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Systemic treatment of metastatic melanoma with BRAF and other molecular alterations

Systemic treatment of metastatic melanoma with BRAF and other molecular alterations
Author:
Jeffrey A Sosman, MD
Section Editor:
Michael B Atkins, MD
Deputy Editor:
Sonali Shah, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 30, 2022.

INTRODUCTION — In patients with metastatic melanoma, genetic sequencing has led to the identification of multiple molecular alterations, some of which are candidates for targeted drug therapy. The most common are mutations in the BRAF gene, which are identified in approximately 40 to 60 percent of patients with metastatic disease [1-4]. Additional molecular alterations include NRAS mutations and the less frequent TRK gene fusions, and KIT mutations, among others. (See "The molecular biology of melanoma".)

Systemic therapy is indicated for most patients with metastatic melanoma harboring such mutations. The choice of therapy is guided by multiple clinical factors including mutation status, patient comorbidities, performance status, and prior therapy in either the adjuvant or metastatic setting. The role of checkpoint inhibitor immunotherapy and targeted therapy in this population is evolving, and enrollment in clinical trials is encouraged, where available. (See "Overview of the management of advanced cutaneous melanoma".)

Available treatment options with clinical benefit in BRAF mutant metastatic melanoma include the following, either as single agents or in combination:

Combination BRAF (dabrafenib, encorafenib, vemurafenib) and MEK inhibitors (trametinib, binimetinib, cobimetinib)

Anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibodies (ipilimumab)

Programmed cell death 1 protein (PD-1) checkpoint inhibitors (nivolumab (table 1), pembrolizumab (table 2))

Programmed cell death ligand 1 (PD-L1) checkpoint inhibitors (atezolizumab) in combination with targeted therapy

Lymphocyte-activation gene 3 (LAG-3) checkpoint inhibitors in combination with PD-1 inhibitors (nivolumab-relatlimab)

The approach to systemic therapy in patients with metastatic melanoma containing a BRAF V600 mutation is reviewed here (algorithm 1).

The approach to checkpoint inhibitor immunotherapy in metastatic melanoma, adjuvant and neoadjuvant therapy for locally advanced cutaneous melanoma, and the surgical management of melanoma, is discussed separately.

(See "Systemic treatment of metastatic melanoma lacking a BRAF mutation".)

(See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

(See "Surgical management of primary cutaneous melanoma or melanoma at other unusual sites".)

(See "Metastatic melanoma: Surgical management".)

ASSESSMENT OF ACTIONABLE MUTATIONS — An understanding of the mitogen-activated protein (MAP) kinase pathway (figure 1) has led to the development of important targeted therapeutic approaches in patients with melanoma, specifically the development of combined BRAF plus MEK inhibitor therapy. Prior to initiation of systemic therapy, patients with metastatic melanoma should have their tumors assessed for actionable mutations (ie, molecular alterations that are candidates for targeted drug therapy) as follows:

Choice of tumor sample — We typically perform genetic sequencing on tumor samples obtained from distant metastases, as these are the sites of disease that will be treated with systemic therapy. If tissue from metastatic disease is unavailable or unable to be obtained, genetic sequencing can alternatively be performed on archived, paraffin-embedded tissue from either the primary tumor or tumor-involved regional lymph nodes.

Approach to genetic assay — For patients with tissue available for genetic assays, our approach is to rapidly assess for a BRAF V600 mutation (including V600E, the most frequent mutation identified in patients with metastatic melanoma), as mutation status influences treatment decisions for systemic therapy. BRAF V600 mutations can be identified using a single gene polymerase chain reaction (PCR) assays that are available either institutionally or commercially, such as the Cobas 4800 BRAF V600 mutation test, among others [5,6].

For patients in whom a BRAF V600 mutation is not identified, we obtain next-generation DNA sequencing (NGS), which is the preferred approach to identify other potentially actionable molecular alterations. NGS platforms can be used to identify frequent driver mutations in melanoma as well as an extensive panel of other mutations that could possibly be targeted in the future [7,8]. This approach maximizes the chances of identifying actionable mutations. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Mutations that should be assessed with NGS include the less common BRAF V600 mutations and non-V600 molecular variants; NRAS; KIT (frequently seen in patients with either an acral or mucosal primary site, or primary melanoma in an area of chronically sun exposed skin); and TRK gene fusions. NGS can also provide information on the level of tumor mutational burden, which influences response to checkpoint inhibitor immunotherapy but not the choice to treat with immunotherapy. (See 'BRAF V600 mutation variants' below and 'Other molecular alterations' below.)

BRAF V600 MUTANT DISEASE

BRAF V600 mutation variants — Activating mutations in BRAF are present in approximately 40 to 60 percent of metastatic melanomas, depending on the primary site on the skin [2-4]. The two most common BRAF mutations are V600E and V600K. Among all tumors harboring a BRAF mutation, the V600E mutation occurs in 80 to 90 percent of cases, and the V600K mutation occurs in approximately 15 percent of cases [9].

Less frequent BRAF mutations include V600R, V600M, V600D, and V600G, occurring in approximately 5 percent of cases. Patients with metastatic melanoma harboring different BRAF V600 mutations exhibit varying degrees of clinical response to targeted therapy with BRAF plus MEK inhibitors, with BRAF V600E tumors demonstrating higher response rates than those with other V600 mutations [10].

Previously untreated patients

Choice of initial therapy — In patients with systemic therapy-naive BRAF V600 mutant metastatic disease, we recommend combination checkpoint inhibitor immunotherapy with nivolumab plus ipilimumab (table 3) rather than combination targeted therapy with BRAF plus MEK inhibitors. In a phase III trial, initial therapy with combination immunotherapy (nivolumab plus ipilimumab) improved overall survival (OS) compared with initial targeted therapy (combination BRAF plus MEK inhibitors (algorithm 1)) [11]. (See 'Nivolumab plus ipilimumab (preferred)' below.)

Initial treatment with immunotherapy offers durable responses, long-term OS benefit, and greater treatment-free survival. By contrast, while targeted therapy may initially offer a rapid treatment response, the duration of response is more limited, and most patients with BRAF mutant disease ultimately experience disease progression after initial targeted therapy [12] and require subsequent therapy. Immunotherapy is also less effective when used after targeted therapy. However, targeted therapy is the preferred option for patients who are ineligible for or decline immunotherapy. (See 'Ineligible for immunotherapy (targeted therapy)' below.)

In a randomized phase III trial (DREAMseq; ECOG-ACRIN EA6134), 265 patients with treatment-naïve BRAF mutant melanoma were randomly assigned to receive either immunotherapy with nivolumab plus ipilimumab followed by maintenance nivolumab, or targeted therapy with dabrafenib plus trametinib [11]. Patients with disease progression were offered the alternative regimen. In preliminary results, at median follow-up of 28 months, compared with the sequence of targeted therapy followed by immunotherapy, immunotherapy followed by targeted therapy improved OS (two-year OS 72 percent [95% CI 62-79 percent] versus 52 percent [95% CI 42-60 percent]; two-year OS benefit 20 percent [95% CI 3-38 percent]). The trial was stopped early for benefit.

This sequence also trended toward improved progression-free survival (PFS; median 11.8 months [95% CI 5.9-33.5] versus 8.5 months [95% CI 6.5-11.3]; two-year PFS 42 versus 19 percent) and median duration of response (not reached versus 13 months). Among the responders to initial immunotherapy, the proportion who remained in remission at a median follow-up of 28 months was 88 percent (37 of 42 patients); in contrast, the proportion remaining in remission among the responders to initial targeted therapy was 48 percent (18 of 37 patients). Grade ≥3 toxicity rates were similar for immunotherapy and targeted therapy (60 versus 52 percent, respectively).

Similar results were also seen in a separate randomized phase II trial (SECOMBIT) comparing varying sequencing approaches of immunotherapy (nivolumab plus ipilimumab) and targeted therapy (encorafenib plus binimetinib), although follow-up of this trial is ongoing. In preliminary results of this study, compared with initial targeted therapy followed by immunotherapy, there is a trend towards higher PFS and OS for those treated with initial immunotherapy followed by targeted therapy and those who received a "sandwich" approach (ie, targeted therapy for a defined period to initially reduce tumor burden, followed by immunotherapy until disease progression, followed by targeted therapy) [13,14].

Data also suggest that immunotherapy is less effective when used upon progression after targeted therapy, likely due to treatment resistance [11,13-15]. In the phase III trial DREAMseq, objective response rates (ORRs) were lower for patients who received immunotherapy following targeted therapy (30 percent), compared with those who received initial immunotherapy (46 percent). In contrast, ORR were similar for targeted therapy whether given as initial therapy (43 percent) or following disease progression on immunotherapy (48 percent) [11].

Defining immunotherapy eligibility — Patients eligible for checkpoint inhibitor immunotherapy typically meet the following criteria:

Eastern Cooperative Oncology Group (ECOG) performance status <2 (table 4)

Fitness to tolerate potential immunotherapy-related adverse events (irAEs (see "Toxicities associated with checkpoint inhibitor immunotherapy"))

No medical comorbidities that would make irAEs difficult to manage (eg, chronic obstructive pulmonary disease [COPD] with low pulmonary reserve or poorly controlled diabetes mellitus)

No active clinically significant autoimmune disease

No immunosuppressive therapy or corticosteroids

Eligible for immunotherapy

Nivolumab plus ipilimumab (preferred) — For patients with BRAF V600 mutant disease who are eligible for immunotherapy, we prefer initial treatment with the combination of nivolumab (a PD-1 inhibitor) and ipilimumab (a cytotoxic T lymphocyte-associated antigen 4 [CTLA-4] inhibitor (table 3)), over a single-agent PD-1 inhibitor, as this approach improved PFS and OS in a phase III trial (algorithm 1) [16,17]. Nivolumab plus ipilimumab is also the preferred treatment in patients with stage IV disease, regardless of BRAF V600 mutation status, who have undergone definitive treatment of their disease with either surgery or radiation therapy. These data are discussed separately. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Metastatic disease (stage IV)'.)

In a double-blind, placebo-controlled phase III trial (CheckMate 067) [16,17], 945 treatment-naïve patients with metastatic melanoma were randomly assigned to one of the following:

Combination nivolumab (1 mg/kg every three weeks for four doses) plus ipilimumab (3 mg/kg every three weeks for four doses), followed by nivolumab 3 mg/kg every two weeks

Nivolumab 3 mg/kg every two weeks

Ipilimumab 3 mg/kg every three weeks for four doses

In a subgroup analysis performed at follow-up of 6.5 years, the 301 patients with BRAF V600 mutant tumors appeared to derive greater benefit with the combination relative to nivolumab [17]. In these patients, compared with nivolumab alone, nivolumab plus ipilimumab improved 6.5-year PFS (37 versus 23 percent, hazard ratio [HR] 0.62, 95% CI 0.44-0.89) and 6.5-year OS (57 versus 43 percent, HR 0.68, 95% CI 0.46-1.02).

Nivolumab plus ipilimumab was also effective in patients with more aggressive disease (eg, elevated lactate dehydrogenase [LDH], brain metastases, or symptomatic systemic metastases). Further details on the efficacy of nivolumab plus ipilimumab in the entire study population and these patient subgroups are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)

Nivolumab-relatlimab — For patients with BRAF V600 mutant disease who are unlikely to tolerate the potential toxicities of nivolumab plus ipilimumab, the combination of nivolumab-relatlimab is an appropriate alternative. As examples, this approach may be appropriate for older adults who are eligible for immunotherapy but seek a more tolerable regimen with lesser risk of irAEs, or those with a history of autoimmune disease. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Patients with vulnerabilities to immunotherapy toxicities'.)

A double-blind phase III trial (RELATIVITY-047) evaluating nivolumab-relatlimab included a subset of 275 patients with BRAF V600 mutant advanced unresectable or metastatic melanoma. In the overall population, there was an improvement in PFS with the addition of relatlimab to nivolumab, an effect that was also seen in the BRAF mutant population [18,19]. Nivolumab-relatlimab also has a more favorable toxicity profile compared with that reported for nivolumab plus ipilimumab in other studies [16,17,20,21]. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab-relatlimab'.)

Alternative immunotherapy options — For treatment-naïve patients with BRAF V600 mutant disease eligible for immunotherapy but who are unable to tolerate the potential toxicities of combination immunotherapy (ie, nivolumab plus ipilimumab or nivolumab-relatlimab) we suggest single-agent PD-1 inhibitors rather than targeted therapy (algorithm 1). Options include pembrolizumab (table 2) [22,23] or nivolumab (table 1) [16]. Data are as follows:

Pembrolizumab In a phase III trial (KEYNOTE-006), 834 patients without prior exposure to immunotherapy were randomly assigned to pembrolizumab versus ipilimumab [22]. Among the subset of 163 treatment-naïve patients with BRAF V600 mutant disease, pembrolizumab improved ORRs compared with ipilimumab (47 versus 18 percent). At median follow-up of 58 months, OS was longer for patients receiving pembrolizumab, although the data were not statistically significant (median not reached versus 26 months, HR 0.7, 95% CI 0.44-1.11). Additionally, there were no differences in efficacy parameters in any other patient subsets, including those with previous exposure to BRAF or MEK inhibitors. Data for the entire study population are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Pembrolizumab'.)

Other studies have also demonstrated similar outcomes for pembrolizumab in patients with BRAF-mutant melanoma compared with those with BRAF wild-type disease and suggested its efficacy as initial therapy. In a post-hoc analysis of three randomized trials (KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006) including 1558 patients with advanced melanoma, patients with BRAF wild-type and BRAF V600E/K-mutant melanoma had similar rates of four-year PFS (23 versus 20 percent) and OS (38 versus 35 percent), although there was a small statistically significant difference in ORRs (40 versus 34 percent, respectively) [23]. Of note, patients with BRAF V600E/K-mutant melanoma previously treated with targeted therapy had worsened outcomes with pembrolizumab compared with those who had not previously received targeted therapy (ORR 28 versus 44 percent; four-year PFS 15 versus 28 percent; and OS 27 versus 49 percent).

Nivolumab – The data for nivolumab (table 1) for patients with BRAF V600 mutant disease are discussed above. (See 'Nivolumab plus ipilimumab (preferred)' above.)

There is no established role for the following immunotherapy options in treatment-naïve patients with BRAF V600 mutant disease.

Atezolizumab – The programmed cell death ligand 1 (PD-L1) inhibitor atezolizumab has been evaluated in combination with the targeted agents vemurafenib plus cobimetinib in a phase III trial and received US Food and Drug Administration (FDA) approval. However, the control arm for this trial was cobimetinib and vemurafenib rather than a single-agent PD-1 inhibitor such as pembrolizumab or nivolumab or the combination of nivolumab plus ipilimumab. It remains uncertain whether initial therapy with the triple combination produces better results than offering an initial pure immunotherapy regimen followed by combination BRAF plus MEK inhibitor therapy upon disease progression. (See 'Is there a role for combined immunotherapy and targeted therapy?' below.)

Pembrolizumab plus ipilimumab – We do not offer the combination of pembrolizumab and ipilimumab in these patients, as this combination does not have regulatory approval. Data for this regimen are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Investigational agents'.)

Ineligible for immunotherapy (targeted therapy) — For previously untreated patients with BRAF V600 mutations who decline or are ineligible for immunotherapy, we recommend targeted therapy with combination BRAF plus MEK inhibitors, rather than either inhibitor as a single agent (algorithm 1). Such combination therapy confers a survival benefit and is less toxic compared with single-agent targeted therapy. (See 'Choice of BRAF plus MEK inhibitor therapy' below and 'Toxicities of BRAF and MEK inhibitors' below.)

Choice of BRAF plus MEK inhibitor therapy — Three different combinations of BRAF inhibitors plus MEK inhibitors are available as initial therapy:

Dabrafenib plus trametinib (see 'Dabrafenib plus trametinib' below)

Encorafenib plus binimetinib (see 'Encorafenib plus binimetinib' below)

Vemurafenib plus cobimetinib (see 'Vemurafenib plus cobimetinib' below)

All combinations are reasonable options as they have not been directly compared in randomized trials, although all appear to have similar efficacy, including ORRs of up to 70 percent. The choice between these regimens is based on multiple factors including sites of metastatic disease, patient convenience, and potential toxicities. As examples:

For patients with CNS metastases, we offer dabrafenib plus trametinib, as this combination has been evaluated in clinical trials including this patient population. These data are discussed separately. (See "Management of brain metastases in melanoma", section on 'BRAF and MEK inhibitors'.)

Encorafenib plus binimetinib may be preferred for patient convenience, as this combination can be taken with or without meals and can be stored at room temperature, as opposed to the combination of dabrafenib and trametinib, which requires administration around meals and refrigeration for trametinib.

Vemurafenib plus cobimetinib is less preferred because it is the combination with the most treatment-related toxicities (eg, skin rash, photosensitivity, diarrhea, and elevations in liver enzymes). (See 'Vemurafenib plus cobimetinib' below.)

Dabrafenib plus trametinib — Dabrafenib is a specific inhibitor of BRAF kinase, and trametinib is a potent, highly specific inhibitor of MEK1/MEK2. Dabrafenib and trametinib improved survival outcomes as single agents when initially compared with chemotherapy [24-26] and delayed treatment resistance while reducing toxicity as combination therapy when initially compared with single-agent BRAF inhibition [27,28].

Based on these prior data, two subsequent phase III trials demonstrated that the combination improved PFS and OS compared with single-agent BRAF inhibition with either dabrafenib (COMBI-d) [29-31] or vemurafenib (COMBI-v) [32,33]. Extended follow-up studies combining the data from these two trials demonstrated long-term survival benefit in approximately one-third of patients treated with the combination of dabrafenib and trametinib [34-36]. Responses lasting for over a year and favorable outcomes are seen among patients with a good performance status and limited disease burden.

Data for the phase III trials (COMBI-d and COMBI-v) are as follows:

Dabrafenib plus trametinib versus dabrafenib – In a placebo-controlled phase III trial (COMBI-d), 423 treatment-naïve patients with a BRAF V600E or V600K mutation were randomly assigned to either dabrafenib (150 mg twice per day) plus trametinib (2 mg once per day) or to dabrafenib alone. At minimum three-year follow-up, compared with single-agent dabrafenib, the combination improved both three-year PFS (22 versus 12 percent, HR 0.71, 95% CI 0.57-0.88) and three-year OS (44 versus 32 percent, HR 0.75, 95% CI 0.58-0.96) [31]. ORRs were higher with the combination (68 versus 55 percent), and complete response rates were similar between the two groups (18 versus 15 percent). Patients on combination therapy were more likely to remain on treatment due to prolonged periods of disease control (19 versus 3 percent).

Cutaneous toxicities of any grade were more frequent for single-agent dabrafenib versus the combination, including dry skin (14 versus 9 percent), pruritus (11 versus 7 percent), hyperkeratosis (33 versus 6 percent), hand-foot syndrome (27 versus 6 percent), alopecia (26 versus 5 percent), skin papilloma (18 versus 1 percent), and squamous cell carcinoma (9 versus 3 percent) [30].

By contrast, other noncutaneous toxicities were more frequent for the combination versus single-agent dabrafenib, included diarrhea (18 versus 9 percent), pyrexia (52 versus 25 percent), and chills (28 versus 14 percent). Treatment discontinuation was more common with the combination (11 versus 7 percent), primarily due to pyrexia and chills. (See 'Toxicities of BRAF and MEK inhibitors' below.)

Dabrafenib plus trametinib versus vemurafenib – In an open-label phase III trial (COMBI-v) trial, 704 patients with treatment-naïve metastatic melanoma with a BRAF V600 mutation were randomly assigned to either dabrafenib plus trametinib or vemurafenib [32,33]. At median follow-up of 11 months, compared with vemurafenib, the combination improved one-year OS (72 versus 65 percent, HR 0.69, 95% CI 0.53-0.89), PFS (median 11 versus 7 months, 95% CI 0.46-0.69), and ORRs (67 versus 53 percent) [32]. In extended follow-up available in abstract form only, the combination continued to improve both PFS and OS (three-year PFS 25 versus 11 percent; three-year OS 45 versus 32 percent) [33]. Over half (58 percent) of patients on combination therapy remained on treatment.

Of note, the incidence of cutaneous squamous cell carcinoma and keratoacanthoma was lower with the combination of dabrafenib plus trametinib compared with vemurafenib alone (1 versus 18 percent) [32]. (See 'Toxicities of BRAF and MEK inhibitors' below.)

Combined analysis of COMBI-d and COMBI-v – In a combined analysis of COMBI-d and COMBI-v, the combination of dabrafenib and trametinib demonstrated a median PFS and OS of approximately 11 and 26 months, respectively [36]. Estimated PFS and OS at five years were approximately 19 and 34 percent, respectively. Among the 19 percent with a complete response, estimated five-year OS was 71 percent.

Factors associated with a favorable outcome from combination dabrafenib and trametinib include good performance status, normal LDH, and <3 organs containing metastases. In this and another study, patients with normal LDH and <3 sites of metastatic disease had estimated five-year OS rates of 51 and 55 percent [35,36].

Based on these data, dabrafenib plus trametinib was approved by the US FDA for the treatment of patients with unresectable or metastatic melanoma containing a BRAF V600E or BRAF V600K mutation [37,38].

Dabrafenib plus trametinib is also approved by the US FDA for the treatment of other unresectable or metastatic tumors containing a BRAF V600E mutation including non-small cell lung cancer, anaplastic thyroid cancer, and solid tumors that have progressed following prior therapies with no satisfactory alternative treatment options in adult and pediatric patients six years of age or older [37,38]. The management of these tumors is discussed separately. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'BRAF mutations' and "Anaplastic thyroid cancer", section on 'BRAF V600E mutation identified'.)

Encorafenib plus binimetinib — Encorafenib is a specific inhibitor of BRAF kinase. Binimetinib is a specific inhibitor of MEK1 and MEK2 that has demonstrated activity in initial phase II trials of patients with advanced melanoma harboring mutations in BRAF V600 and NRAS [39,40]. In a phase III trial, the combination of encorafenib plus binimetinib improved PFS and OS over single-agent BRAF inhibition [41-44].

Based on initial phase I and II trial data [45], a phase III trial (COLUMBUS) was performed in 577 patients with BRAF V600-mutated melanoma, comparing the combination of the BRAF inhibitor encorafenib plus the MEK inhibitor binimetinib versus either encorafenib alone or the single-agent BRAF inhibitor vemurafenib [41-44]. At a median follow-up of approximately four years (49 months), results were as follows [44]:

The combination improved both PFS and OS compared with vemurafenib (median PFS 15 versus 7 months, HR 0.51, 95% CI 0.39-0.67; median OS 34 versus 17 months, HR 0.61, 95% CI 0.47-0.79).

The combination had a nonsignificant trend towards higher PFS and OS compared with encorafenib (median PFS 15 versus 10 months, HR 0.77, 95% CI 0.59-1; median OS 34 versus 24 months, HR 0.81, 95% CI 0.61-1.06).

The ORR for the combination was 64 percent, which was higher than either encorafenib (52 percent) or vemurafenib (41 percent).

Additionally, encorafenib improved both PFS and OS compared with vemurafenib (median PFS 10 versus 7 months, HR 0.68, 95% CI 0.52-0.88; median OS 24 versus 17 months, HR 0.76, 95% CI 0.58-0.98).

Compared with vemurafenib, the combination had lower rates of pyrexia (18 versus 30 percent) and photosensitivity (5 versus 30 percent), but higher rates of retinopathy (20 versus 2 percent) [43]. (See 'Toxicities of BRAF and MEK inhibitors' below.)

Based on these data, the combination of encorafenib plus binimetinib was approved by the US FDA for the treatment of patients with unresectable or metastatic melanoma containing a BRAF V600E or BRAF V600K mutation.

Vemurafenib plus cobimetinib — Vemurafenib is a potent inhibitor of the BRAF kinase that improved survival when initially compared with chemotherapy [12,46,47]. Cobimetinib is a potent, specific inhibitor of MEK1 and MEK2. In a phase III trial, the combination of vemurafenib plus cobimetinib improved PFS and OS over single-agent BRAF inhibition.

Based on initial phase I data from the BRIM-7 study [48,49], the combination of vemurafenib plus cobimetinib was evaluated in a placebo-controlled phase III trial (coBRIM) [50,51]. In this study, 495 patients with previously untreated advanced melanoma with a BRAF V600 mutation were randomly assigned to vemurafenib (960 mg twice per day) plus cobimetinib (60 mg once per day on days 1 to 21 of each 28-day cycle) or vemurafenib alone.

At median follow-up of 14 months, compared with vemurafenib alone, the combination improved both OS (median 22 versus 17 months, HR 0.7, 95% CI 0.55-0.9) and PFS (median 12 versus 7 months, HR 0.58, 95% CI 0.46-0.72) [51]. Objective (70 versus 50 percent) and complete response rates (16 versus 11 percent) were also higher with the combination.

Grade ≥3 toxicities occurring more frequently with the combination included diarrhea (7 versus 1 percent), photosensitivity (3 versus 0 percent), and elevations in alanine aminotransferase (11 versus 6 percent), gamma-glutamyltransferase (15 versus 10 percent), aspartate aminotransferase (9 versus 2 percent), and blood creatine phosphokinase (12 versus <1 percent) [51]. Serious adverse events reported with the combination included pyrexia and dehydration (2 percent each). Cutaneous toxicities of any grade were higher with single-agent vemurafenib compared with the combination, including cutaneous squamous cell carcinoma (13 versus 4 percent) and keratoacanthoma (9 versus 2 percent). (See 'Toxicities of BRAF and MEK inhibitors' below.)

Based on these data, cobimetinib is approved by the US FDA for use in combination with vemurafenib for patients with metastatic melanoma and a V600 mutation in BRAF.

Dosing considerations and toxicities of BRAF plus MEK inhibitors

Continuous versus intermittent therapy — For patients receiving targeted treatment with combined BRAF plus MEK inhibitors, we suggest continuous rather than intermittent therapy. Continuous therapy (ie, administration of targeted therapy without interruption until disease progression or unacceptable toxicity) improved PFS over intermittent therapy in a randomized phase II trial [52]. These data also suggest that intermittent therapy does not necessarily delay the development of disease resistance.

In a phase II trial (SWOG 1320), 206 patients with unresectable or metastatic BRAF V600 mutant melanoma treated with dabrafenib plus trametinib were randomly assigned to continuous or intermittent dosing (five weeks on, three weeks off). Compared with intermittent therapy, continuous therapy improved PFS (median 9 versus 5.5 months). OS and treatment-related toxicities were similar between the two groups.

Toxicities of BRAF and MEK inhibitors — Specific treatment-related toxicities associated with BRAF and/or MEK inhibitors are as follows:

Dermatologic toxicities

Squamous cell carcinomas – Squamous cell carcinomas (SCCs), including keratoacanthomas (KAs), are common with BRAF and MEK inhibitors when administered as single agents. They occur in 19 to 26 percent of cases within weeks of initiating therapy [53]. However, the incidence of SCCs and KAs are significantly mitigated when these drugs are administered in combination.

Molecular studies indicate that the development of SCCs and KAs are due to a paradoxical activation of the mitogen-activated protein (MAP) kinase pathway that bypasses the inhibition of BRAF [54]. However, toxicity data from phase III trials evaluating combination BRAF plus MEK inhibition indicate a reduced incidence of skin toxicity (including skin cancers) compared with single-agent BRAF inhibition. These findings are presumably due to the addition of the MEK inhibitor, which blocks the paradoxical activation of the MAP kinase pathway [55]. (See 'Dabrafenib plus trametinib' above and 'Vemurafenib plus cobimetinib' above.)

Further details on SCCs and KAs in patients treated with BRAF and MEK inhibitors and their management are discussed separately. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'BRAF plus MEK inhibitors' and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions' and "Keratoacanthoma: Management and prognosis" and "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

Other dermatologic toxicities – Other nonmalignant dermatologic complications associated with single-agent BRAF inhibitors include rash, photosensitivity reactions, palmoplantar keratoderma, and delayed wound healing, among others. Such dermatologic toxicities are discussed in detail separately. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'BRAF inhibitors'.)

Acneiform rashes are associated with single-agent MEK inhibitors. Clinical manifestations and management are discussed separately. (See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

Cardiovascular toxicities

Cardiomyopathy – Cardiomyopathy with decreased cardiac ejection fraction has been identified in patients treated with MEK inhibitors as single agents (trametinib) and in combination with BRAF inhibitors (cobimetinib plus vemurafenib). Patients receiving these agents should undergo assessment of left ventricular ejection fraction (LVEF) prior to initiation of and during therapy. Further details are discussed separately. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Cobimetinib, trametinib, and binimetinib' and "Tests to evaluate left ventricular systolic function".)

QTc prolongation – Prolongation of the QTc interval can occur with administration of the BRAF inhibitors vemurafenib and encorafenib. Vemurafenib is a cytochrome P450 3A4 (CYP3A4) substrate, and it should be used with caution in patients with congenital long QT syndrome and those who are receiving other drugs that prolong the QT interval (table 5) or inhibit CYP3A4 (table 6). Patients may be monitored with electrocardiogram (ECG) and electrolytes before treatment and after dose modification. Further details are discussed separately. (See "Cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines", section on 'Vemurafenib and encorafenib'.)

Constitutional toxicities – Pyrexia is relatively frequent with combination BRAF plus MEK inhibitor therapy. Other common constitutional toxicities include fatigue, weakness, and arthralgias (≥20 percent) [12,24,37,38,56].

For most patients with pyrexia, we hold the BRAF inhibitor and manage symptomatically with rest, fluids, cold compresses, acetaminophen, and occasionally low doses of corticosteroids [57,58]. Severe symptoms occur in approximately 4 percent of cases and require dose modification upon reinitiation of therapy. As pyrexia is most common with dabrafenib, some experts may switch patients on dabrafenib plus trametinib with persistent pyrexia (attributed to drug therapy) to one of the other BRAF plus MEK inhibitor combinations.

In phase III trials, the incidence of pyrexia was highest for the combination of dabrafenib plus trametinib (52 percent) [30], versus the combinations of vemurafenib plus cobimetinib (29 percent) and encorafenib plus binimetinib (18 percent) [43,51].

Gastrointestinal toxicities – Diarrhea is the most common gastrointestinal toxicity reported with the combination of BRAF and MEK inhibitors. Gastrointestinal perforation has rarely been reported (<1 percent), specifically for the combination of dabrafenib plus trametinib. Management of these toxicities are discussed separately. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'MEK inhibitors' and "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Trametinib'.)

Pulmonary toxicities – Pneumonitis, interstitial lung disease (ILD), and pulmonary embolism have been reported with both BRAF and MEK inhibitors, and these toxicities are discussed separately. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'BRAF inhibitors' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Trametinib' and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Hepatotoxicity – Hepatoxicity has been associated with both BRAF and MEK inhibitors, and all patients receiving these agents in combination should undergo baseline and periodic monitoring of liver function. Dose adjustment of these drugs for patients with underlying liver disease is discussed separately. (See "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'MEK inhibitors' and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents", section on 'BRAF inhibitors'.)

Nephrotoxicity – Various renal toxicities have been reported with BRAF inhibitors as single agents and in combination with MEK inhibitors. For example, vemurafenib is associated with decreases in creatinine clearance, acute kidney injury, and Fanconi syndrome. The combination of encorafenib and binimetinib is also associated with renal impairment, hyponatremia, and rarely glomerulonephritis. Further details on these toxicities and their management in those with underlying renal impairment are discussed separately. (See "Chemotherapy nephrotoxicity and dose modification in patients with kidney impairment: Molecularly targeted agents and immunotherapies", section on 'BRAF and MEK inhibitors'.)

Neurologic toxicities – Neurologic toxicities reported with vemurafenib include headaches and peripheral facial palsy, which can occasionally be bilateral [56,59]. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Vemurafenib'.)

Radiation sensitization and recall – Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs have been reported in patients treated with radiation prior to, during, or subsequent to treatment with vemurafenib and dabrafenib [60-63]. Holding treatment with a BRAF inhibitor (with or without an MEK inhibitor) for one to three days before and one day after stereotactic radiosurgery appears to minimize the risk of significant toxicity. The same approach is used for both intracranial and extracranial systemic metastases. (See "Management of brain metastases in melanoma", section on 'Radiation sensitization with BRAF inhibitors'.)

Ocular toxicities – Ocular toxicity (including uveitis, conjunctivitis, dry eyes) has been reported with both vemurafenib and dabrafenib. (See "Ocular side effects of systemically administered chemotherapy", section on 'BRAF inhibitors'.)

Visual problems associated with MEK inhibitors are known as MEK inhibitor-associated retinopathy. Retinal vein occlusion is an uncommon but potentially severe side effect that occurs in less than 1 percent of cases. Patients receiving MEK inhibitors should undergo ophthalmologic exams regularly during treatment and in the event of visual disturbances. (See "Ocular side effects of systemically administered chemotherapy", section on 'Mitogen-activated protein kinase inhibitors'.)

Hematologic toxicity Dabrafenib is not recommended for patients with known glucose-6-phosphate dehydrogenase (G6PD) deficiency, as it contains a sulfonamide moiety and may result in hemolytic anemia in these patients [57].

RAS-mutant chronic myelomonocytic leukemia occurring with the initiation of single-agent vemurafenib therapy has been reported [64]. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)

Endocrinologic toxicity – The incidence of grade 3 hyperglycemia in those receiving BRAF and MEK inhibitors is approximately 2 to 6 percent, but this toxicity mainly impacts patients with diabetes mellitus or hyperglycemia [26,57]. Such patients should have regular monitoring of glucose levels while on therapy.

Is there a role for combined immunotherapy and targeted therapy? — In patients with previously untreated advanced BRAF V600 mutant melanoma, the role for combining checkpoint inhibitor immunotherapy with molecularly targeted therapy (using BRAF and MEK inhibitors) is not established, and clinical trials are encouraged, where available. For patients who decline, are ineligible for, or do not have access to clinical trials, our general approach is to use immunotherapy as initial therapy, rather than molecularly targeted therapies, because of the ability of immunotherapy to provide long-term treatment-free survival. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Nivolumab plus ipilimumab (preferred)'.)

The rationale for combining these treatments in patients with BRAF V600 mutant melanoma is to achieve both the high response rates of targeted therapy and the durable responses of immunotherapy, ultimately improving OS [65]. Data from randomized phase II and phase III trials suggest higher PFS and duration of response with combined immunotherapy and targeted therapy [66-68]. The US FDA approved the triplet combination of atezolizumab and vemurafenib plus cobimetinib based on a statistically significant improvement in PFS compared with targeted therapy alone; however, the triplet combination spartalizumab and dabrafenib plus trametinib showed a similar but nonstatistically significant improvement in PFS [69]. Furthermore, OS data, while immature, and ORRs are not significantly improved, and toxicity is greater with this approach. These triplet combinations have also not been directly compared with the sequential approach of initial immunotherapy followed by targeted therapy upon disease progression, which is the preferred treatment strategy for many patients. Therefore, despite the US FDA approval of the atezolizumab and vemurafenib plus cobimetinib triplet regimen, we await further data from these studies before routinely incorporating combined immunotherapy and targeted therapy into clinical practice.

Atezolizumab and vemurafenib plus cobimetinib — In a randomized, placebo-controlled phase III trial (IMspire150), 514 treatment-naïve patients with advanced, unresectable stage IIIC or stage IV BRAF V600 mutant melanoma were randomly assigned to the combination of the PD-L1 inhibitor atezolizumab and vemurafenib plus cobimetinib (immunotherapy plus targeted therapy) versus placebo and vemurafenib plus cobimetinib (targeted therapy alone) [66,70]. During the first cycle of therapy, all patients received vemurafenib and cobimetinib only, with either atezolizumab or placebo added during subsequent cycles.

At median follow-up of 19 months, the addition of atezolizumab to targeted therapy improved PFS based on investigator assessment (median 15 versus 11 months, HR 0.78, 95% CI 0.63-0.97), although the statistical significance of these data was not confirmed on independent review [66]. The two-year OS rates were 60 and 53 percent, respectively; OS data are immature. Median duration of response was longer for those receiving both immunotherapy and targeted therapy (21 versus 13 months). Objective (66 versus 65 percent) and complete (16 versus 17 percent) response rates were similar between the two groups.

Serious treatment-related adverse events were similar between the groups (34 versus 29 percent); however, this data may be confounded, as the toxicities seen in patients receiving combination immunotherapy and targeted therapy but treated with vemurafenib plus cobimetinib during the initial run-in period were combined with the toxicities seen in those receiving placebo with vemurafenib plus cobimetinib, leading to a potentially lower toxicity than would be expected for the combination therapy regimen. No new toxicity signals for the individual therapies were noted.

Based on these data, atezolizumab, in combination with cobimetinib and vemurafenib, is approved by the US FDA for patients with BRAF V600 mutation-positive melanoma [71].

Other combinations

Spartalizumab and dabrafenib plus trametinib – The combination of the PD-1 inhibitor spartalizumab with dabrafenib and trametinib (targeted therapy) did not significantly improve PFS and increased toxicity in a placebo-controlled phase III trial (COMBI-i) [69,72]. Among 532 patients with advanced, unresectable BRAF V600 mutant melanoma, at median follow-up of 27 months, the addition of spartalizumab to targeted therapy numerically increased PFS, but these results did not achieve statistical significance (16 versus 12 months; HR 0.82, 95% CI 0.66-1.03) [69]. Although OS was not formally tested because the primary endpoint for the trial (PFS) was not significant, median OS was not reached (NR) for either treatment arm. ORRs were 69 and 64 percent, respectively. Median duration of response was NR and 21 months, respectively. The addition of spartalizumab to targeted therapy also increased grade ≥3 toxicity rates (55 versus 33 percent), which frequently led to dose adjustments and treatment discontinuation (12 versus 8 percent).

Pembrolizumab and dabrafenib plus trametinib – In a post-hoc analysis of a randomized placebo-controlled phase II trial (KEYNOTE-022) of 120 treatment-naïve patients with advanced BRAF V600 mutant melanoma, at a median follow-up of 37 months, the addition of the PD-1 inhibitor pembrolizumab to dabrafenib plus trametinib improved PFS (median 17 versus 11 months, HR 0.53, 0.34-0.83) and duration of response (median 25 versus 12 months) [67,68]. Two-year OS rates were higher for immunotherapy plus targeted therapy compared with targeted therapy alone, although the results were not statistically significant (63 versus 52 percent, HR 0.64, 95% CI 0.38-1.06), and ORRs were lower (63 versus 72 percent, respectively). Grade ≥3 treatment-related toxicity rates were higher among those receiving combined immunotherapy plus targeted therapy (58 versus 25 percent).

Prior adjuvant systemic therapy — Adjuvant systemic therapy is administered to patients at high risk for recurrence after initial definitive surgical resection. For such patients with BRAF V600 mutant disease, options for adjuvant therapy include checkpoint inhibitor immunotherapy or targeted therapy with combination BRAF plus MEK inhibition. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma".)

Although adjuvant therapy reduces the risk of recurrence, some patients may still relapse with metastatic disease. There are limited prospective data evaluating the optimal treatment in these patients, and enrollment in clinical trials is encouraged, where available.

The approach to systemic therapy in these patients is based on multiple clinical factors including:

Type of adjuvant therapy originally received

Tolerance of prior adjuvant therapy

Interval between completion of adjuvant therapy and disease progression

Patient performance status and comorbidities

Prior adjuvant immunotherapy

Eligible for immunotherapy — For patients with BRAF V600 mutant metastatic melanoma who previously received adjuvant immunotherapy with a single-agent PD-1 inhibitor (eg, nivolumab or pembrolizumab), relapse with metastatic disease, and are eligible for further immunotherapy, we suggest initial treatment with nivolumab plus ipilimumab rather than other systemic therapies, similar to those with BRAF wildtype disease. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)'.)

However, in the absence of comparative data, initial targeted therapy with combination BRAF plus MEK inhibitors is a reasonable alternative. We do not retreat these patients with single-agent PD-1 inhibitors because such treatment is unlikely to be curative, given the demonstrated disease resistance. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Is there a role for PD-1 inhibitor rechallenge?'.)

Combination immunotherapy with CTLA-4 and PD-1 inhibitors results in objective responses in approximately 30 percent of patients with PD-1 inhibitor refractory disease and may offer the opportunity for long-term treatment-free survival. Patients offered this approach must have tolerated prior adjuvant immunotherapy without significant irAEs. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

As an example, a phase II trial evaluated the efficacy of pembrolizumab plus ipilimumab in patients with metastatic disease resistant to PD-1 inhibitors [73]. Among the subset of patients with BRAF V600 mutant tumors, the ORR was 25 percent (5 of 20 evaluable patients). Further details of this trial in the entire study population and other supporting data are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Is there a role for pembrolizumab plus ipilimumab?'.)

For those receiving prior adjuvant therapy with a single-agent PD-1 inhibitor (eg, pembrolizumab (table 2) or nivolumab (table 1)), we do not retreat with a PD-1 inhibitor. Observational retrospective data, which included patients with BRAF mutant advanced or metastatic disease, demonstrated limited activity with this retreatment approach and suggest some form of treatment resistance [74]. While single-agent ipilimumab is also an option in these patients, it is less preferred due to toxicity profile and the availability of other effective treatments. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Ipilimumab'.)

Ineligible for immunotherapy — For those who decline or are ineligible for further immunotherapy, we offer targeted therapy with combination BRAF plus MEK inhibitors. (See 'Ineligible for immunotherapy (targeted therapy)' above.)

Prior adjuvant BRAF plus MEK inhibitors — For patients with BRAF V600 mutant disease previously treated with adjuvant targeted therapy (ie, combination BRAF plus MEK inhibitors), we typically administer checkpoint inhibitor immunotherapy. However, specific treatment options depend upon previous tolerance of targeted therapy and the interval between completion of adjuvant therapy and disease progression. For example, patients with longer intervals between completion of adjuvant targeted therapy and disease progression may be rechallenged with targeted therapy.

Relapsed disease ≤6 months – For patients who relapse within six months of completing adjuvant targeted therapy, we offer immunotherapy rather than retreatment with targeted therapy, given patients likely have disease resistance to the previously received targeted therapy [75,76]. While we prefer combination immunotherapy with nivolumab plus ipilimumab, single-agent PD-1 inhibitors (eg, pembrolizumab (table 2), nivolumab (table 1)) are also an option in these patients, who are treatment-naïve to immunotherapy. Patients ineligible for immunotherapy should be offered enrollment in clinical trials, were available. (See 'Investigational options' below.)

Relapsed disease >6 months – We offer immunotherapy to patients who relapse more than six months after completing adjuvant therapy and/or were intolerant of targeted therapy. Options include combination immunotherapy (eg, nivolumab plus ipilimumab) or single-agent immunotherapy with PD-1 inhibitors (eg, pembrolizumab (table 2), nivolumab (table 1)) or the CTLA-4 inhibitor ipilimumab.

Rechallenging with targeted therapy is an acceptable alternative to immunotherapy for select patients who relapse more than six months after completing adjuvant targeted therapy, if they tolerated it previously without significant toxicity. (See 'Choice of BRAF plus MEK inhibitor therapy' above.)

Subsequent therapy — Although the survival of patients with BRAF V600 mutant metastatic melanoma has dramatically improved with the use of targeted therapy and immunotherapy, some patients may eventually relapse. The choice of treatment regimen is influenced by prior therapy and associated toxicities, patient performance status and comorbidities, and tolerance of the proposed regimen. Patients with symptoms related to rapid disease progression may also require concurrent palliative, symptom-directed care.

Our general approach is to offer an alternative treatment strategy, depending upon the prior therapy (eg, targeted therapy for those previously treated with immunotherapy; immunotherapy for those previously treated with targeted therapy). However, the choice of subsequent therapy is evolving, and clinical trials are encouraged, where available. (See 'Investigational options' below.)

Prior immunotherapy — For patients with BRAF V600 mutant metastatic disease previously treated with immunotherapy who relapse, we propose the following approach:

Prior combination immunotherapy – For patients who previously received combination immunotherapy with nivolumab plus ipilimumab, we offer targeted therapy with combination BRAF plus MEK inhibitors. For those who decline or are ineligible for combination targeted therapy, we offer enrollment in clinical trials. (See 'Choice of BRAF plus MEK inhibitor therapy' above and 'Investigational options' below.)

Prior single-agent immunotherapy – For patients who previously received single-agent immunotherapy with a PD-1 inhibitor, have no prior exposure to ipilimumab, and remain eligible for immunotherapy, we offer the combination of nivolumab plus ipilimumab, as this approach improved PFS in a randomized trial (SWOG 1616) [77]. Further details on this study are discussed separately. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)'.)

For patients who progress on single-agent ipilimumab, we offer single-agent PD-1 inhibitors such as nivolumab (table 1) or pembrolizumab (table 2); however, such patients are rare since initial therapy with ipilimumab is less preferred due to toxicity profile and the availability of other effective treatments. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent ipilimumab'.)

For all of these patients, targeted therapy with BRAF plus MEK inhibitors is also a reasonable alternative. As an example, in a post-hoc analysis of a phase III trial (KEYNOTE-006), among a subset of patients initially treated with single-agent pembrolizumab who received subsequent therapy with BRAF plus MEK inhibitors, ORRs were approximately 30 percent [78].

Ineligible for immunotherapy – For patients who decline or are ineligible for further immunotherapy, we offer combination targeted therapy with BRAF plus MEK inhibitors. (See 'Ineligible for immunotherapy (targeted therapy)' above.)

Prior BRAF plus MEK inhibitors — For patients with BRAF V600 mutant disease previously treated with combination BRAF plus MEK inhibitor who relapse, we prefer combination immunotherapy with nivolumab plus ipilimumab. Single-agent PD-1 inhibitors are an alternative option for those who decline or are anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab.

Patients ineligible for immunotherapy should be evaluated for clinical trials. (See 'Investigational options' below.)

Prior immunotherapy and BRAF plus MEK inhibitors — For patients with BRAF V600 mutant disease who progress on both immunotherapy and targeted therapies, we refer for clinical trials. (See 'Investigational options' below.)

Retreatment with targeted therapy using combination BRAF plus MEK inhibitors is also an option in these patients [79,80]. We reserve this approach for patients who received their last dose of targeted therapy at least three months prior to initiating retreatment and did not experience significant treatment-related toxicities.

In a phase II trial, 25 patients with a driver mutation in BRAF were treated with the combination of dabrafenib and trametinib [79]. All patients had progressed on both checkpoint inhibitor immunotherapy and BRAF inhibitor (with or without trametinib), and a minimum of 12 weeks had elapsed since receiving their last dose of targeted therapy. In this study, partial responses were seen in eight patients (32 percent), with a majority of patients previously treated with a combination of dabrafenib plus trametinib. Stable disease was seen in 10 patients (40 percent). The median PFS during retreatment was 4.9 months.

Prognosis of BRAF V600 mutant disease — The prognosis of patients with BRAF V600 mutant disease has dramatically improved, with up to two-thirds of patients experiencing long-term survival. Among patients treated with immunotherapy or targeted therapy with BRAF plus MEK inhibitors, five-year OS rates are between 34 and 60 percent [16,36,49]. By contrast, initial studies conducted prior to the availability of these treatments reported five-year OS rates of 10 percent or less [4,49].

As examples, in a combined analysis of two phase III trials in patients with BRAF V600 mutant disease treated with dabrafenib plus trametinib, five-year OS in the entire study population and those with a complete response to therapy was 34 and 71 percent, respectively [36]. Similar results were seen in long-term follow-up of a phase Ib trial of vemurafenib plus cobimetinib, with a five-year OS of approximately 40 percent [49].

Immunotherapy also improves survival in patients with BRAF V600 mutant disease. In a phase III trial of patients treated with combination immunotherapy (nivolumab plus ipilimumab), five-year OS was 60 percent in this patient population [16].

OTHER MOLECULAR ALTERATIONS — Molecular alterations other than BRAF V600 may be present in metastatic melanoma. Since these mutations are rare, enrollment in clinical trials is encouraged, where available. The approach to systemic therapy in these patients is discussed below.

BRAF non-V600 mutations — For patients with BRAF non-V600 mutations (L597, K601, or BRAF fusions), we offer initial therapy with checkpoint inhibitor immunotherapy, using a similar treatment approach to those with BRAF V600 mutations. For patients who are ineligible for immunotherapy, there are no established treatments, and patients should be enrolled on clinical trials, where available. Targeted therapy with BRAF plus MEK inhibitors have minimal activity in such patients. (See 'BRAF V600 mutant disease' above.)

Rare BRAF mutations other than those in the 600th codon (V600) are found in approximately 4 to 14 percent of patients with patients with primary cutaneous melanoma [10]. Examples of such mutations include BRAF L597, K601, and BRAF fusion genes [81]. (See 'Assessment of actionable mutations' above.)

Limited data in patients with these rare mutations suggest minimal activity for MEK inhibitors as single agents and in combination with BRAF inhibitors [10,82]. As an example, in an observational study of 103 patients with non-BRAF V600 mutations treated with either BRAF and/or MEK inhibitors, the incidence of BRAF L597 and K601 mutations was 15 and 11 percent, respectively [10]. Among the 38 patients with these two mutations, overall response rates to BRAF inhibition alone, MEK inhibition alone, and combination therapy was 0, 40, and 28 percent respective; median PFS was two, four, and three months, respectively.

NRAS mutation — For patients with NRAS mutant disease who have progressed on immunotherapy, we suggest the MEK inhibitor binimetinib rather than chemotherapy, which improved progression-free survival (PFS) in a phase III trial.

Patients with BRAF wild-type disease may harbor mutations in NRAS, a driver mutation found in the mitogen-activated protein (MAP) kinase pathway. NRAS mutations are found in approximately 15 to 20 percent of patients with primary cutaneous melanoma. (See 'Assessment of actionable mutations' above.)

Based on initial phase II data [39], a phase III trial (NEMO) was conducted in 402 patients with advanced NRAS mutation-positive melanoma, including a subset (21 percent) previously treated with immunotherapy [83]. In this study, patients were randomly assigned to either binimetinib or dacarbazine. Compared with dacarbazine, binimetinib improved PFS (2.8 versus 1.5 months, hazard ratio [HR] 0.62, 95% CI 0.47-0.8) and objective response rates (ORRs; 15 versus 7 percent). However, overall survival (OS) was similar between the two treatment arms (11 versus 10 months). In the subset of 57 patients previously receiving immunotherapy, binimetinib improved PFS more impressively (median 5.5 versus 1.6 months). Objective responses were seen in 9 of 57 patients (16 percent).

TRK fusions — For patients with metastatic melanoma whose tumors test positive for a tropomyosin receptor kinase (TRK) gene fusion and have no other actionable driver mutations, we offer subsequent-line therapy with TRK-gene fusion inhibitors (larotrectinib and entrectinib) after prior treatment with checkpoint inhibitor immunotherapy.

Neurotrophic tyrosine receptor kinase (NTRK) genes encode for TRK proteins. When an NTRK gene fuses with a separate, unrelated gene, it produces an altered TRK fusion protein. Such NTRK gene fusions occur rarely (<1 percent) in patients with primary cutaneous melanoma, whose tumors express TRK oncogenic fusion proteins.

TRK inhibitors such as larotrectinib [84] and entrectinib have clinical activity and manageable toxicity profiles in patients with metastatic melanoma, including those with central nervous system (CNS) metastases [85,86]. As an example, in a combined analysis of three phase I to II studies, 159 patients with various malignancies receiving previous systemic therapy were treated with larotrectinib [84]. Among the seven patients with metastatic melanoma, objective responses were seen in three patients (43 percent).

Further details on the diagnosis and management of patients with TRK gene fusions are discussed separately. (See "TRK fusion-positive cancers and TRK inhibitor therapy".)

KIT mutations (acral and mucosal melanoma) — For patients with metastatic acral or mucosal melanoma with an activating c-kit mutation who progress on or are ineligible for immunotherapy, we offer treatment with imatinib.

Mutations in c-kit are seen most commonly among patients with acral or mucosal melanomas (15 to 20 percent) and in a smaller percentage of melanomas arising in areas of chronic skin damage (2 to 3 percent) [87]. Patients with BRAF wild-type disease may harbor mutations in c-kit. (See 'Assessment of actionable mutations' above.)

KIT inhibitors have clinical activity specifically in patients with melanoma harboring activating mutations of the c-kit gene (eg, exon 11 and 13), but limited efficacy in unselected groups [88-90]. Further details on these studies in patients with mucosal melanoma are discussed separately. (See "Treatment of metastatic mucosal melanoma", section on 'KIT mutation'.)

Tumor mutational burden — In patients with metastatic melanoma, testing for tumor mutational burden (TMB) is not required to guide treatment approach, as most melanomas demonstrate clinical response to checkpoint inhibitor immunotherapy regardless of TMB status. Patients with cutaneous melanoma typically exhibit high levels of TMB due to ultraviolet (UV) radiation damage from sun exposure, which is associated with improved response to checkpoint inhibitor immunotherapy. However, high response rates to immunotherapy have also been demonstrated in patients with melanoma expressing lower TMB and/or negative programmed cell death ligand 1 (PD-L1) expression.

The diagnosis and treatment of other cancers expressing high levels of TMB are discussed separately. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

INVESTIGATIONAL OPTIONS

Pembrolizumab plus lenvatinib — The combination of the programmed cell death 1 protein (PD-1) inhibitor pembrolizumab with the vascular endothelial growth factor receptor (VEGFR) inhibitor lenvatinib has efficacy in patients who have progressed on immunotherapy with a PD-1/programmed cell death ligand 1 (PD-L1) inhibitor alone or in combination with a cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor. Pembrolizumab and lenvatinib remains an investigational option, and further studies are necessary before incorporating this combination into routine clinical practice.

This combination was evaluated in an open-label, single arm trial (LEAP-004) of 103 patients with immunotherapy-refractory, unresectable or metastatic melanoma, including approximately one-third with BRAF V600 mutant disease (37 percent) [91]. In preliminary results, at median follow-up of 12 months, in the entire study population, the overall response rate was 21 percent; median progression-free survival (PFS) and overall survival (OS) were 4 and 14 months, respectively. Among the subset of 29 patients previously treated with a PD-1/L1 and CTLA-4 doublet, the objective response rate (ORR) was 31 percent. However, since this patient population was selected for resistance to checkpoint inhibitor immunotherapy (which has been associated with elevated levels of lactate dehydrogenase [LDH], an indirect measure of tumor hypoxia), it is possible that much of the clinical activity from this combination is driven primarily by lenvatinib alone.

Antiangiogenic therapy — The use of VEGFR inhibitors as single agents also remains an investigational treatment approach, as tumors that are resistant to immunotherapy may respond to these agents. VEGF inhibitors such as axitinib, bevacizumab, and other tyrosine kinase inhibitors (TKIs) of this pathway have demonstrated activity in clinical trials [92-101]. As an example, in a phase II trial of patients with metastatic melanoma (which included a subset of patients refractory to immunotherapy), axitinib demonstrated an ORR of 19 percent, median PFS of seven months, and one-year OS of 28 percent [97].

Adoptive cell therapy — Adoptive cell therapy (ACT) is a promising investigational therapy in patients with metastatic melanoma who have progressed on immunotherapy and/or targeted therapies. Various ACT approaches include tumor infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) T-cell therapy, and T-cell receptor (TCR)-transduced T-cells. As an example, a phase II trial (C-144-01) evaluated the efficacy of TIL therapy with lifileucel (LN-144) in a subset of 66 patients with immunotherapy-refractory melanoma (including 15 patients with BRAF V600 mutant disease with prior exposure to BRAF plus MEK inhibitor therapy). At median follow-up of 18 months, the ORR was 36 percent, with durable responses extending beyond one year noted in 16 patients (24 percent) [102].

Further details on the mechanisms of action for ACT are discussed separately. (See "Principles of cancer immunotherapy", section on 'Manipulating T cells'.)

SPECIAL POPULATIONS

Brain metastases — The efficacy of combination targeted therapy with BRAF plus MEK inhibitors and the role of these agents in the management of brain metastases in patients with melanoma are discussed separately. (See "Management of brain metastases in melanoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)

SUMMARY AND RECOMMENDATIONS

Molecular alterations in metastatic melanoma – Genetic sequencing has led to the identification of multiple molecular alterations, some of which are candidates for targeted drug therapy in patients with metastatic melanoma. While the most common are mutations in the BRAF gene, additional molecular alterations include NRAS mutations, TRK gene fusions, and KIT mutations, among others. (See 'Introduction' above.)

Assessment of actionable mutations – Prior to initiation of systemic therapy, patients with metastatic melanoma should have their tumors assessed for actionable mutations. Our approach is to rapidly assess for a BRAF V600 mutation, as mutation status influences treatment decisions for systemic therapy. For patients in whom a BRAF V600 mutation is not identified, we obtain next-generation DNA sequencing (NGS) to identify other potentially actionable molecular alterations. (See 'Assessment of actionable mutations' above.)

Initial systemic therapy for previously untreated BRAF V600 mutant disease – For previously untreated patients with BRAF V600 mutant metastatic melanoma, our approach is as follows (algorithm 1) (see 'BRAF V600 mutant disease' above):

Eligible for immunotherapy For treatment-naïve patients, we recommend combination immunotherapy with nivolumab and ipilimumab (table 3) rather than targeted therapy with combination BRAF plus MEK inhibitors (Grade 1B), as this approach improves overall survival and offers a greater opportunity for long-term treatment-free survival. For those unlikely to tolerate nivolumab and ipilimumab (eg, older adults who are eligible for immunotherapy but seek a more tolerable regimen; patients with a history of autoimmune disease), the combination of nivolumab-relatlimab is an appropriate alternative. (See 'Previously untreated patients' above and 'Eligible for immunotherapy' above.)

For those who are anticipated to not tolerate the potential toxicities of combination immunotherapy but are candidates for immunotherapy, we suggest single agent PD-1 inhibitors such as nivolumab (table 1) or pembrolizumab (table 2) rather than targeted agents (Grade 2C). (See 'Alternative immunotherapy options' above.)

Ineligible for immunotherapy – For patients who decline or are ineligible for immunotherapy, we recommend targeted therapy with combination BRAF plus MEK inhibitors, rather than either inhibitor as a single agent (Grade 1B) (algorithm 1). (See 'Ineligible for immunotherapy (targeted therapy)' above.)

Available options include dabrafenib plus trametinib, encorafenib plus binimetinib, and vemurafenib plus cobimetinib. All combinations are reasonable options as they have similar efficacy and have not been directly compared in randomized trials. The choice between these regimens is based on multiple factors including sites of metastatic disease, patient convenience, and potential toxicities. (See 'Choice of BRAF plus MEK inhibitor therapy' above and 'Toxicities of BRAF and MEK inhibitors' above.)

For patients receiving targeted therapy with combined BRAF plus MEK inhibitors, we suggest continuous rather than intermittent therapy (Grade 2C). (See 'Continuous versus intermittent therapy' above.)

Prior adjuvant systemic therapy – The approach to systemic therapy in patients with BRAF V600 mutant disease who were previously treated with adjuvant systemic therapy and relapse with metastatic disease is based on the type and tolerance of the adjuvant therapy originally received, interval between completion of adjuvant therapy and disease progression, and patient performance status and comorbidities. (See 'Prior adjuvant systemic therapy' above.)

For patients who previously received adjuvant systemic therapy (eg, either with a single-agent PD-1 inhibitor or combination BRAF plus MEK inhibitor therapy) and are eligible for further immunotherapy, we suggest initial treatment with nivolumab and ipilimumab rather than other systemic therapies (Grade 2C). (See 'Eligible for immunotherapy' above.)

For those who are ineligible for further immunotherapy, we offer targeted therapy with combination BRAF plus MEK inhibitors. (See 'Ineligible for immunotherapy' above.)

For those who received adjuvant targeted therapy with BRAF plus MEK inhibitors, while we prefer combination immunotherapy with nivolumab plus ipilimumab, single-agent PD-1 inhibitors (eg, pembrolizumab (table 2), nivolumab (table 1)) are also an option for these patients who did not receive immunotherapy in the adjuvant setting. (See 'Prior adjuvant BRAF plus MEK inhibitors' above.)

For select patients who relapse more than six months after completing adjuvant targeted therapy, rechallenge with targeted therapy is an acceptable alternative to immunotherapy.

Subsequent therapy – For patients with treatment-refractory BRAF V600 mutant metastatic melanoma who progress on initial therapy, we typically offer an alternative treatment approach, depending upon prior therapy. Patients are encouraged to enroll in clinical trials, where available. (See 'Subsequent therapy' above and 'Investigational options' above.)

Prior combination immunotherapy – For patients with BRAF V600 mutant disease previously treated with combination immunotherapy with nivolumab plus ipilimumab, we offer targeted therapy with combination BRAF plus MEK inhibitors. (See 'Prior immunotherapy' above.)

Prior single-agent immunotherapy – For patients who previously received single-agent immunotherapy with a PD-1 inhibitor, have no prior exposure to ipilimumab, and remain eligible for immunotherapy, we offer the combination of nivolumab plus ipilimumab. Targeted therapy with BRAF plus MEK inhibitors is also a reasonable alternative. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Prior treatment with single-agent PD-1 inhibitors (including adjuvant therapy)' and 'Choice of BRAF plus MEK inhibitor therapy' above.)

Prior BRAF plus MEK inhibitors – For patients with a BRAF V600 mutant disease previously treated with combination BRAF plus MEK inhibitor, we prefer combination immunotherapy with nivolumab plus ipilimumab. Single-agent PD-1 inhibitors are an alternative option for those who decline or are anticipated to not tolerate the potential toxicities of nivolumab plus ipilimumab. (See 'Prior BRAF plus MEK inhibitors' above.)

Other molecular alterations – Molecular alterations other than BRAF V600 may be present in metastatic melanoma, including BRAF non-V600 variants, NRAS, tropomyosin receptor kinase (TRK) fusions, KIT, and tumor mutational burden (TMB). (See 'Other molecular alterations' above.)

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Topic 15408 Version 126.0

References