-mutated melanoma can be difficult, says Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center, codirector of the Melanoma Program, and head of Experimental Therapeutics at NYU Langone Medical Center.

It is still unclear whether BRAF/MEK combinations, such as dabrafenib (Tafinlar) plus trametinib (Mekinist) or vemurafenib (Zelboraf) plus cobimetinib (Cotellic), or immunotherapy combinations, such as nivolumab (Opdivo) and ipilimumab (Yervoy) regimen, should be the standard first-line treatment for

&ldquo;I am not taking bets; there are arguments for both sides,&rdquo; he explained. &ldquo;But, I do think all of these combinations are not only going to delay progression with these agents, but we are going to cure some of these patients.&ldquo;

, Weber discussed recent long-term follow-up data of dabrafenib and trametinib that may shed some light on sequencing questions for

-mutated patients. He also discussed an ongoing randomized trial of a head-to-head comparison of BRAF/MEK inhibitors and immunotherapy as first-line treatment.

How has the role of combination therapies in melanoma evolved in recent years?

Weber: There have been 2 combination therapies approved by the FDA recently for melanoma: dabrafenib plus trametinib and vemurafenib plus cobimetinib, which was approved in 2015.

Back in 2011, there was a revolution that adding a MEK inhibitor to a BRAF inhibitor in patients with metastatic disease not only augmented the efficacy of the treatment, but also clearly decreased the toxicities, particularly with skin toxicities. Over the next several years, combination MEK plus BRAF therapy has become the standard of care for treating patients with

However, for patients who do not have the

mutation in the tumor, it is inappropriate to use these BRAF drugs. For patients who have the mutation, which occurs in about 40% to 50% of all melanomas, the combination of the BRAF and the MEK drugs can be very effective, with high response rates and long survival. I recently presented data on the long-term follow-up of the original phase II and phase III trials looking at the combination of a MEK inhibitor with a BRAF inhibitor.

What were the most significant findings from the long-term follow-up?

The follow-up research suggests a couple of things. First, dabrafenib and trametinib have been tested over a longer period of time, so we have longer follow-up. Second, there appears to be a plateau on the curve as you get out in timein terms of survival follow-up&mdash;for dabrafenib and trametinib.

The &ldquo;urban legend&rdquo; was that the BRAF and MEK inhibitors had a high response rate, but almost all of the patients would progress quickly, progression-free survival would be less than 1 year, and most patients would have to go on another therapy or would die of their disease.

That&rsquo;s not exactly true. There does appear to be a plateau in the curve at about 30% for the patients who receive dabrafenib and trametinib. I am sure it will be virtually identical for vemurafenib and cobimetinib, which have a very similar median survival and 1-year survival track record as dabrafenib and trametinib.

We now have mature follow-up data from both dabrafenib and trametinib and vemurafenib and cobimetinib showing that we have about a 25-month median survival in patients treated upfront with metastatic melanoma that is

-mutated who receive these drugs. That is very impressive.

The interesting data from the longer follow-up of dabrafenib and trametinib showed that there is an obvious association between having a high tumor burden, poor performance status, a high LDH, and not doing well with these drugs.

This means that patients who do best with the combination of BRAF/MEK inhibitors have low disease burden with a normal LDH, few symptoms, etc.

This is very interesting, and not exactly like what we have seen with combination immunotherapies. With the combination of ipilimumab and nivolumab, there was not a strong association between LDHwhich is a surrogate for tumor burden&mdash;and outcome. Patients did very well whether they had a high tumor burden or not. With targeted therapy, that is not the case.

Do these findings make it any easier for oncologists todetermine frontline treatment for

These findings suggest that oncologists probably want to intervene with BRAF and MEK drugs earlier rather than later.

If the BRAF and MEK drugs only work in patients with low disease burden, but the immunotherapy drugs can work with either a low or high disease burden, the argument would be in a mutated patient to first give BRAF/MEK and then immunotherapy if the patient progressed or failed.

The targeted therapy will not work as well if patients are receiving immunotherapy first, then they progress, have high LDH, and high disease burden. The association of patients doing well with targeted therapy with low disease burden bodes well for starting with targeted therapy and using immunotherapy in the second-line setting.

This goes against the current &ldquo;urban legend&rdquo; that patients should have immunotherapy upfront whether they are

wild-type because those are the patients who are going to get the long tail on the curve in terms of survival. That may not be true.

Are there trials exploring sequencing of targeted therapies and immunotherapy agents for

There is an ongoing randomized phase III trial examining this. One group of patients will get upfront immunotherapy with ipilimumab and nivolumab, and at progression, they will receive BRAF/MEK inhibitors. Other patients in the study will receive upfront dabrafenib and trametinib, and then ipilimumab and nivolumab at progression.

Articles

Clinical Articles

With 2 different BRAF/MEK combination regimens approved by the FDA, as well as an immunotherapy combination, treatment and sequencing decisions for metastatic BRAF-mutated melanoma can be difficult.

Weber Compares BRAF/MEK, Immunotherapy Combos in Melanoma

Preferred frontline regimens for patients with

V600-mutant tumors, representing approximately 40% to 50% of patients, include both targeted agents and immunotherapy with checkpoint inhibitors.

The most relevant factors that influence choice of first-line therapy include

mutation status, the tempo of disease, and the presence or absence of cancer-related symptoms.

mutant melanoma who have extensive, symptomatic disease, most clinicians would favor the use of BRAF-targeted therapy (dabrafenib/trametinib). Subgroup analyses from multiple BRAF trials have demonstrated strong clinical benefit in patients with the most advanced and aggressive disease (elevated LDH, M1c),&rdquo; according to Geoffrey T. Gibney, MD, and Michael B. Atkins, MD, with the Medstar-Georgetown University Hospital in Washington, DC.

mutant melanoma without extensive central nervous system disease or symptomatic systemic metastases, the decision for upfront therapy has become debated. The focus has largely shifted to the durability of response with each therapy.&rdquo;

Potential benefits with immunotherapy include a more durable antitumor immune response compared with BRAF and MEK inhibitor therapies with 2-year OS rates as high as 60% with first-line pembrolizumab and 4-year OS rates of 32% with first-line nivolumab.

However, long-term analyses with combined BRAF/MEK inhibitor therapy have shown that approximately 20% of patients remained progression-free after 3 years, with 2- and 3-year OS rates in the range of 51% to 60% and 38% to 47% in all patients, and up to 63% in patients with favorable prognostic baseline criteria.

Retrospective analyses with single-agent therapies have suggested better outcomes with front-line immunotherapy with ipilimumab or interleukin-2 followed by BRAF inhibitor therapy with vemurafenib or dabrafenib compared with the inverse approach.

However, prospective data with the newer more effective therapies are not yet available and a retrospective analysis showed that nivolumab had similar efficacy and safety regardless of prior BRAF inhibitor or ipilimumab treatment.

Study author James Larkin, MD, PhD, with the Royal Marsden Hospital, London, England, and co-authors conclude that: &ldquo;Nivolumab monotherapy may be an effective treatment for mutated

patients regardless of whether they have previously received a

Addressing the lack of prospective data on the choice of immunotherapy versus targeted therapy in the frontline treatment of patients with

-mutant melanoma, the ongoing phase III Intergroup EA6134 study (ClinicalTrials.gov identifier NCT02224781) is comparing frontline targeted BRAF/MEK inhibitor combination therapy (dabrafenib/trametinib) followed by combination immunotherapy ipilimumab/nivolumab with the inverse regimen, i.e., immunotherapy followed by targeted therapy, in patients with

Examining the Optimal Sequencing of Agents:Immunotherapies

Frontline single agent nivolumab and nivolumab/ipilimumab have become available to patients with advanced melanoma irrespective of

mutation status, and have demonstrated significant reductions in the risk for progression compared with ipilimumab monotherapy.

Available PD-1 inhibitors also include pembrolizumab, associated with an ORR of 33%, a 12-month progression-free survival (PFS) rate of 35%, and median overall survival (OS) of 23 months when given as single agent.

Potential PFS benefits of nivolumab/ipilimumab combination therapy versus single-agent nivolumab or ipilimumab come at the cost of significantly increased toxicity. According to Jeffery S. Weber, MD, PhD, with the NYU Langone Medical Center, New York, &ldquo;The spider plots show that very steep immediate rapid response, which makes it the perfect therapy for a

wild-type patient who has aggressive, high-LDH bulk rapidly growing disease, or even a

-mutated patient. I also think it&rsquo;s a great neoadjuvant therapy. It&rsquo;s got a 50-plus percent response rate, which is really what you want in a neoadjuvant therapy. In a patient with low burden disease, low LDH that&rsquo;s not rapidly progressive, you can probably get away with PD-1 alone and do very well.&rdquo;

A randomized phase II study evaluating sequential induction immunotherapy followed by nivolumab found that the order of agents matters. Induction with nivolumab followed by ipilimumab was associated with a two-fold higher ORR than the inverse induction sequencing (41.2% vs 20.0%); in both arms, nivolumab maintenance was given subsequently.

Weber, lead investigator on the study, explained that many patients experienced combination toxicity &ldquo;much of which may well be the ipilimumab,&rdquo; he said. Patients were able to &ldquo;stop, recover, and then go to the nivolumab maintenance.&rdquo;

The availability of combination immunotherapy may also influence the decision of when to switch a patient from BRAF/MEK therapy to immunotherapy. According to Rene Gonzalez, MD, with the University of Colorado Melanoma Research Clinics, data with the combination of ipilimumab/nivolumab have prompted him to more often consider switching some patients to immunotherapy from the BRAF/MEK combination, &ldquo;because with BRAF/MEK combination, half the patients will die in about 2 years,&rdquo; Gonzales said, &ldquo;we might be able to impact better now rather than later.&rdquo;

Observation that at least a quarter of the resistance that develops to combination therapy is immunologically driven12 suggest that moving patients to immunotherapy earlier than later may be beneficial, because, according to Jason Luke, MD, from the University of Chicago, &ldquo;It very well could be that treating all the way to progression actually could kill the immune response.&rdquo;

Optimizing the Use of BRAF/MEK inhibition

Intermittent and sequential dosing regimens are being evaluated as potential approaches to optimize combination BRAF/MEK inhibitor therapies, in which resistance is observed in one third of patients after 6 months, with underlying mechanisms including BRAF amplification and MAPK activation.

Preclinical studies suggest that discontinuous dosing may delay the emergence of acquired resistance to BRAF inhibitor therapy.

Melanoma xenograft studies have shown that vemurafenib-resistant tumor cell clones became dependent on drug exposure for continued growth, which has been termed &ldquo;melanoma drug addiction.&rdquo;

Suspension of treatment caused loss of selective growth advantage and resultant repopulation with drug-sensitive cells.

High sensitivity to acute drug withdrawal has also been observed in melanoma cells with acquired resistance to dual BRAF/MEK inhibitor therapy. Gatien Moriceau, PhD, with the University of California Los Angeles, and co-authors reported that, &ldquo;Paradoxically, acute removal of BRAF inhibitor plus MEK inhibitor disrupts this fine-tuning and results in a p-ERK rebound favoring cell arrest/death (i.e., drug addiction),&rdquo; rendering these cells &ldquo;exquisitely sensitive to acute drug withdrawal.&rdquo;

According to Flaherty, an interrupted schedule may be associated with a retreatment effect, which &ldquo;has been seen with other oncogene-targeted therapies in other cancers, such as with EGFR and ALK inhibitors in lung cancer, imatinib in GIST. It is known to be the case that if patients are off, away from their targeted therapy for a period of time, they can resensitize.&rdquo;

An intermittent dosing schedule of dabrafenib and trametinib is being evaluated in the phase II Southwest Oncology Group (SWOG) study S1320 (NCT02196181). Patients are receiving dabrafenib/trametinib (150mg BID/2mg QD) during an 8-week lead in period, followed by random allocation of patients without disease progression at the end of the lead in period to either continuous dosing or to intermittent dosing on days 1 to 7 and 29 to 56 of a 56-day course.

Sequential administration of BRAF and MEK inhibitor therapy is the focus of a 3-arm randomized phase II study (NCT02314143) comparing continuous dabrafenib/trametinib combination therapy with upfront monotherapy with dabrafenib or trametinib for 8 weeks followed by combination therapy. Biomarkers associated with progression and drug resistance are assessed at randomization, week 2, week 8, week 10, and at progression.

Early clinical trial data are becoming available from combination regimens of targeted and immunotherapeutic agents. Potential synergy between these approaches may result in higher frequency of long-lasting responses.

Findings in tumor biopsies and mouse models have shown that BRAF and MEK inhibitors increase the presence of tumor-infiltrating T cells and expression of melanoma-specific antigens within the tumor microenvironment.

However, as Alexander Menzies, MD, and Georgina Long, MD, with the Melanoma Institute, Sydney, Australia, explain,

&ldquo;the initial immune response is then counteracted by tumor PD-L1 expression within days of initiation of BRAF inhibition. By the time of BRAF inhibitor resistance, melanoma antigen expression and T-cell infiltrates fall to below pretreatment values.&rdquo; According to the authors, &ldquo;these data support the use BRAF inhibitors in combination with immunotherapy (especially PD-1PD-L1 antibodies) from the outset, so that when an antigenic stimulus is generated by BRAF inhibition, immune escape is prevented by blockage of the compensatory PD-1&ndash;PD-L1 tumor defense.&rdquo;

Findings in model studies have demonstrated effective tumor size reduction with trametinib in combination with antiPD-1 agents18 or a triple combination of BRAF and MEK inhibitors with anti-PD1 therapy.

Early reports from an ongoing phase I/II study (NCT02027961) evaluating the PD-L1 agent durvalumab (MEDI4736; 10mg/kg every 2 weeks) in combination with dabrafenib/trametinib (150 mg BID/2 mg QD) found that the regimen had promising clinical efficacy with a manageable side effect profile and no substantial increase in immune-related adverse events. Among 26 patients treated with the triple combination, the ORR was 69%, and responses were ongoing in most patients.

PD-1 checkpoint blockade in combination with dual BRAF/MEK inhibition with dabrafenib/trametinib is also the focus of the ongoing phase I/II KEYNOTE-022 study (NCT02130466).

According to Michael Postow, MD, with Memorial Sloan Kettering Cancer Center, New York, PD-1 combination therapies are likely &ldquo;more tolerable than ipilimumab combinations with targeted therapy drugs.&rdquo; Phase II study findings have shown that the combination of ipilimumab and vemurafenib &ldquo;unfortunately, resulted in a high rate of liver inflammation and skin rash.

Therefore, it was decided that the combination should not be given outside of clinical studies,&rdquo; said Postow. In the same phase II study, &ldquo;dabrafenib, trametinib, and ipilimumab were combined in a triplet that resulted in a high rate of gastrointestinal events, mainly colitis and perforation,&rdquo; such that enrollment to the triple combination arm was stopped.

BRAF/MEK Inhibitor Strategies in Patients With Brain Metastases

In addition to new dosing strategies, BRAF/MEK inhibitors are also being examined specifically in patients with

-mutant melanoma that has metastasized to the brain, which is associated with a poor prognosis and frequently an exclusion criterion in clinical trials.

Evidence exists that dabrafenib and vemurafenib are active in patients with brain metastases and can reduce brain lesions.

An open-label phase II study reported intracranial responses to dabrafenib in patients with

V600E or K mutant melanoma who had undergone previous local treatment for brain metastases (V600E, 30.8%; V600K, 22.2%) and who had not (V600E, 39.2%; V600K, 6.7%).

A small cohort study including patients with measurable intracranial disease found that in response to vemurafenib, >30% intracranial tumour regression occurred in 37% (n = 7), including confirmed partial responses.

To evaluate potential benefits with dual BRAF/MEK inhibitor therapy in patients with melanoma that has metastasized to the brain, an ongoing phase II study (NCT02039947) is examining dabrafenib/trametinib in patients with

V600 E, K, D, or R mutation-positive tumors. The 4-cohort design includes patients with symptomatic and asymptomatic brain metastases, and with or without prior therapy to the brain.

&ldquo;In view of the substantial molecular heterogeneity of melanoma and the potential for drug synergy, a multi-targeted upfront approach, including immunotherapy, is likely to yield the greatest survival benefit to patients, although toxicity might limit this multi-drug approach,&rdquo; Menzies and Long wrote.

&ldquo;MAPK inhibitors and immunotherapies will continue to have a major role in the treatment of

-mutant melanoma, and a real possibility exists of long-term disease control or cure for many patients in the near future.&rdquo;

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines&reg;) Melanoma.

Gibney GT, Atkins MB. Immunotherapy or molecularly targeted therapy: what is the best initial treatment for stage IV BRAF-mutant melanoma?

Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001.

Larkin J, Lao CD, Urba WJ, et al. Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma: A Pooled Analysis of 4 Clinical Trials.

Long GV, Weber JS, Infante JR, et al. Overall Survival and Durable Responses in Patients With BRAF V600-Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib.

Ascierto PA, Simeone E, Sileni VC, et al. Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program.

Ackerman A, Klein O, McDermott DF, et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.

Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.

Ribas A, Hamid O, Daud A, et al. Association of Pembrolizumab With Tumor Response and Survival Among Patients With Advanced Melanoma.

Hodi FS, Gibney G, Sullivan RJ, Flaherty KT. An open-label, randomized, phase 2 study of nivolumab (NIVO) given sequentially with ipilimumab (IPI) in patients with advanced melanoma (CheckMate 064). Paper presented at: European Cancer Congress (ECC) 2015; September 25-29, 2015; Vienna, Austria Abstract 23LBA.

Hugo W, Shi H, Sun L, et al. Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance.

Long GV, Fung C, Menzies AM, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma.

Moriceau G, Hugo W, Hong A, et al. Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction.

Das Thakur M, Stuart DD. The evolution of melanoma resistance reveals therapeutic opportunities.

Das Thakur M, Salangsang F, Landman AS, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.

Wargo JA, Cooper ZA, Flaherty KT. Universes collide: combining immunotherapy with targeted therapy for cancer.

1Liu L, Mayes PA, Eastman S, et al. The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4.

Menzies AM, Long GV. Systemic treatment for BRAF-mutant melanoma: where do we go next?

Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

Ribas A, Butler M, Lutzky J, et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.

Puzanov I. Combining targeted and immunotherapy: BRAF inhibitor dabrafenib (D) &plusmn; the MEK inhibitor trametinib (T) in combination with ipilimumab (Ipi) for V600E/K mutation-positive unresectable or metastatic melanoma (MM).

Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial.

Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study.

With expanding availability of effective single-agent and combination immunotherapies and combination BRAF/MEK inhibitor regimens, all of which have been shown to improve survival and reduce risk of progression, the optimal sequencing of therapies has become increasingly complex.

Treatment Sequencing Considerations for BRAF-Mutant Melanoma

-mutant metastatic melanoma, expanding the number of effective treatment options that can improve quality and length of life for many patients.

Although single-agent therapy with targeted inhibitors of the BRAF kinase yields initial high response rates and a proven survival benefit, approximately half of all patients relapse after 6 to 7 months due to acquired resistance. The underlying escape mechanisms are complex and dynamic and involve reactivation of the mitogen-activated protein kinase (MAPK) pathway through genetic changes affecting BRAF, RAS, and MEK kinase activity, epigenetic changes, and immune evasion.

Concomitant inhibition of both BRAF and MEK kinases with targeted inhibitors has become, &ldquo;The recommend approach for molecularly targeted therapy,&rdquo; according to Keith T. Flaherty, MD, with Massachusetts General Hospital Cancer Center, in Boston, Massachusetts.

When BRAF kinase is constitutively activated due to a mutation (eg, V600E), treatment with BRAF inhibitors results in blockade of downstream MAPK pathway.

In cells with wild-type BRAF, treatment with BRAF inhibitors results in transactivation of CRAF and promotion of RAF dimerization, causing paradoxical activation of downstream MAPK pathway in the presence of upstream oncogenic changes, such as RAS mutations.

The rationale for combining BRAF and MEK inhibition is to delay resistance associated with the reactivation of MEKERK signalling after single-agent BRAF inhibition. Upfront inhibition of both BRAF and MEK kinases can delay emergence of treatment resistance and decrease the incidence of cutaneous hyperproliferative lesions associated with the paradoxical activation of the MAPK pathway following BRAF inhibitor monotherapy.

&ldquo;There are two bases for adding a MEK inhibitor to a BRAF inhibitor,&rdquo; said Flaherty. &ldquo;One related to overcoming resistance and the other to countering a mechanism of toxicity.&rdquo;

Combined BRAF-MEK Inhibition: Dabrafenib/ Trametinib

Based on data from two phase III studies demonstrating overall survival (OS) prolongation, the dabrafenib/trametinib combination regimen received full FDA approval for the treatment of patients with unresectable or metastatic

The most recent analysis from the COMBI-v study presented at the 2015 European Cancer Congress (ECC) reported a 7.6-month prolongation of OS with dabrafenib and trametinib compared with single-agent vemurafenib (25.6 vs 18.0 months; HR, 0.66; 95% CI, 0.53-0.81;

The estimated 2-year OS rate was 51% with dabrafenib and trametinib compared with 38% with vemurafenib monotherapy.

COMBI-v was a two-arm, open-label phase III study comparing dabrafenib/trametinib (150 mg twice daily/2 mg once daily) or vemurafenib (960 mg twice daily) in patients with

V600E/K mutation-positive unresectable or metastatic melanoma (n = 704). The study was stopped early in July 2014 following the demonstration of benefit at an interim analysis (

COMBI-v was the second study to demonstrate superiority for the BRAF/MEK inhibitor combination therapy over monotherapy in advanced melanoma. Final OS data from the COMBI-d trial, which had been initiated concomitantly and randomized 423 patients with

V600E/K-mutant melanoma to receive dabrafenib with trametinib (n = 211) or placebo (n = 212), reported a median OS of 25.1 months with the combination compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92;

= .011). The 2-year OS rate with the combination was 51% versus 42% with single-agent dabrafenib.

According to Caroline Robert, MD, PhD, lead author of the COMBI-v study, &ldquo;Dabrafenib plus trametinib has demonstrated superiority over BRAF inhibitor monotherapy now in two phase III trials, supporting its use as a standard-of-care therapy in patients with

Updated analyses from both trials also demonstrate increasing OS advantages of combination therapy over time. In the COMBI-v study, the absolute OS difference increased from 9% at 1 year, to 10% at 18 months, and to 13% at 2 years,4 and in the COMBI-d study from 6% at 1 year to 9% at 2 years.

In both studies, the addition of MEK inhibition significantly increased the likelihood of having an objective response (ORR; COMBI-d 69% vs 53% for BRAF inhibitor monotherapy,

= .0008), and more patients achieved complete responses (CR; COMBI-d, 16% vs 13%; COMBI-v, 17% vs 10%). Combination therapies also resulted in longer median duration of response (DoR; COMBI-d, 12.9 vs 10.6 months; COMBI-v, 13.8 vs 8.5 months).

Updated analyses of progression-free survival (PFS), the primary endpoint of the COMBI-v study, showed a significant prolongation with the combination (12.6 vs 7.3 months; HR, 0.61; 95% CI, 0.51-0.73,

<.001), which according to Robert &ldquo;is the longest achieved in a randomized study for patients with the

The dabrafenib/trametinib combination was associated with fewer adverse events (AE) compared with dabrafenib monotherapy.

Importantly, both studies confirmed that combination therapy reduced the incidence of oncogenic toxic effects related to MAPK pathway activation following BRAF inhibitor monotherapy.

Cutaneous toxicities including hyperkeratosis (6% vs 33%) and cutaneous squamous carcinoma (3% vs 9%) were less common in the dabrafenib/trametinib group than in the dabrafenib monotherapy group.6 Similarly, in COMBI-v, cutaneous squamous-cell carcinoma and keratoacanthoma were observed in 1% of patients in the combination-therapy group but in 18% in the vemurafenib group.

The most common AE associated with BRAF/MEK inhibition in both studies was pyrexia (52% and 53% in COMBI-v and COMBI-d, respectively).

Patients of the COMBI-v dabrafenib and trametinib treatment arm showed statistically significant and clinically meaningful improvements in health-related quality of life compared with patients on vemurafenib monotherapy, with improvements in overall health, physical and social functioning, and specific symptoms such as pain, insomnia, and loss of appetite.

BRAF/MEK inhibitor combinations have emerged as &ldquo;the new standard of care in terms of targeted agents for melanoma,&rdquo; said Rene Gonzalez, MD, with the University of Colorado Melanoma Research Clinics. &ldquo;All three of those studies were positive in the sense that it without a doubt showed that combination therapy is better than single-agent BRAF inhibitor. The overall survival is in the range of two years. The combination progression-free survival is 11 to 12 months, which is better than a single-agent BRAF inhibitor. I can barely think of a role for when a patient would receive just BRAF or MEK inhibitor alone.&rdquo;

Combined BRAF-MEK Inhibition: Vemurafenib andCobimetinib

The combination of vemurafenib and cobimetinib received FDA approval in November 2015, based on significant prolongation of PFS shown in the phase III coBRIM trial for previously untreated patients (n = 495) with

V600 mutation-positive unresectable locally advanced or metastatic melanoma.

Updated analyses confirmed previously reported clinical benefits from adding cobimetinib (60 mg once daily on days 1-21 of a 28-day cycle) to continuous vemurafenib (960 mg twice daily), which resulted in significant prolongation of PFS (median, 12.3 vs 7.2 months; HR, 0.56; 95% CI, 0.45-0.70;

<.001) and higher probability of response (ORR; 69.6% vs 50%;

<.001), including CR (16% vs 11%) compared with vemurafenib monotherapy.

The median DoR was 12.98 versus 9.23 months, with cobimetinib and placebo, respectively.

Overall survival data after a median of 18.5 months were presented at the 2015 Society for Melanoma Research Congress and revealed OS prolongation of 4.9 months with the combination (median OS, 23.3 vs 17.4 months, combination and vemurafenib alone, respectively; HR, 0.70; 95% CI, 0.55-0.90;

The OS rates at 17 months were 65% versus 50% and after 2 years the rates were 48% and 38%, for the combination and single-agent, respectively.

The presenting author Victoria Atkinson, MD, of the Princess Alexandra Hospital in Queensland, Australia, reported: &ldquo;The benefit of the combination was seen in all subgroups assessed, including ECOG performance status, LDH level, and presence of V600E or V600K mutations.&rdquo;

Unique AEs of the vemurafenib/cobimetinib regimen include phototoxicity, including photosensitivity and central serous retinopathy, which were observed in 28% and 20% of patients.10 Other AE more commonly observed with the combination were diarrhea (57% vs 28%), nausea or vomiting (39% vs 24% and 21% vs 12%, respectively), elevated liver enzyme levels (ALT, 24% vs 18%; AST, 22% vs 13%), and an increased creatine kinase level (30% vs 3%).

Similar to observations with dabrafenib and trametinib, combined BRAF/MEK inhibition was associated with fewer cutaneous toxicities than BRAF inhibitor monotherapy, including hyperkeratosis (10% vs 29%), cutaneous squamous cell carcinomas (3% vs 11%), and keratoacanthomas (<1% vs 8%). Also less frequent were joint pain (33% vs 40%) and hair loss (14% vs 29%).

Combination Immunotherapy: Nivolumab/Ipilimumab

Dual checkpoint blockade with a combination regimen of the CTLA-4 inhibitor ipilimumab and anti-PD-1 agent nivolumab continues to demonstrate efficacy in advanced melanoma. The combination regimen received accelerated approval for the frontline treatment of patients with

wild-type unresectable or metastatic melanoma in October 2015, based on improved PFS and ORR shown in the phase II CheckMate-069 and phase III CheckMate-067 studies, with expansion of the indication in January 2016 to include patients with

Recently reported exploratory data from the 2-year follow-up of the phase II CheckMate-069 trial indicate an OS benefit with the combination.

The 2-year OS rate with first-line combination ipilimumab plus nivolumab therapy (3mg/kg and 1mg/kg, respectively) was 64% versus 54% with nivolumab alone.

Across the entire study population (n = 142), which included patients with

mutant melanoma (n = 33), median OS had not been reached in either treatment group.

Patients with BRAF wild-type melanoma receiving the combination (n = 72) had a 42% OS improvement compared with ipilimumab monotherapy. Median OS had not been reached and was 24.8 months with ipilimumab monotherapy (HR, 0.58; 95% CI, 0.31-1.08). Two-year OS rates were 69% versus 53% with the combination and monotherapy, respectively.

According to lead author Michael Postow, MD, with Memorial Sloan Kettering Cancer Center, New York, high survival rates in the ipilimumab monotherapy arm were related to a large amount of crossover to other agents, including PD-1 agents, at progression.

OS results from the double-blind phase III CheckMate-067 study are pending.

Combination immunotherapy with ipilimumab/nivolumab capitalizes on non-redundant mechanisms of action of CTLA-4 and PD-1 inhibition that may result in synergistic effects. Specifically, ipilimumab blockade of CTLA-4 augments T-cell activation and proliferation, whereas nivolumab-mediated suppression of PD-1 activity restores the active T-cell response within the tumor microenvironment.

Outcomes from CheckMate-067 trial (n = 945 patients with both

V600 mutant and wild-type advanced melanoma) have shown that first-line nivolumab alone or in combination with ipilimumab doubled the median time to disease progression compared with ipilimumab monotherapy (median PFS, 11.5 months for the combination, 6.9 months for nivolumab monotherapy, and 2.9 months for ipilimumab monotherapy).12 Compared with ipilimumab monotherapy, the combination regimen and nivolumab monotherapy were associated with 58% and 43% reduction in the risk of disease progression, respectively (HR, 0.42;

Two-year assessment data from the phase II CheckMate-069 study showed similar findings. Among all randomized patients, median PFS had also not been reached in the combination treatment arm and was 3.0 months with ipilimumab monotherapy (HR, 0.36;

<.0001), which according to Postow &ldquo;reflects a 64% reduction in the hazard of progression or death in this all-randomized patient population, which is very impressive and statistically significant.&rdquo;

Ipilimumab/nivolumab combination therapy has produced ORRs of up to 61% among patients with

wild-type tumors in the CheckMate-069 study,

and 50% in the phase III CheckMate-067 study,

including 22% and 11.5% complete responses, respectively, all of which were significantly higher than those with ipilimumab monotherapy (ORR, 11% and 14%, respectively; CR, 0% and 7%, respectively).

In both studies, the combination regimen delivered rapid and durable responses, with time to response of 2.9 to 2.7 months.12,13 At the 2-year follow-up of the CheckMate-067 study, the median DoR was not reached in either arm, and 80% of responses to the combination (45 of 56) and ipilimumab monotherapy (4 of 5) were ongoing.

Median tumor burden by RECIST v1.1 decreased by 70% and 51% in patients on dual inhibitor therapy in CheckMate-069 and -67, respectively, but increased by 5% and 5.9% among patients receiving ipilimumab only (

TABLE 1. Efficacy of Frontline Combination Regimens in

A number of new combination approaches have gained approval in the past year for the treatment of patients with BRAF-mutant metastatic melanoma, expanding the number of effective treatment options that can improve quality and length of life for many patients.

Combination Regimens for Metastatic Melanoma

mutation status, tumor growth rate, and the presence or absence of cancer-related symptoms.

Immunotherapies with agents that block CTLA-4 or PD-1/PD-L1 checkpoints have been associated with durable responses in a subset of patients, and are often considered for patients with low-volume, asymptomatic metastatic melanoma. Targeted therapies, on the other side, are preferred for patients with

-mutant tumors who have symptomatic disease and benefit from the rapid response associated with these agents.

A main concern with targeted therapies is tumor resistance that ultimately develops in most patients within 6-12 months. However, as Jason J. Luke, MD, with the University of Chicago Medicine states, &ldquo;A sizable fraction of patients do very, very well for a long time on targeted therapy.&rdquo;

A long-term analysis has shown that approximately one fifth of patients with

V600-mutant melanoma receiving combined dabrafenib/trametinib remained progression-free after 3 years, suggesting a plateau of the survival curve.

According to lead author Georgina Long, MD, with the Melanoma Institute Sydney, Australia, and co-authors,

this defines, &ldquo;a need to understand the characteristics of patients who derive the greatest benefit from each mode of therapy.&rdquo; Specifically, &ldquo;future selection of patients for combined BRAF and MEK inhibition, and the rational design of clinical trials for those who fail it, may be assisted by an analysis of the clinicopathological features of those experiencing long-term benefit and those who progress.&rdquo;

In their study, Long and colleagues found that good prognostic features such as normal lactate dehydrogenase (LDH) levels, earlier-stage melanoma, and fewer metastatic sites were consistently associated with durable response and prolonged overall survival (OS) with BRAF/MEK inhibitor therapy.

Patients who survived longest on treatment included those with a complete response (CR), according to RECIST, and patients with a normal baseline LDH (63% and 62%, respectively). Data were from 2 cohorts of BRAF-inhibitor na&iuml;ve patients (n = 78) who had been treated with dabrafenib (150 mg twice daily) plus trametinib (2 mg daily).

Similarly, a study evaluating long-term outcomes of patients who received either BRAF or combined BRAF and MEK inhibitor regimens in phase I to III trials with single agent dabrafenib or vemurafenib, or combined dabrafenib/trametinib found that female sex and normal pretreatment LDH levels were the only factors associated with longer progression-free survival (PFS) and OS.

LDH below the upper limit of normal (ULN) was significantly associated with prolonged survival of patients receiving BRAF/MEK inhibitor combination therapy with dabrafenib/trametinib.2 Patients with a normal LDH at baseline had a median OS of 45.5 months (95% CI, 45.5 to not reached) compared with 16.6 months (95% CI, 11.1-22.6) for patients with an elevated LDH.2 Overall survival rates of patients with normal versus elevated LDH levels at baseline, respectively, were 88% versus 68% at 1 year, 75% versus 18% at 2 years, and 62% versus 5% at 3 years.

Recent data from phase III COMBI-v trial have also linked baseline LDH serum levels to survival benefits with the dabrafenib/trametinib combination.

According to lead author Caroline Robert, MD, of Institut Gustave Roussy in Paris, &ldquo;The longest benefit was in patients with an LDH less than or equal to the upper limit of normal, who had a 2-year overall survival rate of 66% and a median progression-free survival of 17.5 months.&rdquo;

In this patient group, median OS was not yet reached with dabrafenib/trametinib and was 21.5 months with vemurafenib (HR, 0.56), translating to a 44% OS benefit with the combination. Patients with an LDH above the ULN had less benefit with a median OS of 10.6 months with the combination and 8.9 months with vemurafenib monotherapy (HR, 0.81).

Similar observations are emerging from the phase III evaluation of cobimetinib/vemurafenib. OS benefits of the combination were observed in all patient subgroups.

For patients with both LDH baseline levels, median OS was not reached with the combination and was 23.3 months with vemurafenib. Patients with elevated LDH levels had an OS of 14.8 months with the combination and 11.2 months with vemurafenib alone. According to lead author Victoria Atkinson, MD, of the Princess Alexandra Hospital in Queensland, Australia, &ldquo;This is consistent with previous combination studies showing that patients with poor prognostic factors do worse.&rdquo;

Longer-term analyses of patients who had received both BRAF monotherapy and combined BRAF/MEK therapy have also reported a significant association of normal LDH levels with prolonged survival. Patients with normal LDH levels had a median OS of 23.5 months compared with 7.3 months in patients with elevated LDH levels.

Across all studies, normal serum LDH levels correlated with continued long-term response without progression (per Cox proportional hazards regression analysis;

= .024,2 or per univariate and multivariate analyses).

In COMBI-v, in patients with low LDH levels, median PFS was 17.5 and 9.2 months with the combination and monotherapy, respectively (HR, 0.55) and 5.5 versus 4.0 months in patients with elevated LDH levels (HR, 0.70).

According to Alexander Menzies, MBBS, with the Melanoma Institute Sydney, Australia, and co-authors,3 this evidence &ldquo;suggests that LDH is not simply prognostic. The biology of metastatic tumors that produce different levels of LDH may be distinct; for example, it has been shown that a high serum LDH level reflects an anaerobic oxidative metabolic state. As such, the best treatments for metastatic patients with normal and elevated LDH levels may be different.&rdquo;

According to Robert, patients with &ldquo;low LDH respond extremely well to targeted treatment. Patients with high LDH, whatever treatment we use, remain a big medical need. They derive a small benefit each time we evaluate a new, effective therapy. The benefit is always less in this population.&rdquo;

Tumor Burden and Timing of BRAF MEK Inhibitor Therapy

Consistent features associated with better outcomes with combined BRAF/MEK inhibitor in long-term analyses also included earlier-stage melanoma and fewer metastatic sites. Furthermore, according to Long and co-authors, &ldquo;good prognostic features at progression seemed to prolong survival from the time of progression but were also associated with receiving subsequent systemic therapy.&rdquo;

With the development of novel targeted and immunotherapeutic agents that are more efficacious than traditional chemotherapy, treatment paradigms in melanoma have undergone major changes.

BRAF-Mutant Melanoma | Evolving Paradigms

Weber Compares BRAF/MEK, Immunotherapy Combos in Melanoma

Treatment Sequencing Considerations for BRAF-Mutant Melanoma

Combination Regimens for Metastatic Melanoma

Distinct Features Associated With Benefit for BRAF/MEK Inhibition

Intricacies of BRAF Testing in Advanced Melanoma