stands in” for conventional clinical trial endpoints, such as survival. The goal of a surrogate endpoint is to provide a way to more quickly measure whether or not a treatment is working.

Response rate has generally been accepted as such a surrogate and has formed the basis for the approval of many cancer drugs. In clinical trials of solid tumors, including chordoma, the most widely used criteria to determine a patient’s response to an experimental treatment is called RECIST (Response Evaluation Criteria is Solid Tumors). RECIST is a set of guidelines that were developed to define when people with cancer improve (“respond”), stay the same (“stablize”), or get worse (“progress”) during treatment based, primarily, on a change in the size of their tumor. Specifically, RECIST counts a response as a 30% or greater decrease in size of the tumor’s length and width.

While RECIST can reliably detect responses that produce significant tumor shrinkage, Roundtable participants agreed that RECIST, may not accurately measure the true benefit of a drug, as it would miss clinically meaningful responses that did not result in significant tumor shrinkage. For example, a tumor could stop growing or shrink by 10% or 20% in response to a drug ­— at which point it might become resectable or cease to cause neurological symptoms—but still be deemed to not be responsive to treatment according to RECIST.

“The wrong criteria could lead to the underassessment of a drug’s activity in chordoma when in fact that drug could very well be helpful to many people who otherwise have few treatment options,” said Josh Sommer, Executive Director of the Chordoma Foundation.

This is an important issue because many of the drugs currently being developed for cancer, including those being considered for chordoma, work by stopping or slowing the growth of cancer cells but do not necessarily kill them. It would, therefore, be expected that these drugs would not result in massive tumor shrinkage for chordoma patients, even if they significantly prolong or improve life for chordoma patients.

Roundtable participants, therefore, agreed that alternative endpoints that take into consideration smaller dimensional responses and/or changes in patient reported quality of life measures­ — such as pain, mobility, or neurologic symptoms­ — would be more appropriate.  However, before forming the basis of an FDA approval, such new endpoints need to be studied to evaluate their reproducibility and utility.

Specific recommendations and outputs from the meeting are being summarized in a working document that will form the basis for a consensus statement on this important issue. In the mean time, the discussion has spurred the Chordoma Foundation, along with several meeting participants, to begin forming plans to develop and validate new outcome measures.

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