Oncology

Metastatic Pancreatic Cancer

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Why Are Positive Results so Exceptional in Metastatic Pancreatic Cancer Clinical Trials?

expert roundtables by Alok Khorana, MD; Michael Morse, MD, MHS, FACP; Thomas A. Abrams, MD

Overview

Why are positive phase 3 trials so elusive in metastatic pancreatic adenocarcinoma? Experts consider several factors that may be involved, including selection bias and the mixing of distinct populations of patients that have different prognoses. They also explore the possibility of an upward adjustment to benchmarks, noting the importance of judicious phase 3 clinical trial designs—and of persistence in trying novel therapies.

Q:

Why do a large proportion of phase 3 clinical trials in metastatic pancreatic cancer have negative results, and what can be done to improve this situation?

Thomas A. Abrams, MD

Assistant Professor of Medicine
Harvard Medical School
Senior Physician
Dana-Farber Cancer Institute
Boston, MA

A litany of trials have failed, as this question points out, and the few study results that have really been positive have been questioned as to whether they are clinically meaningful or not. Fortunately, a few recent study results have been unequivocally positive, but it is a difficult disease to treat. I think that is really the message that these trial failures have given us. The way to ensure better outcomes is to be more judicious in how we design phase 3 trials and to try to bring drugs to the market that are much more logical and have better single-agent efficacy, instead of just putting drugs together in not-the-most-scientifically-precise ways. We just have to be more judicious, think about things from a scientific perspective, and continue to try out novel drugs. It is a very difficult disease, and not many treatments work. As long as we can be logical about how we think about bringing drugs through the development process, then we can do a better job of having success. 

“Fortunately, a few recent study results have been unequivocally positive, but it is a difficult disease to treat. I think that is really the message that these trial failures have given us.”

Thomas A. Abrams, MD

Alok Khorana, MD

Professor of Medicine
Director, Gastrointestinal Malignancies Program
Cleveland Clinic
Cleveland, OH

Pancreatic cancer to a large extent is the “graveyard” of phase 3 randomized trials. In the past 25 years, there have been 35 randomized clinical trials and only 3 of those have had positive results. It is almost a 90% failure rate. These are phase 3 randomized trials, which means that these agents were tested in phase 1 and phase 2 and sometimes in the randomized phase 2 setting before they are brought to a phase 3 setting. The concern is that there is something flawed in the way we develop drugs for pancreatic cancer from the phase 1, to the phase 2, to the phase 3 setting. There are stopping rules for saying okay, this drug is good enough to go to phase 3 or this drug should just not have further development after phase 2. Obviously, there is something flawed because whatever those rules are, 90% of the time when we get to phase 3, we are failing to advance those drugs into the market. Many people have argued that this is partly a patient selection bias in early phase trials. Early phase trials are often held in large academic centers where you may have an influx of patients who are there specifically for clinical trials, but that also means that they are healthier, more able to travel to academic centers, or have better access to health care. A second issue is the mixing of locally advanced metastatic disease as in the past phase 2 and phase 3 trials. Both included a mix of patients with locally advanced disease and patients with metastatic disease, and the prognosis for those patient groups is different. If you have a greater number with locally advanced disease, the treatment looks more efficacious compared with historical controls, but in the phase 3 setting when there is more distribution of drugs at multiple sites, you will likely end up with more metastatic patients. Then the treatment does not look as efficacious. There has been a call to reform studies designed so that it is just patients with metastatic disease or just locally advanced disease in the trials. In the early phase trials, we have a more homogeneous population. Then people have made the argument that the benchmark should be higher; eg, it should be a 50% improvement or a 75% improvement rather than just a marginal improvement for more clinical trial programs in the phase 3 setting.

"In the past 25 years, there have been 35 randomized clinical trials and only 3 of those have had positive results. It is almost a 90% failure rate.”

Alok Khorana, MD

Michael Morse, MD, MHS, FACP

Professor of Medicine, Division of Medical Oncology
Professor, Department of Surgery
Duke University Medical Center
Durham, NC

This is an area that has been very vexing because we have had way more negative trials than positive trials in pancreatic cancer research—to the point that some people have wondered if the positive trials are just statistical aberrations. However, we now know from analyses that the big problem has been assuming efficacy from studies that have actually shown only marginal improvements from historical data, or even randomized phase 2 studies that show very small differences. If you can have a step up of 50% or 100% improvement in progression-free survival—or, better yet, overall survival improvement compared with historical data—then I think you can infer from that, you have a better chance of showing efficacy in a phase 3 trial. 

References

Notta F, Hahn SA, Real FX. A genetic roadmap of pancreatic cancer: still evolving. Gut. 2017;66(12):2170-2178. 

Rahib L, Fleshman JM, Matrisian LM, Berlin JD. Evaluation of pancreatic cancer clinical trials and benchmarks for clinically meaningful future trials: a systematic review. JAMA Oncol. 2016;2(9):1209-1216. 

Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.

Alok Khorana, MD

Professor of Medicine
Director, Gastrointestinal Malignancies Program
Cleveland Clinic
Cleveland, OH

Michael Morse, MD, MHS, FACP

Professor of Medicine, Division of Medical Oncology
Professor, Department of Surgery
Duke University Medical Center
Durham, NC

Thomas A. Abrams, MD

Assistant Professor of Medicine
Harvard Medical School
Senior Physician
Dana-Farber Cancer Institute
Boston, MA

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