Disclosures: Warner reports grants from the NIH/NCI during the conduct of the study, funding from American Association for Cancer Research, personal fees from Flatiron Health, IBM Watson Health, Melax Tech, Roche and Westat outside the submitted work. and deputy editor/co-founder roles with HemOnc.org LLC outside the submitted work. Please see the study for all other authors' relevant financial disclosures. Clark reports grants from Eli Lilly and Co. and Novartis during the conduct of the study. Martei reports no relevant financial disclosures.
June 22, 2022
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Combination therapies linked to better outcomes for subset of patients with breast cancer

Disclosures: Warner reports grants from the NIH/NCI during the conduct of the study, funding from American Association for Cancer Research, personal fees from Flatiron Health, IBM Watson Health, Melax Tech, Roche and Westat outside the submitted work. and deputy editor/co-founder roles with HemOnc.org LLC outside the submitted work. Please see the study for all other authors' relevant financial disclosures. Clark reports grants from Eli Lilly and Co. and Novartis during the conduct of the study. Martei reports no relevant financial disclosures.
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Combination therapies appeared associated with better outcomes than monotherapies for treatment of hormone receptor-positive, ERBB2-negative metastatic breast cancer, according to study results published in JAMA Network Open.

The information theoretic network meta-analysis (IT-NMA) approach the researchers employed served as a “promising method for longitudinal ranking of anticancer regimens from [randomized clinical trials] with different endpoints, sparse interconnectivity and decades-long timeframes,” the researchers wrote.

Quote from Jeremy L. Warner, MD, MS, FAMIA, FASCO.

“Breast cancer is a leading cause of cancer-related death in women — second only to lung cancer in terms of lethality. Although there have been some notable improvements in therapy, metastatic breast cancer remains a highly lethal condition,” Jeremy L. Warner, MD, MS, FAMIA, FASCO, associate professor of medicine (hematology/oncology) and biomedical informatics at Vanderbilt University and director of the COVID-19 and Cancer Consortium Research Coordinating Center, told Healio.

“With hundreds of randomized clinical trials studying this condition, we wanted to know whether a new method for comparing trials could lead to a sensible ranking of treatments without human expert input,” added Warner, who is moving on from Vanderbilt in June to become founder of the Center for Cancer Bioinformatics and Data Science at Brown University.

Background and methodology

Evaluating the many options for treating hormone receptor-positive, ERBB2-negative metastatic breast cancer has been challenging because few regimens have been directly compared in randomized clinical trials. Thus, researchers tested IT-NMA, a graph theory-based method for regimen ranking that takes into account effect sizes and temporality of evidence.

The analysis included 203 randomized controlled trials with 63,629 patients and 252 distinct regimens for first-line systemic treatment of hormone receptor-positive, ERBB2-negative metastatic breast cancer culled from HemOnc.org, an online resource of interventions and regimens, and published between 1974 and 2019.

Researchers reviewed IT-NMA regimen rankings based on clinical trial variables, including primary endpoint, enrollment number in each trial arm, P value, effect size, years of enrollment and publication year.

Key findings

Results showed combinations of targeted and endocrine therapy ranked highest, particularly combinations of endocrine therapy with CDK 4/6 inhibitors — letrozole plus palbociclib (Ibrance, Pfizer) ranked first and letrozole plus ribociclib (Kisqali, Novartis) ranked third. Regimens ranked lowest included older monotherapies that continue to be used in randomized control trials in comparator groups, such as anastrozole (n = 251 of 252) and letrozole (n= 252). They also reported that many regimens gravitated toward indeterminacy by 2019.

“We were surprised to see regimens containing bevacizumab [Avastin, Genentech] ranked fairly high,” Warner told Healio. “This drug has a controversial history in breast cancer and was withdrawn by the FDA for this indication after failing to demonstrate an OS benefit, despite showing a significant PFS benefit. ... Our study highlights the challenge of trying to compare surrogate endpoints such as PFS with the ‘hard’ endpoint of OS in a way that can preserve meaningful comparisons.”

Implications

Warner told Healio that further research examining efficacy, toxicity, financial and other burdens of treatment would be optimal for a more comprehensive review of the modality.

“We believe that our new method produces rankings that are comparable with those produced by human experts, with some caveats,” he said. “For instance, we found that older single-agent treatments were ranked pretty low due to the fact that they were often used as control arms in randomized trials that combine them with one or more new drugs. These so-called ‘escalation’ designs usually lead to improvements in efficacy, at a cost of more side effects and increased costs.”

In an accompanying editorial, Amy S. Clark, MD, MSCE, deputy director of breast cancer clinical trials at Penn Medicine and assistant professor of medicine at the Hospital of the University of Pennsylvania, and Yehoda M. Martei, MD, MSCE, vice chief of diversity, inclusion and health equity in the division of hematology/oncology at Penn Medicine and assistant professor of medicine at the Hospital of the University of Pennsylvania, wrote that limitations of the study included its lack of evaluating the toxic effects of the therapies under investigation, “which is critical when formulating treatment decisions.”

For example, they noted the IT-NMA results support endocrine therapy with a CDK 4/6 inhibitor in this patient population even though the combination therapy is not the best treatment choice for all patients.

“Clinicians still need to use clinical judgement when considering the best therapy for each individual patient, taking into consideration the patient’s comorbidities, tolerance for toxic effects, and life expectancy both from [metastatic breast cancer] and other illnesses,” Clark and Martei wrote. “For some patients with frailty, endocrine therapy should not be considered an inferior therapy, as the IT-NMA results suggest, but rather one that is kinder, gentler and more appropriate.”

Warner told Healio his team is investigating methods for adopting the ESMO-Magnitude of Clinical Benefit Scale into future research so they can “capture a more holistic measure of value that counterbalances efficacy and toxicity.”

References:

Li X, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.4361.
Martei YM, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.4380
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For more information:

Jeremy L. Warner, MD, MS, FAMIA, FASCO, can be reached at Departments of Medicine and Biomedical Informatics, Division of Hematology/Oncology, Vanderbilt University, 2220 Pierce Ave., Preston Research Building 777, Nashville, TN 37232; email: jeremy.warner@vumc.org.