ASCO癌症临床试验临床意义标准指南（2013年）

New draft recommendations from the American Society of Clinical Oncology set the bar higher for clinically meaningful results from future trials on pancreatic, lung, breast, and colon cancers.

Developed by ASCO’s Cancer Research Committee, the draft recommendations are intended to provide an expected minimum increase in overall survival for each cancer discussed; the hope is to improve accrual and guide definitive Phase III trials based on a strong foundation from Phase II trials. Recognizing that providing guidelines and benchmarks for meaningful clinical trial outcomes is a “daunting task,” the ASCO Research Committee decided to start by selecting and focusing on four cancer types.

The recommendations come at a time when ASCO President Sandra M. Swain, MD, Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center, is calling on Congress to pass a bipartisan bill, HR 1416, which would exempt cancer drugs from sequester budget cuts, cuts that overall could have a chilling effect on cancer research. “More than 120 Members of Congress have signed a letter asking the Secretary [of Health and Human Services] to exercise any authority she has to reverse the cuts and to make it a high priority,” Swain said in a statement. But, she noted, HHS Secretary Kathleen Sebelius has stated that she does not have that authority.

The recommendations on future clinical trial design were developed by working groups convened by the society’s Cancer Research Committee; included were staff from the US Food and Drug Administration and patient advocates. Once public comments on them have been analyzed and consensus has been reached on their final form, they will be submitted to ASCO’s board and then prepared for journal publication, said Lee M. Ellis, MD, Chair of the Cancer Research Committee, lead author on the new recommendations, and Director of the Colorectal Cancer Translational Research Program and Professor of Surgery at the University of Texas MD Anderson Cancer Center.

Ultimate Goal

The ultimate goal, he said, is to work with patient advocacy groups and encourage investigators to design and implement clinical trials using ASCO’s suggested outcomes criteria as benchmarks.  He said he plans to participate in an educational session on the draft guidelines at ASCO’s upcoming annual meeting May 31-June 4 in Chicago.

The recommended benchmarks are a response to ASCO’s sweeping November 2011 Accelerating Progress Against Cancer:  Blueprint for Transforming Clinical and Translational Research (OT, 12/10/11 issue), which was timed to come out 40 years after President Nixon signed the National Cancer Act in December 1971. The ASCO Blueprint was influenced by the National Cancer Institute’s revitalization of the Clinical Trials Cooperative Group Program and a 2010 Institute of Medicine report, A National Cancer Clinical Trials System for the 21st Century.  

ASCO recognized that “cancer science is now in a period of revolutionary change,” said ASCO then-President Michael P. Link, MD, the Lydia J. Lee Professor of Pediatric Cancer at Stanford University School of Medicine, who noted that the molecular era demands new approaches based on cancer biology: smarter, targeted therapy grounded in specific clinical-trial findings. Thus the ASCO Blueprint encouraged smarter, faster clinical trials to provide results in a timely manner targeted to specific patient groups.

Taking into account quality of life, the working groups on meaningful clinical outcomes for the most part agreed that if a therapy is relatively non-toxic, then a smaller improvement in overall survival is acceptable. Although consensus on guideline recommendations was sometimes hard to reach, “nearly all of the working groups agreed that we are in a new era where molecular tools can provide for the identification of new targets that, in turn, will lead to the development of new drugs,” states the draft document.

‘Push the Edge of the Envelope’

The recommendations are just that, and not rules, the committee emphasized. The draft recommendations are intended to “push the edge of the envelope” in an effort to advance cancer care. The document states: “These recommendations must be updated and modified as the current standard of care for each disease evolves.”

Cancer-specific draft recommendations on overall survival follow; a detailed table in the draft document summarizes the recommendations for each cancer discussed.

• Pancreatic cancer.  The recommendations state: “Clinical trials should aim to improve overall survival (OS) by a minimum of 50 percent, or three to five months, while considering the trade-off of toxicity and quality of life that are specific to pancreatic cancer.” The working group focused on metastatic or locally advanced pancreatic cancer. Two patient subgroups were chosen for discussion: those who were FOLFIRINOX-eligible and those who were gemcitabine-eligible. The working group noted that “measurement of OS is feasible in pancreatic cancer due to the short duration of patient survival and limits on the number of lines of therapy received because of morbidity.” Committee members recommended that instead of global quality-of-life questionnaires, that future trials should assess symptoms specific to pancreatic cancer patients: pain, weight loss, anorexia, and fatigue.
• Lung cancer. The recommendations state: “Clinical trials should aim to improve overall survival by a minimum of 25 percent with only a minor increase in toxicity, as compared with standard therapy.” The guidelines focus on two subgroups of patients with advanced metastatic (Stage IV) non-small cell lung cancer: those with non-squamous and those with squamous disease.Since survival after first-line therapy is unfortunately “relatively short” for lung cancer patients, the working group noted that “OS is a feasible endpoint.” Excluded from the recommendations were lung cancer patients whose tumors have EGFR mutations, ALK translocations and ROS translocations, since they are eligible for specific, effective targeted therapy.
• Breast cancer. The recommendations state: “Clinical trials should aim to improve overall survival by a minimum of 20 percent if involving minimal to modest increases in toxicity.” The breast cancer working group recognized that breast cancer is heterogeneous even within a broad genotypic and phenotypic category. The group focused on patients with metastatic triple-negative breast cancer (previously untreated for metastatic disease) because of “the poor survival of this group of patients, the absence of validated targeted therapies, and the urgent need for improved treatment options.” The working group noted that “classical cytotoxic drugs typically improve OS by two to three months, and we should expect better from molecularly targeted agents based on the identification of driver mutations and/or alterations.” There were “widely divergent views” within this working group, but members reached consensus on a clinically meaningful trial outcome of 4.5 months or greater improvement in median overall survival. “Lower (three to four months) improvement in median OS can be considered clinically meaningful if the benefit outweighs the risk,” the working group advised. Patient advocates who contributed to the recommendations stressed that, where metastatic breast cancer is concerned, quality of life is as important, if not more important, than longevity.
• Colon cancer. The recommendations state: “Clinical trials should aim to improve overall survival by approximately three to five months, with minimal increase in toxicity compared with current regimens/drugs utilized in this setting.” The working group said this recommendation takes into account greater efficacy balanced against toxicity. The colon cancer recommendations focus on patients with metastatic colon cancer whose disease has progressed on all standard therapies. Because “there is evolving data that patients whose tumors harbor BRAF mutations have a poorer prognosis than others,” the working group members decided to exclude this patient subpopulation from their recommendations. The working group noted that the FDA approved regorafenib for metastatic colon cancer based on a median improvement of 1.4 months in overall survival. The working stated that in future clinical trials, patients with metastatic colorectal cancer who are refractory to standard therapy can be given regorafenib as best supportive care in the control arm.

Praise for Taking the Lead

When ASCO released its report in 2011 on transforming clinical translational research, the IOM’s National Cancer Policy Forum Chair John Mendelsohn, MD, praised ASCO for taking the lead in moving clinical research forward to produce more timely therapies: “What’s important is that this initiative is coming from doctors,” said Mendelsohn, Co-Director of the Khalifa Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center. “In the future, I see more clinical trials that involve an adaptive design.”

Underlying the ASCO Research Committee’s new recommendations is a basic understanding of how cancer research has evolved: “We can no longer view metastasis or unresectable tumors that originate from an organ as homogeneous, and thus treat with one standard regimen,” the recommendations state.