Michael A. Davies, MD, PhD, the Anne and John Mendelsohn Chair in Cancer Research, professor and chair, Department of Melanoma Medical Oncology, Division of Cancer Medicine, co-leader, Melanoma Moon Shot Program, Department of Moon Shots Program, and director of research activities, Department of Hematology/Oncology Fellowship Program, The University of Texas MD Anderson Cancer Center, discusses the potential utility of ERK inhibitors in melanoma.

BRAF inhibitors and MEK inhibitors have demonstrated efficacy in patients with melanoma, Davies says. As such, there is clinical rationale to evaluate ERK inhibitors, which target the same signaling pathway further down the cascade than BRAF and MEK, says Davies.

Single-agent ERK inhibitors have yielded preclinical data that suggest these agents could be more efficacious compared with MEK inhibitors, Davies explains. However, like MEK inhibitors, effective dosing with ERK inhibitors could be challenging for patients to tolerate, Davies says. 

Notably, the combination of a BRAF inhibitor and a MEK inhibitor appears to be better tolerated vs each inhibitor alone, so combination strategies with ERK inhibitors may be more tolerable for patients vs single-agent ERK inhibitors, concludes Davies. 

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Michael A. Davies, MD, PhD, discusses the potential utility of ERK inhibitors in melanoma.  



Dr. Davies on the Potential Utility of ERK Inhibitors in Melanoma

Michael A. Davies, MD, PhD, the Anne and John Mendelsohn Chair in Cancer Research; professor and chair of the Department of Melanoma Medical Oncology, Division of Cancer Medicine; co-leader, Melanoma Moon Shot Program, Department of Moon Shots Program; and director of research activities in the Department of Hematology/Oncology Fellowship Program at The University of Texas MD Anderson Cancer Center, discusses the management of patients with melanoma during the COVID-19 pandemic.

Patients with melanoma who are receiving immunotherapy have many questions due to concerns about severe lung reactions in those who contract COVID-19, according to Davies. However, there have also been questions as to whether immunotherapy provides a protective effect, he continues.

Currently, there are no answers to these questions, although informally, the international melanoma community has come to the consensus that patients do not appear to be doing better or worse as a result of the pandemic. The melanoma community has been spared the level of concern that has arisen for patients with hematologic malignancies who are receiving chemotherapy, Davies says. Experts in the field feel comfortable administering targeted therapies and immunotherapies during the pandemic, Davies concludes.

Michael A. Davies, MD, PhD, discusses the management of patients with melanoma during the COVID-19 pandemic.

Dr. Davies on Managing Melanoma During the COVID-19 Pandemic

Michael A. Davies, MD, PhD, Anne and John Mendelsohn Chair in Cancer Research, professor and chair, Department of Melanoma Medical Oncology, Division of Cancer Medicine, co-leader, Melanoma Moon Shot Program, Department of Moon Shots Program, director of research activities, Department of Hematology/Oncology Fellowship Program, The University of Texas MD Anderson Cancer Center, discusses the potential role of novel BRAF inhibitors in treating patients with melanoma and brain metastases.

Brain metastases remain a significant challenge in melanoma, says Davies. Combination immunotherapy has demonstrated efficacy and good tolerability among patients with melanoma and asymptomatic brain metastases, including those with 

-mutated disease, Davies explains. However, patients who require steroid treatment derive little benefit from immunotherapy, Davies adds. Moreover, combinations with BRAF and MEK inhibitors are effective, but do not induce durable responses, Davies says.

However, targeted therapies that cross the blood-brain barrier have demonstrated utility in treating patients with brain metastases in the settings of HER2-positive breast cancer and 

-mutant lung cancer, Davies explains. Extrapolating from those settings, BRAF inhibitors that cross the blood-brain barrier may also provide benefit to patients with 

-mutant melanoma and brain metastases, concludes Davies. 

Michael A. Davies, MD, PhD, discusses the potential role of novel BRAF inhibitors in treating patients with melanoma and brain metastases.  



Dr. Davies on the Potential Role of Novel BRAF Inhibitors in Melanoma Brain Metastases 

Michael A. Davies, MD, PhD, Anne and John Mendelsohn Chair in Cancer Research, professor and chair, Department of Melanoma Medical Oncology, Division of Cancer Medicine, co-leader, Melanoma Moon Shot Program, Department of Moon Shots Program, director of research activities, Department of Hematology/Oncology Fellowship Program, The University of Texas MD Anderson Cancer Center, discusses the utility of retreatment with combination BRAF/MEK inhibitors in 

Typically, patients who progress on a BRAF/MEK inhibitor combination will not respond to another BRAF/MEK inhibitor regimen if it is given consecutively, says Davies. However, patients who require a significant dose reduction on 1 regimen may derive efficacy from another if they are able to tolerate the second combination at a higher dose, Davies explains. 

Additionally, resistance to BRAF/MEK inhibitors is not necessarily permanent in patients with 

-mutant melanoma, Davies adds. Patients who progress on a BRAF/MEK combination and subsequently receive another treatment, such as immunotherapy for 3 months, may be rechallenged with another BRAF/MEK combination upon progression on immunotherapy, explains Davies. Data have reported good disease control rates with this approach, Davies concludes.

Michael A. Davies, MD, PhD, discusses the utility of retreatment with combination BRAF/MEK inhibitors in BRAF-mutant melanoma.  



Dr. Davies on the Utility of Retreatment With BRAF/MEK Inhibitors in BRAF-Mutant Melanoma 

Michael A. Davies, MD, PhD, Anne and John Mendelsohn Chair in Cancer Research, professor and chair, Department of Melanoma Medical Oncology, Division of Cancer Medicine, co-leader, Melanoma Moon Shot Program, Department of Moon Shots Program, director of research activities, Department of Hematology/Oncology Fellowship Program, The University of Texas MD Anderson Cancer Center, discusses factors to consider when selecting between combination regimens in 

Currently, 4 regimens are approved by the FDA for use in patients with 

-mutant metastatic melanoma: dabrafenib (Tafinlar) plus trametinib (Mekinist); vemurafenib (Zelboraf) plus cobimetinib (Cotellic); encorafenib (Braftovi) plus binimetinib (Mektovi); and atezolizumab (Tecentriq) plus vemurafenib and cobimetinib. However, head-to-head clinical trials comparing the combinations have not been conducted to inform which regimen is optimal, says Davies.

As such, the toxicity profile of each regimen should be factored into the treatment selection decision, Davies says. Dabrafenib/trametinib causes pyrexia in about half of patients. Although this adverse effect is typically self-limited and manageable, some patients, particularly elderly, isolated individuals, can have reoccurring fevers that can progress into a cytokine storm–like event, Davies explains. Vemurafenib/cobimetinib can cause severe photosensitivity, and patients on the combination can develop burns with limited sun exposure, Davies says. Although similar rates of fatigue and nausea have been reported with encorafenib/binimetinib, the combination has a shorter half-life compared with the other regimens. As such, patients who require dose holds can have a quicker washout period vs the other options, concludes Davies. 

Michael A. Davies, MD, PhD, discusses factors to consider when selecting between combination regimens in BRAF-mutant melanoma. 



Michael A. Davies, MD, PhD

Articles

Dr. Davies on the Potential Utility of ERK Inhibitors in Melanoma

Dr. Davies on Managing Melanoma During the COVID-19 Pandemic

Dr. Davies on the Potential Role of Novel BRAF Inhibitors in Melanoma Brain Metastases

Dr. Davies on the Utility of Retreatment With BRAF/MEK Inhibitors in BRAF-Mutant Melanoma

Dr. Davies on Selecting Between Combination Regimens in BRAF-Mutant Melanoma