Roxanne Nelson

June 14, 2013

CHICAGO — As technology and therapies evolve, so must the design of clinical trials, which provide the evidence base used to improve cancer treatments. To "raise the bar" on clinical trial standards, the American Society of Clinical Oncology (ASCO®) has issued draft recommendations for the design of trials that provide "clinically meaningful outcomes."

During a session here at the 2013 Annual Meeting of ASCO, Lee Ellis, MD, explained why the ASCO cancer research committee decided to put together these guidelines.

"First, we owe it to our patients to do better," said Dr. Ellis, who is committee chair and director of the colorectal cancer translational research program at the University of Texas M.D. Anderson Cancer Center in Houston.

Second, in the current era, "tumors can be defined by their molecular drivers and we have a better understanding of cancer biology. Immune therapy is working, and we need to exploit this and look for biomarkers," he noted.

Third, "with only so much money in the bank" because of economic restraints from funding agencies, there is a choice between doing a few large trials or many small trials. But the small trials need to be smarter, so we have to raise the bar.

Dr. Ellis emphasized that these are only draft recommendations, and the committee continues to receive feedback from the community. "These are not rules, so if you don't meet all of them, it doesn't mean that your clinical trial is not useful," he said. "But we have to set the bar in order to do better, to use the foundation of genomic medicine and what we know about immunology to improve outcomes."

He noted that these guidelines will not please everyone and, in a way, "that's good." There are many valid arguments for various viewpoints, he said.

We believed if we aimed too high or too low, "no one would pay attention," Dr. Ellis explained. "We worked really hard to hit that midpoint, where we would get people intrigued by our recommendations."

Draft Recommendations for Pancreatic Cancer

The committee looked at 2 disease states — metastatic pancreatic cancer and locally advanced disease — and 2 treatments — FOLFIRONOX (irinotecan, oxaliplatin, leucovorin, and 5-fluorouracil) and gemcitabine.

It is recommended that clinical trials aim to improve overall survival by ~50% and that toxicity and quality of life specific to pancreatic cancer be taken into consideration.

For the FOLFIRONOX group, a meaningful benefit in median overall survival would be 4 to 5 months; for gemcitabine, it would be 3 to 4 months.

Draft Recommendations for Lung Cancer

The committee looked at 2 subpopulations of patients with advanced metastatic (stage IV) nonsmall-cell lung cancer — those with squamous cell disease and those with nonsquamous cell disease.

Patients with EGFR and ALK mutations were excluded because there has been some degree of success with those.

It is recommended that clinical trials aim to improve overall survival by ~25% to 30%, with a minimal increase in toxicity. For squamous cell disease, that benefit would be an increase of 2.5 to 3.0 months (target hazard ratio [HR], 0.77 - 0.80); for nonsquamous cell disease, it would be 3.25 to 4.00 (target HR, 0.76 - 0.80).

Draft Recommendations for Breast Cancer

Dr. Ellis noted that the discussion was livelier and the opinions more diverse for breast cancer than for the other cancers.

The committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. In this population, survival is poor, there is an absence of validated targeted therapies, and there is an urgent need for better treatment options.

Currently, the median overall survival in this population is 18 months, and cytotoxic therapies provide only a short benefit (2 to 3 months). The general consensus for a meaningful benefit in median overall survival was 4.5 months, said Dr. Ellis. "This encourages bold approaches."

Draft Recommendations for Colorectal Cancer

Subpopulations are difficult to define in colorectal cancer, and treatment is a continuum, not an orderly progression from first- to second-line therapies. In addition local/regional approaches confound the analysis of common end points. Therefore, the committee focused on patients who have progressed on first- or second-line therapy or who are not candidates for standard therapies, and excluded those with BRAF-mutated tumors.

It is recommended that clinical trials aim to improve overall survival by ~50% in patients who have progressed on standard treatments, and the increase in toxicity should be minimal. The general consensus for a meaningful benefit in median overall survival was 3 to 5 months.

The To-Do List

There is still a to-do list to complete for these draft recommendations, Dr. Ellis noted.

The 1- and 2-year survival recommendations need to be revisited, and progression-free survival needs to be added to tables, where appropriate, he explained. Statistics need to be revised and tables need to be added that define the number of patients needed for the ranges provided in specific tables.

"Once we respond to comments from the ASCO membership and refine our paper, we'd like to submit it for peer reviewed publication," he added.

2013 Annual Meeting of the American Society of Clinical Oncology. Presented June 2, 2013.

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