Advanced melanoma survival improves significantly when immunotherapy is given before targeted therapy

WASHINGTON – A clinical trial led by clinicians at Georgetown Lombardi Comprehensive Cancer Center showed a remarkable 20 percent advantage in the two-year overall survival rate for people with advanced melanoma who first received immunotherapy (72 percent survival rate) versus those who initially got targeted therapies (52 percent survival rate). Progression-free survival, where the cancer is stable or improving, was also trending in favor of those who started on immunotherapy. 

The multicenter, phase III trial, DREAMseq, was led by oncology professor Michael Atkins, MD, deputy director of Georgetown Lombardi Comprehensive Cancer Center, on behalf of the ECOG-ACRIN Cancer Research Group and sponsored by the National Cancer Institute. The findings appeared September 26, 2022, in the Journal of Clinical Oncology and were presented preliminarily at the inaugural American Society of Clinical Oncology (ASCO) Virtual Plenary Series in November 2021.

“While still a potentially devastating disease, advances in treatment for patients with metastatic melanoma have been nothing short of remarkable this past decade,” Atkins said. “In addition to DREAMseq, results from a major nationwide clinical trial (1) that enrolled patients at Georgetown  Lombardi showed that if an immunotherapy called pembrolizumab was given both before and after, rather than after just surgery to remove tumor tissue, the two-year tumor-free survival rate increased from 49% to 72%.  These two findings, along with other recent advances, point to significant promise for many people with melanoma.”

The DREAMseq trial found that for patients with melanoma that have a mutation in the BRAF gene, specifically a BRAF V600 mutation, immunotherapy is the better initial approach than giving drugs that specifical target this mutated pathway.  

Starting in 2015, 265 trial participants with metastatic melanoma were randomly assigned to two groups: one group received a targeted drug combination (dabrafenib and trametinib) followed by an immunotherapy combination (ipilimumab and nivolumab) if their cancer resisted the first combination and the other group received the immunotherapy combination first and the targeted therapy if necessary. The trial was stopped early due to the clear evidence of benefit for giving immunotherapy first.

According to the National Cancer Institute, there will be an estimated 99,780 new cases diagnosed and 7,650 deaths due to melanoma in 2022. A steep drop in melanoma deaths from 2015 to 2019 of about 4% per year is largely attributable to advances in treatment.

"With further analysis of the data since our initial report, we not only know that patients with metastatic BRAF-mutant melanoma in general do better when combination immunotherapy is administered prior to combination targeted therapy, but we also have a better idea as to why. Specifically, combination immunotherapy, in contrast to targeted therapy, produces more long-lasting tumor shrinkage, reduces the risk of disease progression in the central nervous system and doesn't interfere with the subsequent effectiveness of the alternative treatment approach,” said Atkins.

“NCI-designated cancer centers and consortiums like ours are valuable and essential for practice-changing research,” said Andrew Pecora, MD, who led the clinical trial at John Theurer Cancer Center, a part of Georgetown Lombardi. “Our clinical trial collaborations allow more opportunities for patients across a wider geographic area to have access to these important studies and that in turn leads to advances that can make a significant difference in people’s lives.”

A sub-analysis of the DREAMseq findings to look at the impact of the treatments on quality of life was recently presented and further analysis of the primary finding is ongoing and will be reported in 2023. What this study does not resolve is which immunotherapy regimen is the best initial treatment, Atkins explains. That question is continuing to be addressed in other clinical trials.

The investigators are conducting cellular therapy trials that are designed to improve the immune system's ability to fight cancer and, so far, the outcomes are encouraging. Also, in a national trial led by Georgetown Lombardi’s Geoffrey T. Gibney, MD, investigators are looking at biomarkers that may help clinicians decide when it is safe to stop an immunotherapy in order to prevent toxicity and lift the burden from patients of the need for frequent visits to the oncology clinic for therapy. Preliminary data look promising, and the approach is currently being validated in a large nationwide trial (2). Those results are still several years away.

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ClinicalTrials.gov Identifier: NCT02224781: DREAMSeq: Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma

In addition to Atkins, the other authors of the manuscript include Sandra Lee, Dana Farber Cancer Institute, Boston; Bartosz Chmielowski and Antoni Ribas, Jonsson Comprehensive Cancer Center, University of California Los Angeles; Ahmad A. Tarhini, H. Lee Moffitt Cancer Center and Research Institute, Tampa; John M. Kirkwood, Pittsburgh Cancer Institute; Gary I. Cohen, Greater Baltimore Medical Center; Thach-Giao Truong, Kaiser Permanente Northern California, Vallejo CA;  Helen H. Moon, Kaiser Permanente Southern California, Riverside CA;  Diwakar Davar, Hillman Cancer Center and University of Pittsburgh; Mark O’Rourke and Joseph J. Stephenson, Greenville Health System Cancer Institute, Greenville SC; Brendan D. Curti and Walter Urba, Providence Cancer Institute, Portland OR; Joanna M. Brell, MetroHealth Cancer Center, Case Western Reserve University, Cleveland OH; Pauline Funchain, Cleveland Clinic Taussig Cancer Center; Kari L. Kendra, Ohio State University Comprehensive Cancer Center, Columbus OH; Alexandra P. Ikeguchi, University of Oklahoma Medical Center, Oklahoma City OK; Anthony Jaslowski, Saint Vincent Hospital Cancer Center at Saint Mary’s, Green Bay WI; Charles L. Bane, Dayton Physicians LLC-Atrium, Dayton OH; Mark A. Taylor, Lewis Ca & Res Pavilion at Saint Joseph's/Candler, Savannah GA; Madhuri Bajaj, Illinois CancerCare-P.C., Peoria IL; Robert M. Conry, University of Alabama at Birmingham; Robert J. Ellis, CoxHealth South Hospital, Springfield MO; Theodore F. Logan, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indianapolis IN; Noel Laudi, Mercy Hospital, Saint Louis Park MN; Jeffrey A. Sosman and Sunandana Chandra, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago IL; David G. Crockett, Nebraska Cancer Specialists, Grand Island NE;  Andrew L. Pecora, John Theurer Cancer Center, Hackensack NJ; Ian J. Okazaki, Straub Medical Center - Kahului Clinic, Honolulu; Sowjanya Reganti, Renown Regional Medical Center, Reno NV;, Samantha Guild, AIM at Melanoma Foundation, Richmond CA; Helen X. Chen and Howard Z. Streicher, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda MD; and Jedd D. Wolchok, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York NY.

Atkins reports that he serves or has served recently on advisory boards for Bristol-Myers Squibb, Merck & Co., Genentech, Amgen, Novartis, Pfizer, Arrowhead, Eisai, Aveo, Werewolf, Fathom, Pneuma, Leads, Pyxis Oncology, PACT, Elpis, X4Pharma, ValoHealth, ScholarRock, Surface, Takeda and Simcha. He has also been a consultant to Bristol-Myers Squibb, Merck, Novartis, Pfizer, Genentech-Roche, Exelixis, ImmunoCore, Iovance, COTA, Idera, Agenus, Apexigen, Asher Bio, Neoleukin, Adagene, AstraZeneca, Calithera, SeaGen and Sanofi.

This study was supported by the National Cancer Institute under award numbers: U10CA180794, U10CA180821, U10CA180820, U10CA180868, U10CA180888, UG1CA189804, UG1CA189809, UG1CA189822, UG1CA189829, UG1CA189830, UG1CA189863, UG1CA189953, UG1CA189957, UG1CA189997, UG1CA233184, UG1CA233193, UG1CA239769, UG1CA233234, UG1CA233290, UG1CA233320, UG1CA233270, UG1CA233330, UG1CA233331, UG1CA239758.

Additional support was provided from Bristol-Myers Squibb and Novartis for correlative specimen and Quality of Life data collections. 

ECOG-ACRIN received funding for this trial from the National Cancer Institute, with additional support from Bristol-Myers Squibb, the manufacturer of ipilimumab (Yervoy®) and nivolumab (Opdivo®), and from Novartis, the company that commercializes dabrafenib (Tafinlar®) and trametinib (Mekinist™).

1. S1801: ‘A Phase II Randomized Study of Adjuvant versus Neoadjuvant Pembrolizumab for Clinically Detectable Stage III-IV High-risk Melanoma,’ coordinated by the Southwest Oncology Research Group (SWOG) and sponsored by the National Cancer Institute.Trial EA6192: Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients with Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial

2. Trial EA6192: Using Biomarkers to Help Guide Safe Immunotherapy Discontinuation in Patients with Unresectable Stage IIIB-IV Melanoma, The PET-Stop Trial