The landscape of treatment options for patients with advanced and/or metastatic melanoma continues to expand, with immunotherapies and targeted therapies, as well as combinations thereof, gaining approval in recent years. As such, it is becoming increasingly important to understand the patient-specific oncogenic drivers, as a means of selecting treatments. The current National Comprehensive Cancer Network (NCCN) guidance recognizes the importance of

testing (for patients with metastatic disease).

As clinical experience grows with new agents, combinations, and sequences of therapy, the use of molecular profiling in metastatic melanoma is likely to become an essential means of choosing among treatment options.

Patients with metastatic or unresectable melanoma are now candidates for first-line systemic therapy with antiPD-1 receptor antibodies (Category 1) as monotherapy (pembrolizumab and nivolumab), but targeted therapies are preferred if

mutated, in cases where an early response is clinically desirable.

Other options include the nivolumab/ipilimumab (antiCTLA-4) combination.

demonstrated that the use of nivolumab, an anti-PD-1 agent, either alone or in combination with ipilimumab, an antiCTLA-4 agent, significantly improved median progression-free survival (PFS) compared with ipilimumab alone.

Keith T. Flaherty, MD director of clinical research and of the Henri and Belinda Termeer Center for Targeted Therapies and at Massachusetts General Hospital Cancer Center, notes that a range of treatment options now exist for patients with

Current NCCN guidance recommends considering targeted therapies for patients with

-mutant melanoma with symptomatic disease, or who progress on immunotherapies.

Vemurafenib was the first targeted therapy to become available for patients with metastatic melanoma, and was shown to improve overall and progression-free survival (PFS) over conventional chemotherapy (dacarbazine), the standard of care at the time.

Vemurafenib is currently approved for use in patients with

-mutationpositive melanoma, as determined by an FDA-approved test (Cobas).

Subsequently, a second BRAF inhibitor dabrafenib, became available for use after it was shown to also improve PFS compared with dacarbazine.

Adverse events (AEs) associated with these BRAF-targeted therapies include skin toxicities, which were observed in a sizable proportion of patients.

It now appears that these toxicities stemmed from a paradoxical activation of the MAP kinase pathway by these agents, and these observations, in addition to the propensity to develop resistance to monotherapy, have more recently paved the way for their use in combination with MEK-directed agents in patients with

Recent phase III trials have established the clinical feasibility of using BRAF inhibitors and MEK inhibitors in combination.

One trial combined dabrafenib with the MEK inhibitor trametinib (compared with dabrafenib and placebo) in previously untreated patients with unresectable advanced melanoma harboring

The results showed significantly improved PFS (primary endpoint, HR = 0.75;

= .03), as well as response and overall survival (OS) for patients receiving the combination versus those receiving the single agent (

Notably, the incidence of cutaneous squamous cell carcinoma and cutaneous hyperkeratoses was lower with the combination, although the incidence of other AEs (eg, pyrexia 51% vs 28%) was higher.

In a similarly designed trial comparing vemurafenib combined with the MEK inhibitor cobimetinib with vemurafenib alone, the use of the BRAF/MEK combination therapy also resulted in significantly improved PFS (HR = 0.51;

<.001), response, and interim OS (Table 1), with a similar impact on skin toxicities.

Table 1:  Selected Efficacy and Safety Endpoints in Phase III Trials of BRAF/MEK Inhibitor Combinations

Dabrafenib/Trametinib vs Dabrafenib/Placebo

Vemurafenib/Cobimetinib vs Vemurafenib/Placebo

Articles

Clinical Articles

With the continuously expanding landscape of treatment options for advanced and/or metastatic melanoma, it is becoming increasingly important to understand the patient-specific oncogenic drivers as a means of selecting treatments.

BRAF Testing Important for Clinical Decision-Making in Metastatic Melanoma

MAP kinase pathway activation due to mutations in the

genes is observed in majority of patients with advanced melanoma. Inhibition of the activated pathway slows disease progression. Abundant clinical data availability supporting the effectiveness of these targeted therapies in controlling tumor progression in patients with melanoma who have activating mutations has led to approval of several inhibitors of

genes. These include FDA-approved BRAF inhibitors (BRAFi) vemurafenib and dabrafenib, MEK inhibitors (MEKi) trametinib, and KIT inhibitor imatinib (

Although single-target inhibitors and have demonstrated significant clinical benefit, the effects are not limited to cancer cells alone and associated toxicities and adverse events (AEs) are often observed. Although the AEs are mild to moderate and rarely life threatening, the therapies present characteristic patterns of drug-related toxicities. Optimal use to maximize their therapeutic potential therefore depends on efficient side-effect management. Some of the common reported AEs and their management strategies from various studies are reported here.

Common BRAF and MEK Inhibitors and Associated Toxicities

The majority of patients on these inhibitors experience (>90%) experience AEs; however, these are generally mild to moderate (Common Toxicity Criteria of Adverse Events, CTCAE v4.0, grade 1-2).

The basic recommendations for managing the general AEs and common toxicities associated with targeted inhibitors are summarized in

The management based on specific drugs is also presented along with recommendations for toxicity management.

The most common AEs with vemurafenib treatment are rash (49%), arthralgia (39%), fatigue (34%), photosensitivity (31%), alopecia (26%) and nausea (19%). 46% patients have experienced grade 3 or 4 AEs, which are most commonly cutaneous SCC (12%), rash (5%), liver function abnormalities (5%), arthralgia (3%) and fatigue (3%). Vemurafenib side effects appear in a predictable pattern: photosensitivity and rash occur usually within days of starting the drug. Arthralgia, diarrhea, fatigue, alopecia and occurrence of other skin lesions tend to occur over weeks and months. While photosensitivity continues with drug use, other AEs including rash, skin lesions and arthralgia can regress and be less problematic after the first few months.

The most common dabrafenib-induced AEs are hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Other skin toxicities included keratocanthoma and SCC (10%), but unlike vemurafenib, photosensitivity is extremely rare. Grade 3 to 4 AEs are uncommon, but pyrexia was identified as a new and potentially serious toxicity occurring in some 5% of treated patients, not previously seen with vemurafenib.

Rash, diarrhea, fatigue, peripheral edema, and acneiform dermatitis are the most common side effects observed after treatment with trametinib. Cardiac (decreased ejection fraction or ventricular dysfunction), ocular and interstitial lung disease (ILD) or pneumonitis events are also reported in 7%, 9%, and 2% of patients treated in the METRIC trial, which are not recognized side effects of BRAFi. However, secondary skin neoplasms do not occur with the MEKi.

The combination regimen of dabrafenib and trametinib using full doses of both agents appears to generate fewer skin AEs compared with BRAFi monotherapy. AEs that occur more frequently with combination therapy are fever (51%) and chills (30%), fatigue (35%), diarrhea (24%), hypertension (22%), and vomiting (20%). Alopecia is reported less often in the combination arm

Rash, photosensitivity, pruritis, dry skin, papilloma, alopecia, keratoacanthoma, and SCC are the signature of BRAFi monotherapy.

Routine use of sunscreen with sun protection factor of at least 30

To be managed symptomatically on an outpatient basis

Immediate initiation of loperamide, dose interruption, and lower dose retreatment initiation

Dietary modifications for patients continuing on treatment with tolerable chronic loose bowel motions, including eating small frequent meals, introduction of a BRAT diet (bananas, rice, apples, and toast)

No consumption of lactose-containing products and maintaining fluid intake with electrolyte replacement

Specifically associated with dabrafenib rather than vemurafenib treatment.

When accompanied by hypotension or general malaise, may require patient hospitalization.

Unwell patients who are pyrexial but not septic, dose interruption, use of paracetamol or low-dose prednisolone; allow reintroduction of drug on recovery

Patients with intermittent fever pattern due to their chronic therapy without complicated factors or sepsis:remain at home and manage their fever with paracetamol, steroids, and/or temporary drug dose interruption

Severity of arthralgia is probably higher with vemurafenib compared with dabrafenib: 56% versus 35% incidence overall.

Administration of analgesics and antiinflammatory drugs improves simple arthralgia

Severe arthralgia: dose interruption, nonsteroidal antiinflammatory drugs, and low-dose corticosteroids; followed by reintroduction of vemurafenib at a lower dose.

Observed with use of many oral kinase inhibitors.

Chronic fatigue managed with dose modifications or low-dose steroids

Dabrafenib or vemurafenib not recommended in patients with uncorrectable electrolyte abnormalities (including low magnesium), long QT syndrome, or those who are taking medicinal products known to prolong the QT interval

Initiation of treatment with dabrafenib or vemurafenib is also not recommended in patients with QTc greater than 500 ms

Close monitoring recommended in patients with moderate to severe hepatic impairment, which may impact drug metabolism

Although single-target inhibitors and have demonstrated significant clinical benefit, the toxicities are not limited to cancer cells alone and associated toxicities and adverse events are often observed. 

Managing Toxicities in Targeted Therapies for Metastatic Melanoma

The Weizmann Institute of Science recently revealed a new gene belonging to the tumor suppressor gene group,

, which is driving a particular deadly subset of melanomas for patients with dysfunctioning RAS pathways. The understanding of this new tumor suppressor gene type has the potential to open news doors in the knowledge of the cancer&rsquo;s growth and as guidance toward future treatments.

comes after Yardena Samuels, PhD of the Institute&rsquo;s Molecular Cell Biology Department and her team searched their database of more than 500 melanoma genomes and exomes for protein-building sequences. The database explores the targeted genes crucial to understanding the cancer&rsquo;s biology and is the largest to date.

&ldquo;The identification of targetable alterations in melanoma is an urgent need. An in-depth understanding of the functional effects of mutations in these genes is the first step toward revealing the underlying mechanism of melanoma growth,&rdquo; said Nouar Qutob, PhD, a postdoctoral fellow in Samuels&rsquo; lab and participant in the research, in a statement.

Tumor suppressor genes usually impede cell growth, especially the growth of cancer cells; however, its mutation acts as &ldquo;defective brakes on cellular proliferation.&rdquo;

Among the many known mutated tumor suppressor genes, the Weizmann researchers discovered a new gene that stood out in their researchthe

. Through examination and cloning of the normal protein and the mutated versions, the team found that the

regulated a key component of the cell, the RAS.

The RAS is a part of the cell that has been known to contribute to unchecked cell growth. Upon restoring the production of protein in the cells that contained

mutations, the team discovered that cells stopped growing and died.

According to the research, the mutation of the

was discovered in 5.4% of human melanomas, and its expression was lost in 30% of human melanoma&rsquo;s, which was found to contribute to a reduced survival rate.

Researchers indicated that patients with dysfunctional RAS pathways generally have a worse prognosis than patients with other types of melanoma. Scientists have yet to discover any treatments plans targeted specifically to the RAS pathway.

&ldquo;As the RAS pathway is highly dysregulated in cancer, the discovery of an alternative mechanism for its activation is likely to stimulate an avalanche of further research in this field, and is highly likely to have direct clinical relevance,&rdquo; said Samuels in a statement.

, to find out what proteins it communicates with in healthy cells and melanoma, as well as in the cells&rsquo; response to targeted therapy.&rdquo;

Weizmann Wonder Wander. A newly-discovered tumor suppressor gene affects melanoma survival. http://wis-wander.weizmann.ac.il/a-newly-discovered-tumor-suppressor-gene-affects-melanoma-survival#.VjaSXelCbFI. Accessed November 1, 2015.

The Weizmann Institute of Science recently revealed a new gene belonging to the tumor suppressor gene group, RASA2, which is driving a particular deadly subset of melanomas for patients with dysfunctioning RAS pathways.

New Tumor Suppressor Gene in Melanoma Discovered

While cancer immunotherapy generally leads to therapeutic responses, patient response does vary.

by a group at the University of Michigan details a mechanism by which epigenetic modulation can increase the number of tumor infiltrating CD8+ T cells and could potentially lead to increased immunotherapy response.

&ldquo;Clinical trials with PD-L1 and PD-1 blockade suggested that tumors with a high number of inflammation-causing T cells were more responsive to the immunotherapy-based PD-L1 and PD-1 inhibitors. Tumors with low inflammation, or low T cells, were less responsive,&rdquo; a University of Michigan press release stated.

Clinical trials in melanoma with antiPD-1 agents, such as pembrolizumab and nivolumab, have reported varying response rates. Data from a phase I expansion study of pembrolizumab in patients with advanced melanoma indicated a response rate of 38% across all dose cohorts, with 52% response rates in the patients administered 10 mg/kg every 2 weeks.

In a follow-up open-label randomized expansion cohort, the overall response rate was 26% in both arms of the study (2 mg/kg or 10 mg/kg every 3 weeks).

Data from a phase III trial showed objective responses in 31.7% of patients with advanced melanoma receiving 3 mg/kg of nivolumab every 2 weeks versus 10.6% in patients treated with investigators choice of chemotherapy.

Research to identify agents to combine with immunotherapy and potentially increase response rates in patients with cancer is actively under way, with two recent papers describing the potential of RRx001 and COX inhibitors in this role.

The University of Michigan group led by Weiping Zou, MD, PhD, Charles B. de Nancrede professor of Surgery, Immunology and Biology at the University of Michigan Medical School, have&nbsp;revealed a novel mechanism. They show that the invasion of the tumor microenvironment by T cells is impeded by the activity of enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation. The resulting epigenetic histone modification and DNA methylation inhibits the production of T helper (Th1)-type chemokines CXCL9 and CXCL10 that would normally attract T cells into the tumor. The group explored manipulating the activity of EZH2 and DNMT1 with epigenetic modulators and found that when their activities are repressed, there is an increase in infiltration of effector T &nbsp;cells, a reduction in tumor growth, and an increase in the therapeutic efficacy of PD-L1 checkpoint blockade and adoptive T-cell transfusion in a mouse tumor model.

&ldquo;We defined a molecular mechanism to explain why some tumors are inflamed and others are not and consequently why some patients will be responsive to therapy and others not,&rdquo; said Zou in a press release. &ldquo;We hope this could be developed into a clinical trial, testing a combination of PD-L1 and PD-1 blockade with epigenetic therapy. We want to see if we can make the responders more responsive and turn the nonresponders into responders.&rdquo;

The research was driven by the hypothesis that possible epigenetic silencing of immune protective signature genes results in progressive malignancy and downregulates responses to immunotherapy. The researchers tested this idea using drugs that inhibited EZH2 (DZNep and EPZ6348) and DNMT1, (5-aza-2

-deoxycytidine [5-AZA-dC]) to reprogram the epigenetic pathways.

Using a mouse model of ovarian cancer, namely ID8 ovarian cancer in C57/BL6 mice, it was shown that while the drugs had a weak impact as single agents, in combination, they reduced tumor growth, increased the expression of the Th1-type chemokines and increased the number of T cells entering the tumor (

< .05 for combination versus control or group treated with either DZNep or 5-AZA-dC).

Expecting the addition of DZNep and 5-AZA-dc would potentiate the efficacy of an antiPD-L1 agent in the ID8-bearing mice; they treated mice with either anti&ndash;PD-L1 alone or in combination with DZNep and 5-AZA-dC. The combination demonstrated greater antitumor activity inducing larger decreases in tumor volume, increased tumor entry by CD8+ T cells, and increased expression of Th1-type chemokines (

<.5, combination versus control). The authors stated that, &ldquo;Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.&rdquo;

Given that activities of EZH2 and DNMT1 resulted in a blunted antitumor immune response, the team examined samples of human ovarian cancer tissue and quantified nuclear levels of EZH2 and DNMT1 by immunohistochemical methods to assess the impact on patient survival. Guided by staining intensity, patients were divided into low and high groups. Overall survival (OS) and disease-free interval (DFI) were significantly lower in patients with high versus low levels of either EZH2 or DNMT1 (

<.0001), and high levels of both versus just one had a bigger negative impact on OS and DFI (

<.0001). Uni- and multivariate analyses confirmed that tumor EZH2 and DNMT1 were positive predictors of risk of death.

The group also performed a time-dependent receiver operating characteristic (ROC) curve analysis to calculate the ability of EZH2, DNMT1, and intratumoral CD8+ T cells to predict survival. The areas under the curves AUCs (&plusmn; standard error) for DNMT1, EZH2, and CD8+ T cells were similar in predicting OS, at 82.66 &plusmn; 3.34, 83.63 &plusmn; 3.53, and 75.13 &plusmn; 4.18, respectively. Values of AUCs for predicting disease-free survival were also similar for DNMT1, EZH2, and CD8+ T cells at 81.06 &plusmn; 3.91, 71.98 &plusmn; 6.28, and 76.53 &plusmn; 5.86, respectively. Researchers also found that patients with high levels of both EZH2 and DNMT1 (n = 57) experienced shorter OS and DFI than patients with low levels of both EZH2 and DNMT1 (n = 50) in univariate and multivariate analyses (

<.0001). In contrast, patients with mixed levels (high + low) experienced similar and moderate survival. The authors stated, &ldquo;Thus, the combination of EZH2 and DNMT1 allows for improved prognostic stratification of ovarian cancer survival compared to EZH2 or DNMT1 alone.&rdquo;

In agreement with the mechanisms revealed, the increasing levels of EZH2 and DNMT1 were negatively correlated with the number of intratumoral CD8+ T cells (

Concluding their paper, and speaking to the potential of their findings for oncology, the authors state, &ldquo;Applicably, our work suggests that epigenetic reprogramming may condition tumors from poor T-cell infiltration to rich T-cell infiltration, and ultimately potentiate cancer therapy.&rdquo;

Peng D, Kryczek I, Nagarsheth N, et al. Epigenetic silencing of T(H)1-type chemokines shapes tumour immunity and immunotherapy.

University of Michigan Health System. Research explains limits of cancer immunotherapy drugs. http://www.mcancer.org/news/archive/research-explains-limits-cancer-immunotherapy-drugs. Accessed October 23, 2015.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.

Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomized dose-comparison cohort of a phase 1 trial.

Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.

Reid T, Oronsky B, Scicinski J, et al. Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study.

. 2015. pii: S1470-2045(15)00089-3. doi:10.1016/S1470-2045(15)00089-3.

Zelenay S, van der Veen AG, B&ouml;ttcher JP, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 2015;162(6):1257-1270.

A paper recently published online by a group at the University of Michigan details a mechanism by which epigenetic modulation can increase the number of tumor infiltrating CD8+ T cells and could potentially lead to increased immunotherapy response.

Increasing Immunotherapy Responses Possible With Selective Epigenetic Reprogramming

Keith T Flaherty, MD is director of the Termeer Center and Clinical Research at Massachusetts General Hospital Cancer Center, in Boston, Massachusetts.

spoke with Flaherty about the use of combined BRAF/MEK inhibition in patients with advanced/metastatic melanoma.

Q:  What type of molecular testing do you recommend for your patients with unresectable and/or metastatic melanoma?

At the moment, the only molecular feature in melanoma that is critical to treatment decision-making is the presence or absence of a

mutation. Approximately 45% of all patients with advanced melanoma will harbor an activating

mutation at this position. We&rsquo;ve learned that

mutations arise at a very early point in the development of a melanocytic proliferation. In fact, some studies suggest that as many as 80% of benign nevi have these same

mutations. The best available evidence indicates that

mutations are stably present in all tumor cells in lymph node and visceral metastases, whereas there can be heterogeneity in the primary melanoma. It is this data that drives the recommended practice of performing

mutation testing in metastatic tumor sites, with previously resected regional lymph nodes (for patients who had stage III disease prior to developing stage IV disease) being a reliable source of tumor material for this testing. At the time of approval of BRAF and MEK inhibitors for the treatment of this population, specific PCR-based methods were developed and approved by the FDA as a basis for identifying candidates for these drugs.

Q: How else may molecular testing be informative in melanoma?

mutations have been identified. They are largely confined to acral and mucosal melanomas. Phase II trials have demonstrated that cKIT inhibitors that are FDA approved for treatment of GIST (

mutations are present in 60% of cases) are associated with approximately 20% response rates. This has led to inclusion of cKIT testing and use of these drugs in NCCN guidelines, but none of these agents have been considered for FDA approval.

mutations, there are other types of mutations and gene translocations events involving

that are found in approximately 5% of all melanomas. Laboratory evidence suggests that the FDA-approved BRAF inhibitors are not effective at blocking the activated form of

mutations or translocations. There are other mutations that we believe can serve a similar function to mutated

mutations occur in a mutually exclusive 20% subpopulation of patients with melanoma. Inactivating mutations in

occur in another 12% of cases, but can occur with or without

mutations or other mutations noted above is helpful for navigating clinical trial options.

Q:  What is the current standard of care for patients with unresectable and/or metastatic melanoma harboring a

An important observation from clinical trials establishing the benefit of immune checkpoint antibody therapy is the roughly equal efficacy in patients with or without

mutations. In light of that, patients with

mutations have multiple options for therapy in the metastatic setting, including both immunotherapy and molecularly targeted therapy. Phase III trials have demonstrated that single-agent BRAF (vemurafenib or dabrafenib) or MEK (trametinib) inhibitor therapy improves response rates, progression and overall survival compared with historically standard chemotherapy. More recently, combined BRAF and MEK inhibition (dabrafenib/trametinib or vemurafenib/cobimetinib) have demonstrated improved response rates, progression and overall survival compared to BRAF inhibitor monotherapy. And, toxicities are largely comparable with regard to moderate and severe toxicity rates seen with BRAF-inhibitor monotherapy. For these reasons, combined BRAF/MEK-inhibitor therapy is considered to be the recommend approach for molecularly targeted therapy. Presently, we lack data that informs the choice between molecularly targeted therapy and immunotherapy. In addition to data showing clear benefit for treatment-na&iuml;ve patients, there are phase II data that indicate that BRAF inhibitor-based therapy or PD-1 antibody therapy can produce meaningful response rates in patients who have progressed following first-line treatment.

Q:  What is the rationale for using a BRAF inhibitor and a MEK inhibitor in combination?

There are two bases for adding a MEK inhibitor to a BRAF inhibitor: one related to overcoming resistance and the other to countering a mechanism of toxicity. Analysis of patients&rsquo; tumor specimens at the time of progression on single-agent BRAF-inhibitor therapy is typically associated with evidence of reactivation of the BRAF (aka MAP kinase) pathway. Taken in conjunction with evidence of consistent and profound suppression of the pathway early in the course of therapy, this evidence suggests that

-mutant tumors require the activity to be restored in most cases. A number of molecular drivers of this pathway reactivation have been identified, but none of them have yet been identified in tumor prior to initiation of therapy. Therefore, preclinical and clinical trials were initiated to investigate the potential for a MEK inhibitor to impede some of these resistance mechanisms, as MEK is a molecule downstream of BRAF in the pathway.

With regard to toxicity, proliferative skin lesions are commonly seen in the setting of BRAF-inhibitor monotherapy. These can include benign keratoses, papillomas, keratoacanthomas, but also well-differentiated cutaneous squamous cell carcinomas. These observations were made in parallel with laboratory discoveries regarding the ability of BRAF inhibitors (like vemurafenib and dabrafenib) to activate the BRAF/MAP-kinase pathway in some contexts. A notable example is the pathway and growth-stimulating effects of these drugs in cell-harboring

mutations. In the BRAF-inhibitortreated patient population, the majority of squamous cell carcinomas have

mutations. This evidence supported the use of MEK inhibitors to block these effects, as MEK inhibitors block pathway activity in

-mutated cells, and most other cell types.

Q:  What clinical data support the use of dabrafenib and trametinib in combination?

Dabrafenib and trametinib combination therapy is the most extensively studied of the BRAF/MEK combinations, and is the only one to be approved by the FDA for use in

mutant melanoma. Two phase III trials have been conducted, one compared with dabrafenib monotherapy and the other with vemurafenib. In both cases, response rates, progression and overall survival were improved compared with BRAF-inhibitor monotherapy. Now achieving objective responses in 75% of patients, median progression-free survival of 11 months, and median overall survival of 2 years, this combination has become the treatment standard.

Q: &nbsp; What patients would not be appropriate for this type of combination therapy?

&nbsp; There are no specific clinical or demographic characteristics that preclude consideration of BRAF-inhibitorbased therapy. However, in clinical trials, patients were required to have good performance status and near normal renal and liver function. That leaves uncertainty with regard to preserved efficacy in patients with poor performance status or with organ dysfunction. Dedicated phase II trials have been initiated in these populations.

Melanoma (Issue 5) | Special Reports

BRAF Testing Important for Clinical Decision-Making in Metastatic Melanoma

Managing Toxicities in Targeted Therapies for Metastatic Melanoma

New Tumor Suppressor Gene in Melanoma Discovered

Increasing Immunotherapy Responses Possible With Selective Epigenetic Reprogramming

Combined BRAF/MEK Inhibition in Metastatic Melanoma: Choosing the Right Patient