The Role of Systemic Therapy in Melanoma Brain Metastases

A Narrative Review

Kainat Saleem; Diwakar Davar

Chin Clin Oncol. 2022;11(3):24

Abstract and Introduction

Abstract

Background and Objective: Melanoma is a disease notorious for the development of brain metastases, with consequently poor outcomes for patients who develop melanoma brain metastases (MBM). The treatment options for patients with MBM were limited to radiotherapy and surgery. MBM patients, particularly those with symptomatic disease, were excluded from clinical trials of immune checkpoint inhibitors (ICI) and BRAF/MEK inhibitors. Recent post-approval studies have, demonstrated important roles for existing systemic ICIs and BRAF/MEK inhibitors in untreated MBM, dramatically altering the landscape of melanoma patients in general and MBM in particular. These trials have also identified key areas for which more effective strategies are needed including: symptomatic MBM, and leptomeningeal disease (LMD).

Methods: PubMed, Scopus and Embase databases were systematically queried to obtain records pertaining to the etiology of and treatment for MBM. Clinical trial databases were reviewed to obtain details regarding MBM clinical trials.

Key Content and Findings: We discuss the etiopathogenesis of MBM and the novel immune, molecular and metabolic features of MBM that make this disease a unique therapeutic challenge. We review advances in systemic therapy with ICIs and BRAF/MEK inhibitors in untreated MBM, along with novel combinations. Finally, we debate challenging situations such as LMD, and delineate novel treatments and new paradigms for therapeutic interventions.

Conclusions: The historically poor outcomes for MBM patients have been transformed with the advent of effective systemic therapies including ICIs and BRAF/MEK inhibitors. An improved understanding of the molecular and immunogenomic characterization of MBMs has provided new targets that are being exploited in the clinic.

Introduction

Cutaneous melanoma exhibits the highest level of cerebral tropism of all cancer types, with up to 30–40% of advanced melanoma patients having melanoma brain metastases (MBM) at diagnosis,^[1–3] and up to 75% at the time of death in autopsy series.^[2] MBM are associated with a higher risk of complications and death compared to other cancers.^[4,5] While surgical resection and stereotactic radiosurgery (SRS) are highly effective for local control of oligometastatic MBM,^[2,6] patients with multiple brain metastases and/or leptomeningeal disease (LMD) are typically treated with whole-brain radiation therapy (WBRT) with poor outcomes. The prognosis of MBM patients has remained poor, with a median overall survival (OS) of 4–5 months, and a durable survival rate of 5%.^[6]

Historically, patients with untreated brain metastases were excluded from clinical trials for all currently approved targeted and immune therapies given the uncertain penetrance of the blood-brain barrier (BBB) by systemic agents and consequent perceived uncertainties over central nervous system (CNS) efficacy. Several post-marketing clinical trials subsequently clarified that immune checkpoint inhibitors (ICI) and small molecules targeting BRAF and MEK kinases had intracranial activity in MBM patients. These trials also identified key areas for which more effective strategies are needed. Concurrently, recent translational and preclinical research have provided insights into novel immune, molecular and metabolic features of MBM that mediate the aggressive biology and therapeutic resistance of these tumors. In this systematic review, we review the etiopathogenesis of MBM, and describe the various therapeutics options available with a focus on new paradigms for therapeutic interventions in MBM. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-1/rc).

1 2 3 4 5 6

Next Section

Table 1. The search strategy summary
Items	Specifications
Date of search (specified to date, month and year)	4/1/2022
Databases and other sources searched	PubMed, Scopus and Embase
Search terms used (including MeSH and free text search terms and filters)	("melanoma" OR "brain" OR "melanoma brain metastases") and ("epidemiology") and ("tumor microenvironment" OR "TME" or "pathway") and ("targeted therapy" OR "BRAF" OR "MEK") and ("immune therapy" OR "programmed cell death 1" OR "PD-1" OR "PD1" OR "programmed death 1 receptor" OR "cytotoxic T-lymphocyte-associated antigen 4" OR "CD152" OR "CTLA-4")
Timeframe	Published until 4/1/2022
Inclusion and exclusion criteria (study type, language restrictions, etc.)	Studies matching the search terms above were included
Selection process (who conducted the selection, whether it was conducted independently, how consensus was obtained, etc.)	All authors
Any additional considerations, if applicable	None

Table 2. Completed studies of immune checkpoint inhibitors in MBM
First author; study identifiers	Study design		Patient population			Intervention	Intra-cranial response rate	Extra-cranial response rate	Grade 3/4 AEs
First author; study identifiers	Cohorts	Sample size	General features of brain disease	BRAF status	Size and No. of target lesions	Intervention	Intra-cranial response rate	Extra-cranial response rate	Grade 3/4 AEs
Margolin; CA184-042 (NCT00623766)	Cohort A	51	Asymptomatic; no steroid use; prior local therapy	N/A	0.5–3 cm; number N/A	Ipilimumab 10 mg/kg Q3W × 4; then Ipilimumab 10 mg/kg Q12W	16%	14%	62%
Margolin; CA184-042 (NCT00623766)	Cohort B	21	Asymptomatic; on systemic steroids; prior local therapy	N/A	0.5–3 cm; number N/A	Ipilimumab 10 mg/kg Q3W × 4; then Ipilimumab 10 mg/kg Q12W	5%	5%	55%
Ascierto; CA184-169 (NCT01515189)	Arm 1	365 (65 with MBM)	Asymptomatic, not requiring treatment	22% mutant, 62% WT, 16% UNK	N/A	Ipilimumab 10 mg/kg	15%		36%
Ascierto; CA184-169 (NCT01515189)	Arm 2	362 (62 with MBM)	Asymptomatic, not requiring treatment	22% mutated, 65% WT, 13% UNK	N/A	Ipilimumab 3 mg/kg	12%		20%
Goldberg; NCT02085070	Single-arm	18 (14 evaluable)	Asymptomatic; with or without prior local treatment	33% mutant	5–20 mm; 1–5 BM per patient	Pembrolizumab 10 mg/kg Q2W	22%	22%	12%
Tawbi; CheckMate-204 (NCT02320058)	Cohort A	101 (94 evaluable)	Asymptomatic; no prior radiotherapy	65.3% mutant, 32.7% WT, 2% UKN	0.5–3.0 cm; 77.2% with 1–2 BM, 22% ≥3 BM	Ipilimumab 3 mg/kg + nivolumab 1 mg/kg Q3W × 4; then nivolumab 3 mg/kg Q2W	54.4%	49%	54.5%
Tawbi; CheckMate-204 (NCT02320058)	Cohort B	18	Symptomatic; no prior radiotherapy	44.44% mutant, 44.44% WT, 11% UKN	0.5–3.0 cm; 61% w/1–2 BM, 39% ≥3 BM		22.2%	22.2%	55.6%
Long; ABC (NCT02374242)	Cohort A	36	Asymptomatic; no prior local therapy	54% mutant	0.5–4 cm; 31% w/1 BM, 40% w/>4 BM	Nivolumab 1 mg/kg + ipi 3 mg/kg Q3W X 4; then nivolumab 3 mg/kg Q2W	46%	57%	63%
	Cohort B	27	Asymptomatic; no prior local therapy	56% mutant	0.5–4 cm; 24% w/1 BM, 20% w/>4 BM	Nivolumab 3 mg/kg Q2W	20%	29%	16%
	Cohort C	16	Symptomatic or failed local therapy or LMD	81% mutant	0.5–4 cm; 6% w/1 BM, 50% w/>4 BM	Nivolumab 3 mg/kg Q2W	6%	25%	13%
Di Giacomo; NIBIT-M1 (NCT01654692)	Single-arm	86 (20 with MBM)	Asymptomatic; 7 patients with prior radiotherapy	48% mutated; 35% WT; 17% UNK	Size NA; 30% w/1 BM, 15% w/>3 BM	Ipi 10 mg/kg Q3W × 4 + fotemustine 100 mg/m² QWeekly × 3; then fotemustine Q3W + ipi Q12W	40%	29%	55%

MBM, melanoma brain metastases; AE, adverse event; N/A, not available; W, weeks; WT, while-type; UKN, unknown; LMD, leptomeningeal disease.

Table 3. Completed studies of BRAF, BRAF/MEK and other targeted therapies in MBM
First author; study identifiers	Study design		Patient population			Intervention	Intra-cranial response rate	Extra-cranial response rate	Grade 3/4 AEs
First author; study identifiers	Cohorts	Sample size	General features	BRAF status	Size and No. of target lesions	Intervention	Intra-cranial response rate	Extra-cranial response rate	Grade 3/4 AEs
Long; BREAK-MB (NCT01266967)	Cohort A	89	Asymptomatic; no prior local treatment	BRAF V600E/K	0.5–4 cm; 46% w/1 BM, 9% w/>4 BM	Dabrafenib 150 mg BID	20%	N/A	14%
Long; BREAK-MB (NCT01266967)	Cohort B	83	Asymptomatic; prior SRS, WBRT or surgical resection with progression	BRAF V600E/K	0.5–4 cm; 36% w/1 BM, 17% w/>4 BM	Dabrafenib 150 mg BID	30%	N/A	13%
McArthur; MO25743 (NCT01378975)	Cohort 1	90	No prior local treatment	BRAF V600E	≥0.5 cm; 44% w/1 BM, 14% w/>4 BM	Vemurafenib 960 mg BID	18%	33%	66%
McArthur; MO25743 (NCT01378975)	Cohort 2	56	Prior SRS, WBRT or surgical resection with progression. 7% had LMD	BRAF V600E	≥0.5 cm; 20% w/1 BM, 18% w/>4 BM	Vemurafenib 960 mg BID	18%	23%	64%
Dummer; MO25653 (NCT01253564)	Single-arm	24 (19 evaluable for IC response, 21 for EC response)	Symptomatic vs. asymptomatic; failure of one prior line of treatment for brain disease	BRAF V600 subtypes N/A	Size N/A; 8% w/1 BM, 54% w/>3 BM	Vemurafenib 960 mg BID	16%	62%	17%
Amaral; BUMPER (NCT02452294)	Single-arm	22 (17 evaluable for response)	Asymptomatic; with or without prior local therapy	BRAF V600E/K (53%) vs. BRAF WT (43%)	Size N/A; 100% w/>5 BM	Buparlisib 100 mg once daily	0%	0%	12%
Goldinger (NCT record not available)	Single-arm	11	Symptomatic vs. asymptomatic; with or without prior systemic and local therapy	NRAS mutated	Size N/A; 18% w/1 BM, 46% w/>3 BM	Binimetinib 45 mg BID	18%		55%
Davies; COMBI-MB (NCT02039947)	Cohort A	76	Asymptomatic; no local therapy; ECOG 0, 1	BRAF V600E	0.5–4 cm; 54% w/1 BM, 10% w/≥4 BM	Dabrafenib 150 mg BID + Trametinib 2 mg daily	58%	55%	45%
	Cohort B	16	Asymptomatic; prior local therapy; ECOG 0, 1	BRAF V600E	0.5–4 cm; 44% w/1 BM, 0% w/≥4 BM		56%	44%	56%
	Cohort C	16	Asymptomatic; with or without prior local therapy; ECOG 0, 1	BRAF V600D/K/R	0.5–4 cm; 44% w/1 BM, 6% w/≥4 BM		44%	75%	56%
	Cohort D	17	Symptomatic; with or without prior local therapy; ECOG 0, 1, 2	BRAF V600D/E/K/R	0.5–4 cm; 41% w/1 BM, 12% w/≥4 BM		59%	41%	47%

MBM, melanoma brain metastases; AE, adverse event; BM, brain metastases; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy; W, weeks; BID, twice daily; N/A, not available; LMD, leptomeningeal disease; EC, extracranial response; IC, intracranial response; WT, while-type.

Table 4. Ongoing studies of targeted therapies and immune checkpoint inhibitors in MBM patients
Study (title/reference); phase	Trial identifier	Sample size	Target population	Intervention	Pertinent study endpoints
Pembrolizumab Plus Bevacizumab for Treatment of Brain Metastases in Metastatic Melanoma or Non-small Cell Lung Cancer; Phase II	NCT02681549	53 (40 melanoma patients)	Asymptomatic, lesions 5–20 mm in size, no high-dose (≤10 mg prednisone or equivalent) steroid use	Systemic pembrolizumab + bevacizumab	Primary: brain metastases response rate. Secondary: PFS in the brain or the body; safety and toxicity of combination pembrolizumab and bevacizumab
PD-L1 Therapy Combined With Anti-VEGF Therapy in Unresectable or Metastatic Melanoma; Phase II	NCT04356729	30	Asymptomatic, not on corticosteroids	Atezolizumab + bevacizumab	Primary: Overall RR. Secondary: OS, time to progression, DOR, incidence of AE
Low Dose Ipilimumab With Pembrolizumab in Treating Patients With Melanoma That Has Spread to the Brain; Phase II	NCT03873818	30	Asymptomatic, lesions 5–30 mm in size, no prior local treatment	Systemic pembrolizumab and low-dose ipilimumab 1 mg/kg	Primary: CBR. Secondary: OS; PFS; incidence of AEs and SAEs
Pembrolizumab and Lenvatinib in Patients With Brain Metastases From Melanoma or Renal Cell Carcinoma; Phase II	NCT04955743	56	Asymptomatic, lesions 5–30 mm in size, no prior local treatment	Pembrolizumab + Lenvatinib	Primary: best brain metastasis RR. Secondary: best overall objective RR; PFS; OS; brain metastasis DOR
Substudy 02D: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Melanoma Brain Metastasis (MK-3475-02D/KEYMAKER-U02); Phase I/II	NCT04700072	300	Asymptomatic; no systemic steroids	Coformulation pembrolizumab/quavonlimab + Lenvatinib vs. pembrolizumab + lenvatinib	Primary: % patients with AEs; % patients who discontinue study due to AEs; objective response rate. Secondary: DOR; brain metastasis response rate; brain metastasis DOR; PFS
Troriluzole or Placebo Plus Ipi Plus Nivo in Mel Brain Mets; Phase II	NCT04899921	103	Asymptomatic, lesions 5–30 mm in size, no prior local therapy or WBRT, not on steroids, must have prior anti-PD-1 therapy	Ipilimumab + nivolumab +/− troriluzole	Primary: PSF. Secondary: OS; intracranial RR; intracranial PFS; extracranial RR; extracranial PFS; treatment related AEs; treatment tolerability; corticosteroid usage; frequency of SRS and surgical intervention to brain
Study Comparing Investigational Drug HBI-8000 Combined With Nivolumab vs. Nivolumab in Patients With Advanced Melanoma; Phase III	NCT04674683	480	No prior ICI use, no steroid use	Nivolumab +/− HBI-8000	Primary: objective RR; PFS. Secondary: OS; safety; DOR; disease control rate
A Study of Fotemustine (FTM) vs. FTM and Ipilimumab (IPI) or IPI and Nivolumab in Melanoma Brain Metastasis (NIBIT-M2); Phase III	NCT02460068	168	Asymptomatic, lesions 5 to 20 mm in size, no prior therapy for advanced disease	Fotemustine +/− ipilimumab vs. ipilimumab/nivolumab	Primary: OS. Secondary: safety; intracranial and extracranial disease control rate; PFS; ORR; TTR; DOR; brain-PFS
E6201 Plus Dabrafenib for the Treatment of Metastatic Melanoma Central Nervous System Metastases; Phase I	NCT03332589	24	Symptomatic vs. asymptomatic, lesion 5 to 30 mm in size	E6201 + dabrafenib	Primary: intracranial ORR. Secondary: intracranial disease duration of response; systemic disease overall response rate; PFS; OS; safety of E6201
Bevacizumab and Atezolizumab With or Without Cobimetinib in Treating Patients With Untreated Melanoma Brain Metastases (TACo-BEAT-MBM); Phase II	NCT03175432	60	Asymptomatic or mildly symptomatic, lesion 5–30 mm in size	Systemic atezolizumab and bevacizumab +/− Cobimetinib	Primary: objective intracranial response rate (OIRR); safety, tolerability, and efficacy of atezolizumab, bevacizumab, and cobimetinib. Secondary: incidence of adverse events; ORR (intracranial + extracranial); DOR; PFS; OS
A Study to Compare the Administration of Encorafenib + Binimetinib + Nivolumab Versus Ipilimumab + Nivolumab in BRAF-V600 Mutant Melanoma With Brain Metastases; Phase II	NCT04511013	112	Lesions ≥5 mm in size, no steroids higher than 8 mg daily dexamethasone, no prior systemic therapy for metastatic disease	Binimetinib + encorafenib + nivolumab vs. ipilimumab + nivolumab	Primary: PFS. Secondary: OS; intracranial RR; objective RR; DOR
Melanoma Metastasized to the Brain and Steroids (MEMBRAINS); Phase II	NCT03563729	80	Need for systemic steroids	Arm B: pembrolizumab Arm C: ipilimumab + nivolumab Arm D: ipilimumab + nivolumab Arm E: BRAF/MEK inhibitor → ipilimumab/nivolumab	Primary: 6-month PFS; 6-month OS. Secondary: overall PFS; OS; ORR; extracranial RR; intracranial RR; intracranial CBR
Safety and Efficacy in Participants With Metastatic BRAF-mutant Melanoma Treated With Encorafenib With and Without Binimetinib in Combination With Nivolumab and Low-dose Ipilimumab (QUAD01); Phase I/II	NCT04655157	84	Symptomatic vs. asymptomatic; steroids less than 4 mg daily dexamethasone or equivalent	Cohort 1: encorafenib + nivolumab/ipilimumab Cohort 2: encorafenib/binimetinib + nivolumab/ipilimumab	Primary: Phase II doses of both combinations. Secondary: RR; CBR; AEs; PFS
A Study Evaluating the Safety and Efficacy of Cobimetinib Plus Atezolizumab in BRAFV600 Wild-type Melanoma With Central Nervous System Metastases and Cobimetinib Plus Atezolizumab and Vemurafenib in BRAFV600 Mutation-positive Melanoma With Central Nervous System Metastases (MO39136); Phase II	NCT03625141	80	No prior WBRT	Cohort 1: cobimetinib + atezolizumab Cohort 2: cobimetinib/vemurafenib + atezolizumab	Primary: Intracranial ORR. Secondary: Extracranial ORR; Overall ORR; PFS; DOR; DCR; OS; Occurrence and severity of AEs
Vemurafenib and Cobimetinib Combination in BRAF Mutated Melanoma With Brain Metastasis (CONVERCE); Phase II	NCT02537600	43	Cohort A: asymptomatic, no prior local treatment Cohort B: asymptomatic, prior local treatment Cohort C: symptomatic, with or without prior local treatment Lesions 5–40 mm in size	Vemurafenib + cobimetinib	Primary: intracranial RR in cohort A. Secondary: intracranial RR in cohorts B, C; intracranial DOR, overall DOR, ORR, OS, frequency of AEs, PFS
Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-mutant Melanoma Brain Metastasis (POLARIS); Phase II	NCT03911869	13	Asymptomatic, lesions 5–40 mm in size Cohort 1: can have prior local treatment Cohort 2: no prior local treatment	Cohort 1: Binimetinib + standard dose encorafenib Cohort 2: Binimetinib + high dose encorafenib	Primary: intracranial RR. Secondary: extracranial RR, global RR, DCR, DOR, PFS, OS, incidence of AEs
A FIH Study of PF-07284890 in Participants With BRAF V600 Mutant Solid Tumors With and Without Brain Involvement; Phase I	NCT04543188	225	Part B Cohort 1: asymptomatic, no prior BRAFi or MEKi Cohort 2: symptomatic, no prior no prior BRAFi or MEKi Cohort 3: asymptomatic, prior BRAFi use Cohort 4: symptomatic, prior BRAFi use Cohort 5: LMD +/− brain disease, symptomatic vs. asymptomatic	Part A: ARRY-461 +/− binimetinib	Primary: overall RR. Secondary: treatment related AEs, PFS, DCR, OS, DOR, TTR
	NCT04543188	225		Part B: ARRY-461 + binimetinib
Pembrolizumab and Stereotactic Radiosurgery for Melanoma or Non-Small Cell Lung Cancer Brain Metastases; Phase I	NCT02858869	30	Asymptomatic, 1–10 untreated lesions, largest lesions <14.15 cc³	Pembrolizumab + SRS	Primary: dose limiting toxicity. Secondary: ORR; OS; rate of distant brain failure; rate of LMD; rate of local recurrence; rate of symptomatic RN
Combining Radiosurgery and Nivolumab in the Treatment of Brain Metastases; Phase II	NCT02978404	26	No prior local treatment	Nivolumab + SRS	Primary: Intracranial PFS. Secondary: Treated brain lesion control rate; OS; maximum response rate of distant non-irradiated disease; PFS; correlation between PD-L1 expression and clinical outcomes; neurocognitive function; acute and late toxicity
SRS and Nivolumab in Treating Patients With Newly Diagnosed Melanoma Metastases in the Brain or Spine; Phase I	NCT02716948	17	Asymptomatic, untreated lesions, ≥3 mm in size	Nivolumab + SRS	Primary: incidence of SAE. Secondary: incidence of toxicity; local DCR; PFS; systematic DCR
Anti-PD 1 Brain Collaboration + Radiotherapy Extension (ABC-X Study); Phase II	NCT03340129	218	Asymptomatic, lesions 5–40 mm in size, No prior local or systemic treatment for BM	Ipilimumab + nivolumab +/− SRS	Primary: neurological specific cause of death. Secondary: intracranial and extracranial RR; ORR; overall PFS; non-neurological specific cause of death; OS; incidence of RN; requirement of salvage radiotherapy or intracranial surgery; change in neurocognitive function scores; time to and duration of neurological deterioration; PS; AEs
Encorafenib and Binimetinib Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain (EBRAIN-MEL); Phase II	NCT03898908	38	Asymptomatic vs. symptomatic, no prior local therapy	Neoadjuvant encorafenib/binimetinib prior to local therapy	Primary: intracranial objective response (iORR) in Cohort 1 (asymptomatic patients, N=48). Secondary: iORR in Cohort 2 (symptomatic patients, N=15); global intracranial response; duration of intracranial response; duration of global response; intracranial PFS; global PFS; % patients free of progression; OS; % patients alive; number of subjects with treatment-related AEs until and after local treatment; change in QoL
Vemurafenib Plus Cobimetinib After Radiosurgery in Patients With BRAF-mutant Melanoma Brain Metastases (RadioCoBRIM); Phase II	NCT03430947	20	Symptomatic, lesions 5–40 mm in size, <10 lesions	Adjuvant vemurafenib + cobimetinib after radiosurgery	Primary: intracranial ORR. Secondary: extracranial ORR; ORR for whole-body tumor sites; intracranial DOR; extracranial DOR; PFS; OS; incidence of adverse events
Concurrent Dabrafenib + Trametinib With Sterotactic Radiation in BRAF Mutation-Positive Malignant Melanoma and Brain Metastases; Phase II	NCT02974803	6	Lesions 10–40 mm in size, 1–10 lesions	Dabrafenib + trametinib + SRS	Primary: intracranial RR. Secondary: extracranial RR, DOR, intracranial PFS, overall PFS, overall RR
Binimetinib Encorafenib Pembrolizumab +/− SRS in BRAFV600 Melanoma With Brain Metastasis (BEPCOME-MB); Phase II	NCT04074096	150	Asymptomatic, lesions 5–30 mm in size, <10 lesions	Encorafenib + binimetinib + pembrolizumab +/− upfront SRS	Primary: intracranial PFS. Secondary: Intracranial RR; intracranial DC; extracranial RR; ORR; duration of intracranial, extracranial and overall response; duration of response of treated targeted lesions; PFS; OS; cognitive performance; AEs
Optune Device - TT Field Plus Nivolumab and Ipilimumab for Melanoma with Brain Metastasis; Phase II	NCT03903640	23	Lesions >10 mm, no prior WBRT, steroids less than 4 mg daily dexamethasone or equivalent	Ipilimumab + nivolumab + Optune device	Primary: intracranial PFS. Secondary: OS; best intracranial RR; beat extracranial RR; extracranial PFS; safety of treatment regimen
Safety and Efficacy of Sonocloud Device Combined with Nivolumab in Brain Metastases From Patients with Melanoma (SONIMEL01); Phase I/II	NCT04021420	21	Lesions 5–35 mm in size, no prior local therapy, no prior anti-PD1 therapy	SonoCloud + nivolumab	Primary: most successful dose. Secondary: best ORR; ORR; best intracranial ORR; intracranial ORR; best extracranial ORR; extracranial ORR
NovoTTF-200A + Pembrolizumab In Melanoma Brain Metastasis; Phase I/II	NCT04129515	30	Lesions 10–30 mm in size; 4mg daily or higher dexamethasone use	Systemic pembrolizumab + NovoTTF-200A	Primary: number of participants with dose limiting toxicity. Secondary: ORR; 6-month PFS; QoL assessment
STAT3 Inhibitor WP1066 in Treating Patients With Recurrent Malignant Glioma or Progressive Metastatic Melanoma in the Brain; Phase I	NCT01904123	8	Progression on or tolerance to standard of care therapies, Lesions ≥10 mm in size	STAT3 Inhibitor WP1066	Primary: maximum tolerated dose, incidence of AEs. Secondary: RR, DOR, OS, PFS, % patients with additional metastatic lesions

MBM, melanoma brain metastases; PFS, progression free survival; RR, response rate; OS, overall survival; DOR, duration of response; AEs, adverse events; CBR, clinical benefit rate; SAE, serious adverse event; WBRT, whole-brain radiation therapy; DCR, disease control rate; LMD, leptomeningeal disease; ORR, overall response rate; PS, performance status; QoL, quality of life; RN, radiation necrosis; stereotactic SRS, radiosurgery; TTR, time to response.