New data on brain metastases in melanoma are practice changing, and clinicians can now consider systemic therapy alone and not use local therapy such as radiation," Tara C. Gangadhar, MD, assistant professor of medicine at the Abramson Cancer Center of the University of Pennsylvania, told attendees here at the American Society of Clinical Oncology (ASCO) 2017 Annual Meeting.
Treatment of melanoma brain metastases is a critical, unmet need, because such metastases are a common clinical presentation and are associated with a poor prognosis, she commented.
Speaking at a Highlights of the Day session, Dr Gangadhar summarized data from CheckMate 204 (abstract 9507) and the Australian Anti-PD1 Brain Collaboration (ABC) study (abstract 9508), which showed a high degree of intracranial responses (50% to 60%) in patients with metastatic melanoma treated with the combination of two checkpoint inhibitors, ipilimumab (Yervoy, Bristol-Myers Squibb) and nivolumab (Opdivo, Bristol-Myers Squibb). These responses were durable, she noted.
Data from the COMBI-MB study (abstract 9506), which used the targeted combination of BRAF and MEK inhibitors, also showed high intracranial responses (75%) in a similar patient population with BRAF V300E melanoma. However, the responses in this study were not durable, she said.
All three presentations were discussed at the meeting by Lynn Schuchter, MD, C. Willard Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, who put the new data in the context of clinical practice.
Currently, when a melanoma patient presents with brain metastases, there is consultation with neurosurgery and radiation oncology to determine whether surgery and/or radiotherapy, such as stereotactic radiotherapy or whole-brain radiotherapy, are appropriate. These patients are generally excluded from enrolling in clinical trials, she noted. "And while we consider systemic therapy, we don't have a good understanding of its role in this patient population," she added.
All the presentations addressed up-front treatment of melanoma brain metastases in asymptomatic patients. CheckMate 204 and the ABC study evaluated the combination of ipilimumab and nivolumab at standard doses. The ABC study evaluated nivolumab monotherapy in asymptomatic and symptomatic patients. The COMB-MB study evaluated the combination of dabrafenib (Tafinlar, Glaxo-Smith Kline) and tremitinib (Mekinist, Glaxo-Smith Kline) in asymptomatic patients.
The three studies enrolled remarkably similar groups of patients. The median age of the patients was 59 years. Notably, patients in CheckMate 204 and COMBI-MB had three to five brain metastases; more patients in the ABC study had more than four brain lesions. In addition, all patients in the COMBI-MB study had BRAF V300E mutant melanoma; this mutation was present in a little more than 50% of patients in the other two studies, Dr Schuchter noted.
Intracranial disease was measured using gadolinium contrast-enhanced MRI. Responses were measured using modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Extracranial disease was measured using contrast-enhanced CT or MRI.
Across the three studies, intracranial clinical benefit rates (complete response [CR] + partial response [PR] + stable disease of longer than 6 months) were similar: 60% in CheckMate 204; 50% in the ABC study; and 78% in the COMBI-MB study. Corresponding objective response rates were 54% (CR, 21%), 42% (CR, 15%), and 58% (CR, 4%), respectively.
Extracranial clinical benefit rates were generally in concordance with the intracranial responses: 52%, 67%, and 79% in Checkmate 204, the ABC study, and the COMBI-MB study, respectively.
In CheckMate 204, responses were ongoing in 93% of patients who responded. In the COMBI-MB study, median duration of response was 6.5 months. Median progression-free survival (PFS) was not reached for patients in the CheckMate 204 study; it was 5.6 months for patients in COMBI-MB. Six-month PFS rates were 67%, 62%, and 44% in the Checkmate 204 study, the ABC study, and the COMBI-MB study, respectively.
The overall response rate (ORR) for asymptomatic patients who received nivolumab monotherapy in the ABC cohort was lower, at 20%, than in patients who received the combination immunotherapy; it was lower still for patients with symptomatic brain metastases (ORR, 6%).
"Overall, these are very well-done studies, asking the critically important question in clinically relevant patient population," Dr Schuchter said.
These new data are sufficient to warrant up-front systemic therapy for patients with melanoma brain metastases, Dr Schuchter commented.
"Yes, they are practice changing," she said. "Our approach for this patient population was to think of local therapy first. With these data, we can think of using up-front systemic therapy as our initial approach to these patients," she added.
She stressed, however, that this is applicable to asymptomatic patients only, and added that "there is concern about concurrent steroid use in limiting the activity of immunotherapy."
A number of questions remain, she said. For example, what should be the sequence of these treatments in clinical practice? Dr Schuchter noted that in the ABC study, responses to immunotherapy were low in a subset of patients who had received prior therapy with BRAF and MEK inhibitors (intracranial response rate, 16%) and were higher in treatment-naive patients (intracranial response rate, 50%). Longer follow-up is needed to define the best way to sequence these therapies, she observed.
She noted that in clinical practice, several variables need to be considered, such as whether the patient has a solitary metastasis or multiple metastases, the extent of extracranial disease, the presence of BRAF mutation, the patient's performance status, and whether the patient has received prior radiotherapy.
In combining local therapy with systemic therapy, Dr Schucher noted that in light of reports of CNS radiation necrosis when radiation is given concurrently with BRAF inhibitors, the recommendation is to withhold targeted therapy for several days prior to radiotherapy. To help in wound healing, the same applies for the combination of targeted therapy and surgery.
In general, immunotherapy appears safe when combined with radiotherapy, she said. She noted that efficacy may be enhanced when radiotherapy and immunotherapy are combined. "However, there is concern about concurrent steroid use in limiting the activity of immunotherapy," she concluded.
Dr Gangadhar receives honoraria from Bristol-Myers Squibb, Merck, Medscape, and Novartis and receives institutional research funding from Bristol-Myers Squibb, Incyte, Roche, and Merck. Dr Schuchter is a paid consultant for Incyte and receives institutional research funding from Bristol-Myers Squibb, Glaxo-Smith Kline, and Merck.