A first-of-its-kind randomized clinical trial offers strong and perhaps surprising evidence that a combination of two targeted melanoma drugs when given continuously keeps patients' cancer from growing or spreading longer when compared with intermittent treatment, according to study results to be presented at the 2020 virtual annual meeting of the American Association for Cancer Research.
The findings will be presented at the AACR's opening clinical plenary on Monday, April 27 at 10:25 a.m. EDT by Alain Algazi, MD, an associate professor in the Department of Medicine at University of California San Francisco and the study chair with SWOG Cancer Research Network, which led the research. SWOG is a cancer clinical trials network funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and a member of the oldest and largest publicly-funded research network in the nation.
Algazi's study, SWOG S1320, focuses on treatment for melanomas with mutations in the BRAF gene, changes that cause cancer cells to grow rapidly. About half of all melanomas diagnosed involve a BRAF mutation, and Algazi's study focused on treatments for patients with the most common melanoma mutations - BRAFV600E and BRAFV600K. These cancers can be difficult to treat because they often become resistant to drugs designed to target BRAF mutations, and can return months after treatment even more difficult to defeat. In 2013, results of a high-profile study in mice were published that suggested giving the standard drug combination intermittently may be a way to beat this cunning cancer and help patients live longer before their cancer grew or spread, an outcome known as progression-free survival. Algazi wanted to test this idea in humans, and his phase II randomized trial is the first do so.
SWOG is part of the NCI's National Clinical Trials Network (NCTN), which includes more than 2,000 cancer centers, university hospitals, and community sites in the U.S. and abroad. Using this network, Algazi's team enrolled 249 eligible melanoma patients from 68 clinical sites over a five-year period. Of the 249 patients, 206 were randomized. Every patient was given the commonly prescribed BRAF and MEK inhibitor combination regimen of dabrafenib and trametinib. One group of patients took the combination of pills each day until their cancer progressed. Another group took the same daily combination for five weeks, then took a three-week break, then resumed treatment for another five weeks, then took a break, and so on, until their cancer progressed. During the treatment period, each patient had a CT scan every eight weeks to measure their tumor size. Patients also gave blood and tumor samples.
Results showed that the patients who received continuous drug doses were, on average, did not have their cancer progress for nine months. Patients who received intermittent doses, on average, did not have their cancer progress for five months.
So continuous dosing was more effective in this study. And the positive results on intermittent dosing found in mice - now the subject of dozens of clinical trials - did not appear to hold up in humans, SWOG results show.
"What works in pre-clinical studies doesn't always work in real-world clinical studies," Algazi said. "In melanoma research, we're all trying to figure out ways to optimize these targeted drugs and find a way around resistance so people live longer. We're going to have to keep at it because the current standard of continuous dosing seems to hold the most benefit."
Why continuous treatment proved more effective isn't clear, although Algazi said the tissue and blood samples taken during the trial may hold clues and can be used for further study. While measuring overall survival was not the primary research objective of the trial, Algazi's team also found that, regardless of their dosing schedule, melanoma patients on the trial have lived about the same amount of time. About half of the patients who participated in the trial have died over the course of the study, which continues to follow those who are still alive.
Antoni Ribas, MD, PhD, is the senior leader on the trial, the former chair of the melanoma research committee at SWOG, and the AACR president. He is also a professor of medicine at the David Geffen School of Medicine at the University of California Los Angeles, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, and director of the Parker Institute for Cancer Immunotherapy Center at UCLA.
"The idea of prescribing therapy intermittently made sense," Ribas said. "Cancer cells wouldn't have enough time to get used to it, and become resistant - a notion that was supported scientifically by well-conducted studies in the laboratory. This clinical study illustrates the importance of ultimately testing hypotheses in human patients, which is the underlying reason for the existence of NCI-funded groups like SWOG."
SWOG S1320 was sponsored by NCI. Novartis Pharmaceuticals, Inc. provided study drugs and partial funding to support the study through a Collaborative Research and Development Agreement between NCI and Novartis. The trial was designed and managed in partnership with the ECOG-ACRIN Cancer Research Group, another member of the NCI's NCTN. S1320 was funded by the NIH through NCI grant awards CA180888, CA180819, CA180820, CA180850, CA239767, CA189808, CA46282, CA189858, CA189830, CA233230, CA189829, CA189954, CA189860, CA189822, CA189953, CA180834, CA189809, CA189957, and CA189958 (to SWOG), as well as R35 CA197633 (to Antoni Ribas), and P01 CA244118 (to Antoni Ribas and Roger S. Lo).
Algazi will present the S1320 findings at the virtual AACR meeting. Along with Ribas, other members of the SWOG study team include: Megan Othus, PhD, of the SWOG Statistics and Data Management Center at Fred Hutchinson Cancer Research Center; Adil I. Daud, MD, of UCSF; Roger S. Lo, MD, PhD, of UCLA; Janice M. Mehnert, MD, of Rutgers Cancer Institute of New Jersey; Thach-Giao Truong, MD, of Kaiser Permanent Northern California; Robert Conry, MD, of University of Alabama; Kari Kendra, MD, PhD, of Ohio State University; Gary C. Doolittle, MD, of University of Kansas Hospital and Westwood Cancer Center; Joseph I. Clark, MD, of Loyola University; Michael J. Messino, MD, of Messino Cancer Centers and the Southeast Clinical Oncology Research Consortium NCORP; Dennis F. Moore, Jr., MD, of Cancer Center of Kansas and the Wichita NCORP: Christopher Lao, MD, of University of Michigan; Bryan A. Faller, MD, of Missouri Baptist Medical Center and Cancer Center and Heartland NCORP; Rangaswamy Govindarajan, MD, of University of Arkansas; Amy Harker-Murray, MD, of Froedtert and the Medical College of Wisconsin; Luke Dreisbach, MD, of Eisenhower Medical Center; James Moon, MS, of Fred Hutch; and Kenneth F. Grossmann, MD, PhD,of Huntsman Cancer Institute at the University of Utah.
SWOG Cancer Research Network is part of the National Cancer Institute's National Clinical Trials Network and the NCI Community Oncology Research Program, and is part of the oldest and largest publicly-funded cancer research network in the nation. SWOG has nearly 12,000 members in 47 states and six foreign countries who design and conduct clinical trials to improve the lives of people with cancer. SWOG trials have led to the approval of 14 cancer drugs, changed more than 100 standards of cancer care, and saved more than 3 million years of human life. Learn more at swog.org.