Clinical Trials and Tribulations in Oncology

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There has been significant progress in the development of novel cancer therapies.
There has been significant progress in the development of novel cancer therapies.

Over the past decade, there has been significant progress in the development of novel cancer therapies.1 These treatments have contributed to the increase in survival rates and in the health-related quality of life (HRQoL) benefits for many patients with formerly limited treatment options.

Consisting of newer agents such as the targeted therapies and novel combinations, improved outcomes have been seen across a number of cancers including metastatic colorectal cancer where median overall survival (OS) has doubled from 12 months (associated with earlier single-agent therapy) to more than 24 months; or in chronic myeloid leukemia (CML) where the 10-year survival rate dramatically improved from 20% to 80%.2,3

The development of new therapies for patients with cancer is a welcomed development. However, the availability of more effective treatments today is, in some ways, challenging the development of newer drugs for tomorrow.

RELATED: The Future of Clinical Trials: 'Smaller and Smarter'

Clinical trials are facing practical and statistical challenges associated with the greater number of treatment options and the relative extended rates of survival in some conditions. One issue lies in the ability for investigators to detect an OS benefit among experimental lines of therapy.

Mario Sznol, MD
Stephen A. D'Amato, PharmD, MS

As trial participants live longer, and as more treatment options are available, clinical trials will likely require more participants and more time to satisfy the statistically significant difference necessary to prove an advantage in OS, the gold standard primary endpoint in metastatic disease. In one example, it took 8 years after a trial for metastatic breast cancer was opened, and 2 years after the initial results were made public, before median survival data was reached.4 Those initial results were not based on OS data, but progression-free survival (PFS), another endpoint.

Recognizing that it may be appropriate in some settings, a growing number of trials have been using PFS as the primary clinical endpoint to prove effectiveness and gain approval. Between 2000 and 2010, 29% of the randomized controlled trials that led to approvals used PFS or time to progression as study primary endpoints among anticancer agents approved for solid tumors.5

Waiting years to detect an OS benefit after a study drug shows superiority to the standard of care treatment isn't an attractive option from an ethical standpoint. As a result, regulatory bodies like the U.S. Food and Drug Administration have accepted PFS as a surrogate endpoint for approvals in certain types of cancers; providing that the magnitude of benefit is deemed sufficient and the side-effect profile is acceptable.6

When an investigational therapy shows a substantial improvement in delaying disease progression, this can represent a clear benefit to a patient, especially when tumor growth is symptomatic, and is accompanied by debilitating effects, including severe pain. Prolonging PFS can provide meaningful palliation, sustainment of HRQoL, and, in some cases, an improvement in QoL.7



“In advanced breast cancer, disease progression is often symptomatic and uncomfortable, so if we can delay that, it's a benefit to the patient.”

– Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics at the National Cancer Institute's Division of Cancer Treatment and Diagnosis.8


OS is still the gold standard endpoint because it represents a clear sign of benefit; a patient lives longer because he or she received a particular medication or sequence of medications. But being able to show this, and doing so within a reasonable timeframe considering the lethality of a disease like cancer, might be too high of a bar to set. 

Understanding why this is, and recognizing the value associated with certain clinical responses, like the delaying of disease progression, is important to ensure that the most effective treatment options are made available for patients.

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