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Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy:

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in... 616934 TAM0010.1177/1758834015616934Therapeutic Advances in Medical OncologyZ Eroglu and A Ribas research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Combination therapy with BRAF and MEK 2016, Vol. 8(1) 48 –56 DOI: 10.1177/ inhibitors for melanoma: latest evidence and © The Author(s), 2015. Reprints and permissions: place in therapy http://www.sagepub.co.uk/ journalsPermissions.nav Zeynep Eroglu and Antoni Ribas Abstract: Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. Keywords: BRAF inhibitors, MEK inhibitors, melanoma Correspondence to: Introduction first-line therapy in this patient population Antoni Ribas, MD, PhD Nearly half of the patients with advanced mela- [Flaherty et al. 2012b]. Department of Medicine, Division of Hematology- nomas harbor a valine to glutamine substitution Oncology, UCLA, 11-934 (V600E) in codon 600 of the serine-threonine The rapid antitumor responses observed with Factor Building, 10833 Le Conte Avenue, Los kinase BRAF [Davies et al. 2002]; less common BRAF or MEK inhibitor monotherapy are not Angeles, CA 90095-1782, BRAF mutations such as lysine (V600K) or argi- long lasting in most cases (although in a minority USA aribas@mednet.ucla.edu nine substitutions (V600R) have also been can last for over 5 years) due to the development Zeynep Eroglu, MD reported. In the past 4 years, two BRAF inhibi- of acquired resistance with progression after a Moffitt Cancer Center, tors that target these mutations, vemurafenib and period of objective tumor response. Drivers of Tampa, FL, USA dabrafenib, have been approved by the US Food acquired resistance to BRAF inhibitor therapy are and Drug Administration (FDA). These drugs diverse and include mechanisms leading to reacti- have shown high rates of rapid response not pre- vation of the mitogen-activated protein kinase viously seen in melanoma patients, with response (MAPK) pathway in over two-thirds of tumors rates ranging from 48% to 59% in phase II (such as activating mutations in upstream NRAS, and III trials of vemurafenib and dabrafenib BRAF amplification or truncation, overexpres- [Chapman et  al. 2011; Ascierto et  al. 2013; sion of genes such as COT, or mutations in the Hauschild et al. 2012]. However, the duration of downstream kinase MEK1), along with promo- responses is limited in the majority of patients, tion of parallel signaling networks such as the with median progression-free survival (PFS) in PI3K–PTEN–AKT pathway [Shi et  al. 2014; these patients ranging from 5.1 to 6.8 months Rizos et  al. 2014; Wagle et  al. 2011]. Sequential [Sosman et  al. 2012; Hauschild et  al. 2012]. therapy with a MEK inhibitor following progres- Treatment with the MEK inhibitor trametinib sion on a BRAF inhibitor has also not shown ben- has also shown similar PFS (4.8 months) and efit, as no responses and a PFS of only 1.8 months response rates (48%) when administered as was observed in a study of 40 patients, suggesting 48 http://tam.sagepub.com Z Eroglu and A Ribas that resistance to BRAF inhibitors also confers combination at the time of disease progression. resistance to MEK inhibitors [Kim et  al. 2013]. Updated data showed a median OS of 25 months Therefore, the premise behind the subsequent with the combination with a 3-year OS rate of 38%, clinical trials combining inhibitors of both MEK and normal lactate dehydrogenase (LDH) and <3 and mutant BRAF kinase was that they would sites of metastases were associated with longer sur- help to delay this MAPK-driven acquired resist- vival [Daud et  al. 2015b]. (Another analysis of ance and result in longer duration of responses, BRAF inhibitor treated patients, which included 31 higher rate of tumor responses, and decrease the treated with dabrafenib and trametinib combina- toxicities observed from paradoxical MAPK path- tion, also found that normal LDH was associated way activation with BRAF inhibitor monother- with improved PFS and OS [Menzies et al. 2015]). apy. In this review, we discuss existing clinical The most frequent adverse events (AEs) observed trial data on BRAF and MEK inhibitors together in the 150/2 group were pyrexia (all grades, 71%; and in combinations with other therapeutic grade 3, 5%) and chills (all grades, 58%; grade 3, agents. 2%); the most frequently occurring grade 3 or 4 toxicity in the 150/2 group was neutropenia (in 11% of patients), with one case of febrile neutropenia. Dabrafenib and trametinib Dabrafenib and trametinib were in the first BRAF Skin toxicities such as cutaneous squamous cell and MEK inhibitor combination in clinical trials, carcinoma with BRAF inhibitor monotherapy and currently the FDA approved combination in had been linked to paradoxical activation of the patients with advanced BRAFV600 mutated mel- MAPK pathway activation during BRAF inhibi- anoma. In the first phase I/II study (BRF113220), tion, while a mouse model had shown blockage of 8 patients received repeated doses of trametinib this effect with the addition of a MEK inhibitor and a single dose of dabrafenib to confirm absence [Su et  al. 2012]. The trial results also supported of a drug–drug interaction, and 77 patients these findings, as cutaneous squamous cell carci- received escalating doses of dabrafenib [75 and noma was observed in 19% of patients treated 150 mg twice daily (BID)] in combination with with dabrafenib alone, but only in 2% of combi- trametinib [1, 1.5 and 2 mg every day (QD)] to nation 150/1 and 7% of combination 150/2 determine toxicity profile and pharmacokinetic patients (p = 0.004 and p = 0.09, respectively). activity [Flaherty et al. 2012a]. The 45 patients who had disease progression on In the phase II portion of this study, 162 patients this study while receiving dabrafenib monother- with BRAFV600 mutated advanced melanoma apy could cross over to receive combination with no prior BRAF targeted therapy were 150 mg/2 mg dosing regimen, which was reported assigned 1:1:1 to receive combination therapy in a subsequent analysis, along with another with dabrafenib (150 mg QD) and trametinib cohort of 25 patients who received the combina- (either 1 or 2 mg daily) or dabrafenib (150 mg) tion after disease progression with single agent monotherapy. For these patients, median (PFS BRAF inhibitor [Johnson et  al. 2014]. For these for those in the combination 150/2 group was 9.4 patients who received dabrafenib and trametinib months versus 5.8 months for patients who after progression on BRAF inhibitor monother- received dabrafenib monotherapy [hazard ratio apy, an ORR of only 13% [95% confidence inter- (HR) for progression or death, 0.39; p < 0.001) A val (CI): 5–27%) to 15% (95% CI: 4–35%) was 1-year PFS rate of 41% was observed in the com- reported. Median PFS was only 3.6 months (95% bination 150/2 group versus 9% in the monother- CI: 2–4), and median OS was 11.8 months (95% apy group (p < 0.001). Table 1 shows key findings CI: 8–25) for the 45 crossover patients. Patients from several BRAF/MEK inhibitor combination who previously received dabrafenib for at least 6 clinical trials. months had better outcomes with the combina- tion compared with those treated for <6 months, In the combination 150/2 group, an objective with median PFS of 3.9 versus 1.8 months (HR, response rate (ORR) of 76% versus 54% with dab- 0.49; p = 0.02) and ORR of 26% versus 0%. rafenib monotherapy was observed (p = 0.03). The 1-year overall survival (OS) rate was 79% in the Two phase III trials were subsequently conducted combination 150/2 group and 70% in the mono- with dabrafenib and trametinib therapy. A rand- therapy group, even though 80% of patients in omized phase III study (COMBI-d) compared the monotherapy group crossed over to the combination of first-line therapy with dabrafenib http://tam.sagepub.com 49 Therapeutic Advances in Medical Oncology 8(1) Table 1. Results from BRAF and MEK inhibitor combination trials. Trial Treatment arms Median PFS Median OS/OS ORR Grade 3/4 AE % rates BRF113220 Phase II 9.4 months with 25 months with 76% with combo 58% with combo [ClinicalTrials. section with combo versus combo, 2-year OS versus 54% with versus 43% with gov identifier: dabrafenib 5.8 months with rate of 51%, 3-year dabrafenib dabrafenib NCT0107217] (150 mg BID) dabrafenib OS rate of 38% and trametinib with combo (2 mg QD) versus dabrafenib COMBI-d Phase III 11 months with 25.1 months with 69% with combo 35% with combo [ClinicalTrials. dabrafenib and combo versus combo versus versus 53% with versus 37% with gov identifier: trametinib versus 8.8 months with 18.7 months dabrafenib dabrafenib NCT01584648] dabrafenib dabrafenib dabrafenib, 2-year OS rate of 51% versus 42% COMBI-v Phase III 11.4 months with Not reached 64% with combo 52% with combo [ClinicalTrials. dabrafenib and combo versus for combo, 17.2 versus 51% with versus 63% with gov identifier: trametinib versus 7.3 months with months for vemurafenib vemurafenib NCT0159790] vemurafenib vemurafenib vemurafenib BRIM7 Phase Ib 13.7 months 28.5 months, 87% 62% for all [ClinicalTrials. vemurafenib and 2-year OS rate of patients gov identifier: cobimetinib (BRAF 61% NCT01271803] inhibitor naïve patient group) coBRIM Phase III 12.3 months with Not available yet 70% with combo 65% with combo [ClinicalTrials. vemurafenib and combo versus versus 50% with versus 59% with gov identifier: cobimetinib versus 7.3 months with vemurafenib vemurafenib NCT01689519] vemurafenib vemurafenib CMEK162X210 Phase Ib/2 11.3 months Not available yet 74.5% 67% for encorafenib and 600 mg dose of binimetinib encorafenib AE, adverse event; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. (150 mg BID) and trametinib (2 mg QD) in 211 conducted using the European Organisation for patients to dabrafenib and placebo in 212 patients. Research and Treatment of Cancer (EORTC) Patients with unresectable stage IIIC or stage IV Quality of Life Questionnaire-C30 which included metastatic melanoma with BRAF V600E or questions on functional status and symptoms. V600K mutations were eligible and stratified Improved preservation of quality of life in physical, according to baseline LDH concentration and social and cognitive functioning, and pain were BRAF genotype, with PFS as the primary end- observed in the patients treated with the combina- point [Long et  al. 2014b]. Median PFS was 9.3 tion compared with dabrafenib alone [Schadendorf months in the combination arm and 8.8 months in et al. 2015]. the dabrafenib monotherapy arm (HR 0.75; p = 0.03); an ORR of 67% in the dabrafenib– While statistically significant, the small absolute trametinib group and 51% in the dabrafenib-only difference in PFS between the two arms of the group (p = 0.002) was observed. Congruent with COMBI-d study was initially surprising; how- the phase II findings, frequency of cutaneous squa- ever, updated results from the trial were pub- mous cell carcinoma was lower in the dabrafenib lished earlier this year with an additional and trametinib combination than dabrafenib alone 17 months of follow up [Long et  al. 2015]. (2% versus 9%), while pyrexia was more frequent Median PFS was now reported at 11.0 months in the combination arm (51% versus 28%) versus (95% CI: 8.0–13.9) versus 8.8 months (95% dabrafenib alone. A health-related quality of life CI: 5.9–9.3), with an HR of 0.67 (p = 0.0004). analysis of the COMBI-d study patients was also Median OS was also reported in this update, 50 http://tam.sagepub.com Z Eroglu and A Ribas observed at 25.1 months (95% CI: 19.2 to not progressed on vemurafenib, with a median PFS reached) for the dabrafenib and trametinib com- of 2.8 months (95% CI: 2·6–3·4). The study bination arm, and 18.7 months (95% CI: 15.2– results were updated recently with an additional 23.7) for dabrafenib monotherapy. Forty-seven 11 months of follow up; a median OS of 28.5 percent of 211 patients in the dabrafenib and months in the vemurafenib-naïve and 8.4 months trametinib group had died versus 58% of 212 in in the vemurafenib-progressing patients was the dabrafenib only group, with an HR of 0.71 reported, with 2-year OS rates of 61.1% and (p = 0.0107). The survival benefit was present in 15.1% respectively [Pavlick et al. 2015]. all of the subgroup analyses, including patients with elevated LDH concentrations and regardless Survival and ORR findings of the phase III coBRIM of the BRAF V600 mutation subtype. trial with vemurafenib and cobimetinib were also analogous to the COMBI-d and COMBI-v phase A second phase III trial (COMBI-v) compared the III trials of dabrafenib and trametinib discussed dabrafenib-trametinib combination to vemu- earlier. In the coBRIM trial, addition of cobi- rafenib monotherapy [Robert et  al. 2015a]. The metinib (60 mg QD for 21 of 28 days) to vemu- median PFS of the 352 patients who received the rafenib (960 mg BID) led to an improvement in combination regimen was similar to the COMBI-d median PFS of 9.9 in the 247 patients versus 6.2 trial at 11.4 months versus 7.3 months with vemu- months in the 248 patients who received vemu- rafenib therapy (HR 0.56; p < 0.001) and ORR of rafenib with placebo, with HR for death or disease 64% with the combination compared with 51% progression of 0.51 (p < 0.001) [Larkin et al. 2014]. with vemurafenib alone (p < 0.001). Median OS The ORR was 68% in the combination arm com- for the combination had not been reached, while it pared to 45% in the control arm. was 17.2 months for the vemurafenib arm (HR 0.69, p = .005). The prespecified stopping bound- The combination was associated with a nonsig- ary of the trial was crossed, and it was stopped for nificant higher incidence of grade 3 or 4 AEs efficacy and amended to allow patients to crosso- compared with vemurafenib and placebo (65% ver to the combination arm. Cutaneous squamous versus 59%) and there was no significant differ- cell carcinoma and keratoacanthoma were ence in the rate of study drug discontinuation. observed in only 1% of patients in the combination Toxicities observed more frequently with the arm and in 18% of those in the vemurafenib arm. combination compared with single agent vemu- rafenib included central serous retinopathy, diar- rhea, nausea or vomiting, photosensitivity, Vemurafenib and cobimetinib elevated aminotransferase levels and an increased Similar results in responses rates, PFS and OS creatine kinase level. As expected, the incidence have been reported with the combination clinical of secondary cutaneous squamous cell cancers trials of the BRAF inhibitor vemurafenib and decreased with the combination therapy com- MEK inhibitor cobimetinib. Patients with pared with vemurafenib alone (down to 2% com- advanced BRAFV600 mutated melanoma who pared with 11%). Study results were updated were either BRAF inhibitor naïve (n = 63) or had with an 8 months additional follow up, with a either recently progressed on vemurafenib (n = 66) PFS of 12.3 months for the combination arm were included in the phase Ib BRIM7 trial [Ribas compared with 7.3 for monotherapy, HR 0.58, et al. 2014]. In the dose escalation phase, patients and ORR of 70% versus 50% respectively [Larkin received vemurafenib 720 or 960 mg BID con- et al. 2015]. Co-existing baseline activating RAS/ tinuously and cobimetinib 60, 80 or 100 mg QD RAF/RTK mutations together with BRAFV600 for 14 days on and 14 days off, or 21 days on and mutation were not associated with worse PFS or 7 days off, or continuously. The maximum toler- ORR. OS analysis data from the coBRIM trial are ated dose was established as vemurafenib 960 mg not yet available. BID in combination with cobimetinib 60 mg for 21 days on, 7 days off. The ORR rate was 87% in the 63 BRAF inhibitor naïve patients, with a Encorafenib and binimetinib median PFS of 13.7 months (95% CI: 10·1– The third BRAF and MEK inhibitor combina- 17·5). Comparable with the ORR and PFS results tion in clinical trials is encorafenib and bin- in the dabrafenib/trametinib patients after they imetinib. In a phase Ib/II trial (CMEK162X2110) had progressed on dabrafenib alone, the ORR of patients with advanced BRAFV600 melanoma, was only 15% in the 66 patients who had already patients were treated with 400, 450 or 600 mg http://tam.sagepub.com 51 Therapeutic Advances in Medical Oncology 8(1) QD of encorafenib and 45 mg BID of binimetinib with a 5 weeks on, 3 weeks off schedule [Algazi [Sullivan et al. 2015]. For the 55 patients without et al. 2015]. Serial biopsies are used to determine prior BRAF inhibitor therapy, the combined mechanisms associated with disease progression. ORR was 74.5%, with a median PFS of 11.3 months (95% CI: 7.4–14.6) for all of the BRAF inhibitor naïve patients. A 64% frequency of BRAF and MEK inhibitors in combination grade 3/4 toxicities was observed in patients with other targeted therapies treated with 600 mg encorafenib, such as Besides intermittent therapy, other drugs have increased alanine aminotransferase (ALT) (18%), been combined with BRAF and MEK inhibitors lipase (15%), aspartate transaminase (AST) in an attempt to overcome acquired resistance. (13%), and creatine phosphokinase (13%). A Preclinical studies have demonstrated that heat phase III trial (COLUMBUS) is ongoing with 3 shock protein 90 (HSP90) inhibitors such as arms: encorafenib 450 mg daily with 45 mg BID XL888 can overcome the onset of BRAF inhibi- of binimetinib, encorafenib alone at 300 mg daily, tor resistance [Paraiso et  al. 2012]. HSP90 is a and vemurafenib alone [ClinicalTrials.gov identi- chaperone protein involved in resistance mecha- fier: NCT01909453]. nisms to BRAF targeted therapies and inhibition of HSP90 was shown to degrade proteins critical for vemurafenib resistance such as IGF1R, Intermittent dosing and sequencing of PDGFRβ, CRAF and cyclin D1 and to inhibit therapies AKT, extracellular-signal-regulated kinase Preclinical studies have demonstrated that inter- (ERK) and S6 signaling. There is an ongoing mittent as opposed to continuous therapy with a phase I study of vemurafenib with XL888 in BRAF inhibitor may delay the development of patients with advanced BRAF V600-mutant mel- acquired resistance [Thakur and Stuart, 2013]. anoma [ClinicalTrials.gov identifier: Acquired resistance to BRAF and MEK inhibitor NCT01657591], with plans for a triple combina- therapy combination is also of significant concern tion with BRAF and MEK inhibitor therapy. with these drugs, and resistance mechanism are PI3K–PTEN–AKT–upregulating genetic altera- similar to mechanisms of resistance to BRAF tions have also been observed as a resistance inhibitors alone, except in greater magnitudes or mechanism to BRAF targeted therapies [Shi et al. in combinations such as BRAF ultra-amplifica- 2014] and AKT inhibitors are undergoing clinical tion [Long et al. 2014a]. Melanoma clones resist- trials including in a triple combination of ant to BRAF and MEK inhibitor therapy also GSK2141795 with dabrafenib and trametinib in appear to display increased drug addiction com- the SWOG study S1221 [ClinicalTrials.gov iden- pared with those resistant to BRAF inhibitors tifier: NCT01902173]. MDM2 is an oncogene alone [Moriceau et al. 2015]. that is a major negative regulator of the tumor suppressor p53; AMG 232 is a small molecule Therefore, studies examining sequential or inter- inhibitor of MDM2 designed to block the mittent dosing of BRAF and MEK inhibitors MDM2–p53 interaction and is currently under are ongoing. In the phase II randomized investigation in a phase I/II trial with dabrafenib COMBAT study [ClinicalTrials.gov identifier: and trametinib [ClinicalTrials.gov identifier: NCT02224781], patients are randomized to the NCT02110355]. combination of dabrafenib and trametinib versus their combination after 8 weeks of monotherapy with dabrafenib or trametinib. Biopsies are taken BRAF and MEK inhibitors in combination at randomization, week 2, week 8, week 10, and with immunotherapy at progression to assess biomarkers linked to While response rates up to 70% have been treatment response and resistance [Mateus et  al. observed with BRAF and MEK inhibitors in clini- 2014]. The SWOG study S1320 [ClinicalTrials. cal trials, given the limited durability of responses, gov identifier: NCT02196181] is looking at an there has been interest in combination with check- intermittent dosing schedule, with patients point inhibitors such as anti-cytotoxic T lympho- treated with dabrafenib at 150 mg BID and cyte antigen-4 (anti-CTLA-4) and anti-programed trametinib 2 mg QD during an 8-week lead in death 1 (anti-PD-1)/programmed death-ligand 1 period, and randomizing patients without disease (PD-L1) antibodies. These therapies offer less fre- progression at the end of the lead in period to quent objective responses compared with targeted either continuous dosing or to intermittent dosing therapies (10–15% range with the anti-CTLA-4 52 http://tam.sagepub.com Z Eroglu and A Ribas antibodies ipilimumab or tremelimumab, up to importantly, further follow up will determine how 30–40% with the anti-PD-1 antibodies nivolumab durable the tumor responses of these patients or pembrolizumab in patients with advanced mel- will be. Another ongoing phase I/II trial anoma), but with significant durability of responses KEYNOTE-022 [ClinicalTrials.gov identifier: compared with BRAF and MEK inhibitor thera- NCT02130466] is looking at the combination of pies; a 2-year OS rate of 60% with first-line pem- pembrolizumab with dabrafenib and trametinib. brolizumab and 4-year OS rate of 32% with first-line nivolumab have been reported [Schadendorf et  al. 2015; Robert et  al. 2015b; Patients with brain metastases Ribas et  al. 2013; Hodi et  al. 2010, 2014; Daud There has been a special focus in patients with et  al. 2015a]. BRAF and MEK inhibition have brain metastases in metastatic melanoma. While been shown in tumor biopsies to modulate the animal studies have suggested that BRAF inhibi- immune microenvironment and increase CD8 tors may have limited brain distribution due to positive T cells and melanoma differentiation efflux from transporters such as P-glycoprotein, antigens like MART-1 and gp100, which may activity has been seen clinical trials [Mittapalli have role in T-cell recognition [Frederick et  al. et  al. 2013]. In the BREAK-MB trial of 171 2013; Wilmott et al. 2012; Wargo et al. 2014] and patients with at least one asymptomatic brain animal studies have demonstrated improved sur- metastasis treated with 150 mg dabrafenib BID, vival with BRAF/MEK inhibitors when combined there was an ORR of 39.2% in patients with mel- with anti-PD1 therapy [Hu-Lieskovan et al. 2015]. anoma brain metastases without previous local Subsequently clinical trials have been undertaken (brain) therapy, with a 39.2% intracranial to determine if the combination of BRAF and response rate which went down to 30.8% in MEK targeted therapies with immunotherapy patients with prior local therapy [Long et  al. would indeed result in higher frequency of long- 2012]. In a small study of 24 patients with unre- lasting responses in patients with advanced BRAF sectable and previously treated brain metastases, mutated melanoma. a 42% ORR was observed at both intracranial and extracranial sies of disease with vemurafenib In a study undertaken to determine the safety of treatment [Dummer et  al. 2014]. Limited data dabrafenib with and without trametinib and ipili- have been reported on low cerebrospinal fluid mumab at the doses of dabrafenib 100 mg BID, (CSF) concentrations of vemurafenib in patients, trametinib 1 mg QD and ipilimumab at the FDA- although CSF drug concentration may not neces- approved dose of 3 mg/kg every 3 weeks for 4 sarily be the optimum surrogate marker for con- doses, 2 out of 7 advanced melanoma patients centration of a drug in brain tumor tissue developed grade 3 colitis complicated by perfora- [Sakji-Dupré et  al. 2015]; there have also been tion [Puzanov, 2015]. Therefore, enrollment to case reports of melanoma patients with leptome- the triple combination arm was stopped, although ningeal disease who have had responses to vemu- the dabrafenib and ipilimumab combination arm rafenib [Schäfer et  al. 2013; Kim et  al. 2015]. is ongoing. Another ongoing trial is looking at the There is an ongoing phase II study of the dab- combination of the anti-PD-L1 antibody rafenib and trametinib combination in patients MEDI4736 at 10 mg/kg every 2 weeks, together with BRAF mutation-positive melanoma that has with dabrafenib 150 mg BID and trametinib 2 mg metastasized to the brain; cohorts will include QD [Ribas et al. 2015]. Tumor biopsies from the patients with symptomatic and asymptomatic patients have revealed evidence of immune acti- brain metastases, and with or without prior ther- vation post-treatment, with frequency of tumor- apy to the brain [Davies et  al. 2014]. Another infiltrating CD8+ T cells and levels of interferon-γ study, coBRIM-B, is focusing on vemurafenib increased post-treatment. For the 26 BRAF and cobimetinib therapy in patients with active mutated advanced melanoma patients treated melanoma brain metastases with the primary with the triple combination, an ORR of 69% was objective of determining the objective intracranial obtained and 16 out of 18 patients have ongoing response rate [Yee et al. 2015]. responses. There was no exacerbation of immune- related AEs. While an ORR of 69% does not appear to be higher than the ORR of BRAF and Conclusion MEK inhibitor combinations alone, some of the In comparison with single agent BRAF inhibitors, responses may not have declared yet during the the combination of BRAF and MEK inhibitors short follow up presented for this study; more have shown significant improvement in response http://tam.sagepub.com 53 Therapeutic Advances in Medical Oncology 8(1) rates, PFS and OS in addition to fewer side effects Funding related to paradoxical activation of the MAPK The author(s) received no financial support for pathway; the combination has now become the the research, authorship, and/or publication of standard of care in patients with BRAFV600 this article. mutated advanced melanoma for whom targeted therapy is used. While there has not yet been Conflict of interest statement direct comparison of the three different BRAF– The author(s) declared the following potential MEK inhibitor combinations in clinical trials, conflicts of interest with respect to the research, they have shown similar clinical efficacy. There authorship, and/or publication of this article: are some differences in the toxicity profiles of the A.R.: consultant or advisory role with Merck combinations, such as much more frequent Sharp & Dohme Corp., Amgen, Astellas, Daiichi- pyrexia with dabrafenib and trametinib compared Sankyo, GlaxoSmithKline, Genentech-Roche, with vemurafenib/cobimetinib and encorafenib/ Novartis, Pierre Fabre; DSMB member for binimetinib, and vice versa with photosensitivity MedImmune/AstraZeneca and Novartis; stock much more common with vemurafenib/cobi- or ownership interests from Kite Pharma, metinib; hepatic enzyme elevations were reported Compugen. Z.E. declares no conflicts of interest more frequently with encorafenib/binimetinib in in preparing this article. comparison with the other two combinations. However, the decision about whether to use tar- geted therapy or immunotherapy first in these References Algazi, A., Othus, M., Daud, A., Mehnert, J., Lao, patients is still not fully delineated. While response C., Kudchadkar, R. et al. (2015) SWOG S1320: rates of up to 70% have been observed with first- a randomized phase II trial of intermittent versus line BRAF/MEK targeted therapy, the duration of continuous dosing of dabrafenib and trametinib in responses is still only about a year. Although anti- BRAFV600E/k mutant melanoma. J Clin Oncol 33: PD-1 inhibitors are now FDA approved for BRAF TPS9093. mutated melanoma only after progression on tar- Ascierto, P., Minor, D., Ribas, A., Lebbe, C., geted therapy and ipilimumab, it is expected that O’Hagan, A., Arya, N. et al. 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J Clin SAGE journals in patients treated for brain metastatic BRAF-V600 Oncol 33: TPS9088. 56 http://tam.sagepub.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy:

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616934 TAM0010.1177/1758834015616934Therapeutic Advances in Medical OncologyZ Eroglu and A Ribas research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Combination therapy with BRAF and MEK 2016, Vol. 8(1) 48 –56 DOI: 10.1177/ inhibitors for melanoma: latest evidence and © The Author(s), 2015. Reprints and permissions: place in therapy http://www.sagepub.co.uk/ journalsPermissions.nav Zeynep Eroglu and Antoni Ribas Abstract: Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents. Keywords: BRAF inhibitors, MEK inhibitors, melanoma Correspondence to: Introduction first-line therapy in this patient population Antoni Ribas, MD, PhD Nearly half of the patients with advanced mela- [Flaherty et al. 2012b]. Department of Medicine, Division of Hematology- nomas harbor a valine to glutamine substitution Oncology, UCLA, 11-934 (V600E) in codon 600 of the serine-threonine The rapid antitumor responses observed with Factor Building, 10833 Le Conte Avenue, Los kinase BRAF [Davies et al. 2002]; less common BRAF or MEK inhibitor monotherapy are not Angeles, CA 90095-1782, BRAF mutations such as lysine (V600K) or argi- long lasting in most cases (although in a minority USA aribas@mednet.ucla.edu nine substitutions (V600R) have also been can last for over 5 years) due to the development Zeynep Eroglu, MD reported. In the past 4 years, two BRAF inhibi- of acquired resistance with progression after a Moffitt Cancer Center, tors that target these mutations, vemurafenib and period of objective tumor response. Drivers of Tampa, FL, USA dabrafenib, have been approved by the US Food acquired resistance to BRAF inhibitor therapy are and Drug Administration (FDA). These drugs diverse and include mechanisms leading to reacti- have shown high rates of rapid response not pre- vation of the mitogen-activated protein kinase viously seen in melanoma patients, with response (MAPK) pathway in over two-thirds of tumors rates ranging from 48% to 59% in phase II (such as activating mutations in upstream NRAS, and III trials of vemurafenib and dabrafenib BRAF amplification or truncation, overexpres- [Chapman et  al. 2011; Ascierto et  al. 2013; sion of genes such as COT, or mutations in the Hauschild et al. 2012]. However, the duration of downstream kinase MEK1), along with promo- responses is limited in the majority of patients, tion of parallel signaling networks such as the with median progression-free survival (PFS) in PI3K–PTEN–AKT pathway [Shi et  al. 2014; these patients ranging from 5.1 to 6.8 months Rizos et  al. 2014; Wagle et  al. 2011]. Sequential [Sosman et  al. 2012; Hauschild et  al. 2012]. therapy with a MEK inhibitor following progres- Treatment with the MEK inhibitor trametinib sion on a BRAF inhibitor has also not shown ben- has also shown similar PFS (4.8 months) and efit, as no responses and a PFS of only 1.8 months response rates (48%) when administered as was observed in a study of 40 patients, suggesting 48 http://tam.sagepub.com Z Eroglu and A Ribas that resistance to BRAF inhibitors also confers combination at the time of disease progression. resistance to MEK inhibitors [Kim et  al. 2013]. Updated data showed a median OS of 25 months Therefore, the premise behind the subsequent with the combination with a 3-year OS rate of 38%, clinical trials combining inhibitors of both MEK and normal lactate dehydrogenase (LDH) and <3 and mutant BRAF kinase was that they would sites of metastases were associated with longer sur- help to delay this MAPK-driven acquired resist- vival [Daud et  al. 2015b]. (Another analysis of ance and result in longer duration of responses, BRAF inhibitor treated patients, which included 31 higher rate of tumor responses, and decrease the treated with dabrafenib and trametinib combina- toxicities observed from paradoxical MAPK path- tion, also found that normal LDH was associated way activation with BRAF inhibitor monother- with improved PFS and OS [Menzies et al. 2015]). apy. In this review, we discuss existing clinical The most frequent adverse events (AEs) observed trial data on BRAF and MEK inhibitors together in the 150/2 group were pyrexia (all grades, 71%; and in combinations with other therapeutic grade 3, 5%) and chills (all grades, 58%; grade 3, agents. 2%); the most frequently occurring grade 3 or 4 toxicity in the 150/2 group was neutropenia (in 11% of patients), with one case of febrile neutropenia. Dabrafenib and trametinib Dabrafenib and trametinib were in the first BRAF Skin toxicities such as cutaneous squamous cell and MEK inhibitor combination in clinical trials, carcinoma with BRAF inhibitor monotherapy and currently the FDA approved combination in had been linked to paradoxical activation of the patients with advanced BRAFV600 mutated mel- MAPK pathway activation during BRAF inhibi- anoma. In the first phase I/II study (BRF113220), tion, while a mouse model had shown blockage of 8 patients received repeated doses of trametinib this effect with the addition of a MEK inhibitor and a single dose of dabrafenib to confirm absence [Su et  al. 2012]. The trial results also supported of a drug–drug interaction, and 77 patients these findings, as cutaneous squamous cell carci- received escalating doses of dabrafenib [75 and noma was observed in 19% of patients treated 150 mg twice daily (BID)] in combination with with dabrafenib alone, but only in 2% of combi- trametinib [1, 1.5 and 2 mg every day (QD)] to nation 150/1 and 7% of combination 150/2 determine toxicity profile and pharmacokinetic patients (p = 0.004 and p = 0.09, respectively). activity [Flaherty et al. 2012a]. The 45 patients who had disease progression on In the phase II portion of this study, 162 patients this study while receiving dabrafenib monother- with BRAFV600 mutated advanced melanoma apy could cross over to receive combination with no prior BRAF targeted therapy were 150 mg/2 mg dosing regimen, which was reported assigned 1:1:1 to receive combination therapy in a subsequent analysis, along with another with dabrafenib (150 mg QD) and trametinib cohort of 25 patients who received the combina- (either 1 or 2 mg daily) or dabrafenib (150 mg) tion after disease progression with single agent monotherapy. For these patients, median (PFS BRAF inhibitor [Johnson et  al. 2014]. For these for those in the combination 150/2 group was 9.4 patients who received dabrafenib and trametinib months versus 5.8 months for patients who after progression on BRAF inhibitor monother- received dabrafenib monotherapy [hazard ratio apy, an ORR of only 13% [95% confidence inter- (HR) for progression or death, 0.39; p < 0.001) A val (CI): 5–27%) to 15% (95% CI: 4–35%) was 1-year PFS rate of 41% was observed in the com- reported. Median PFS was only 3.6 months (95% bination 150/2 group versus 9% in the monother- CI: 2–4), and median OS was 11.8 months (95% apy group (p < 0.001). Table 1 shows key findings CI: 8–25) for the 45 crossover patients. Patients from several BRAF/MEK inhibitor combination who previously received dabrafenib for at least 6 clinical trials. months had better outcomes with the combina- tion compared with those treated for <6 months, In the combination 150/2 group, an objective with median PFS of 3.9 versus 1.8 months (HR, response rate (ORR) of 76% versus 54% with dab- 0.49; p = 0.02) and ORR of 26% versus 0%. rafenib monotherapy was observed (p = 0.03). The 1-year overall survival (OS) rate was 79% in the Two phase III trials were subsequently conducted combination 150/2 group and 70% in the mono- with dabrafenib and trametinib therapy. A rand- therapy group, even though 80% of patients in omized phase III study (COMBI-d) compared the monotherapy group crossed over to the combination of first-line therapy with dabrafenib http://tam.sagepub.com 49 Therapeutic Advances in Medical Oncology 8(1) Table 1. Results from BRAF and MEK inhibitor combination trials. Trial Treatment arms Median PFS Median OS/OS ORR Grade 3/4 AE % rates BRF113220 Phase II 9.4 months with 25 months with 76% with combo 58% with combo [ClinicalTrials. section with combo versus combo, 2-year OS versus 54% with versus 43% with gov identifier: dabrafenib 5.8 months with rate of 51%, 3-year dabrafenib dabrafenib NCT0107217] (150 mg BID) dabrafenib OS rate of 38% and trametinib with combo (2 mg QD) versus dabrafenib COMBI-d Phase III 11 months with 25.1 months with 69% with combo 35% with combo [ClinicalTrials. dabrafenib and combo versus combo versus versus 53% with versus 37% with gov identifier: trametinib versus 8.8 months with 18.7 months dabrafenib dabrafenib NCT01584648] dabrafenib dabrafenib dabrafenib, 2-year OS rate of 51% versus 42% COMBI-v Phase III 11.4 months with Not reached 64% with combo 52% with combo [ClinicalTrials. dabrafenib and combo versus for combo, 17.2 versus 51% with versus 63% with gov identifier: trametinib versus 7.3 months with months for vemurafenib vemurafenib NCT0159790] vemurafenib vemurafenib vemurafenib BRIM7 Phase Ib 13.7 months 28.5 months, 87% 62% for all [ClinicalTrials. vemurafenib and 2-year OS rate of patients gov identifier: cobimetinib (BRAF 61% NCT01271803] inhibitor naïve patient group) coBRIM Phase III 12.3 months with Not available yet 70% with combo 65% with combo [ClinicalTrials. vemurafenib and combo versus versus 50% with versus 59% with gov identifier: cobimetinib versus 7.3 months with vemurafenib vemurafenib NCT01689519] vemurafenib vemurafenib CMEK162X210 Phase Ib/2 11.3 months Not available yet 74.5% 67% for encorafenib and 600 mg dose of binimetinib encorafenib AE, adverse event; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. (150 mg BID) and trametinib (2 mg QD) in 211 conducted using the European Organisation for patients to dabrafenib and placebo in 212 patients. Research and Treatment of Cancer (EORTC) Patients with unresectable stage IIIC or stage IV Quality of Life Questionnaire-C30 which included metastatic melanoma with BRAF V600E or questions on functional status and symptoms. V600K mutations were eligible and stratified Improved preservation of quality of life in physical, according to baseline LDH concentration and social and cognitive functioning, and pain were BRAF genotype, with PFS as the primary end- observed in the patients treated with the combina- point [Long et  al. 2014b]. Median PFS was 9.3 tion compared with dabrafenib alone [Schadendorf months in the combination arm and 8.8 months in et al. 2015]. the dabrafenib monotherapy arm (HR 0.75; p = 0.03); an ORR of 67% in the dabrafenib– While statistically significant, the small absolute trametinib group and 51% in the dabrafenib-only difference in PFS between the two arms of the group (p = 0.002) was observed. Congruent with COMBI-d study was initially surprising; how- the phase II findings, frequency of cutaneous squa- ever, updated results from the trial were pub- mous cell carcinoma was lower in the dabrafenib lished earlier this year with an additional and trametinib combination than dabrafenib alone 17 months of follow up [Long et  al. 2015]. (2% versus 9%), while pyrexia was more frequent Median PFS was now reported at 11.0 months in the combination arm (51% versus 28%) versus (95% CI: 8.0–13.9) versus 8.8 months (95% dabrafenib alone. A health-related quality of life CI: 5.9–9.3), with an HR of 0.67 (p = 0.0004). analysis of the COMBI-d study patients was also Median OS was also reported in this update, 50 http://tam.sagepub.com Z Eroglu and A Ribas observed at 25.1 months (95% CI: 19.2 to not progressed on vemurafenib, with a median PFS reached) for the dabrafenib and trametinib com- of 2.8 months (95% CI: 2·6–3·4). The study bination arm, and 18.7 months (95% CI: 15.2– results were updated recently with an additional 23.7) for dabrafenib monotherapy. Forty-seven 11 months of follow up; a median OS of 28.5 percent of 211 patients in the dabrafenib and months in the vemurafenib-naïve and 8.4 months trametinib group had died versus 58% of 212 in in the vemurafenib-progressing patients was the dabrafenib only group, with an HR of 0.71 reported, with 2-year OS rates of 61.1% and (p = 0.0107). The survival benefit was present in 15.1% respectively [Pavlick et al. 2015]. all of the subgroup analyses, including patients with elevated LDH concentrations and regardless Survival and ORR findings of the phase III coBRIM of the BRAF V600 mutation subtype. trial with vemurafenib and cobimetinib were also analogous to the COMBI-d and COMBI-v phase A second phase III trial (COMBI-v) compared the III trials of dabrafenib and trametinib discussed dabrafenib-trametinib combination to vemu- earlier. In the coBRIM trial, addition of cobi- rafenib monotherapy [Robert et  al. 2015a]. The metinib (60 mg QD for 21 of 28 days) to vemu- median PFS of the 352 patients who received the rafenib (960 mg BID) led to an improvement in combination regimen was similar to the COMBI-d median PFS of 9.9 in the 247 patients versus 6.2 trial at 11.4 months versus 7.3 months with vemu- months in the 248 patients who received vemu- rafenib therapy (HR 0.56; p < 0.001) and ORR of rafenib with placebo, with HR for death or disease 64% with the combination compared with 51% progression of 0.51 (p < 0.001) [Larkin et al. 2014]. with vemurafenib alone (p < 0.001). Median OS The ORR was 68% in the combination arm com- for the combination had not been reached, while it pared to 45% in the control arm. was 17.2 months for the vemurafenib arm (HR 0.69, p = .005). The prespecified stopping bound- The combination was associated with a nonsig- ary of the trial was crossed, and it was stopped for nificant higher incidence of grade 3 or 4 AEs efficacy and amended to allow patients to crosso- compared with vemurafenib and placebo (65% ver to the combination arm. Cutaneous squamous versus 59%) and there was no significant differ- cell carcinoma and keratoacanthoma were ence in the rate of study drug discontinuation. observed in only 1% of patients in the combination Toxicities observed more frequently with the arm and in 18% of those in the vemurafenib arm. combination compared with single agent vemu- rafenib included central serous retinopathy, diar- rhea, nausea or vomiting, photosensitivity, Vemurafenib and cobimetinib elevated aminotransferase levels and an increased Similar results in responses rates, PFS and OS creatine kinase level. As expected, the incidence have been reported with the combination clinical of secondary cutaneous squamous cell cancers trials of the BRAF inhibitor vemurafenib and decreased with the combination therapy com- MEK inhibitor cobimetinib. Patients with pared with vemurafenib alone (down to 2% com- advanced BRAFV600 mutated melanoma who pared with 11%). Study results were updated were either BRAF inhibitor naïve (n = 63) or had with an 8 months additional follow up, with a either recently progressed on vemurafenib (n = 66) PFS of 12.3 months for the combination arm were included in the phase Ib BRIM7 trial [Ribas compared with 7.3 for monotherapy, HR 0.58, et al. 2014]. In the dose escalation phase, patients and ORR of 70% versus 50% respectively [Larkin received vemurafenib 720 or 960 mg BID con- et al. 2015]. Co-existing baseline activating RAS/ tinuously and cobimetinib 60, 80 or 100 mg QD RAF/RTK mutations together with BRAFV600 for 14 days on and 14 days off, or 21 days on and mutation were not associated with worse PFS or 7 days off, or continuously. The maximum toler- ORR. OS analysis data from the coBRIM trial are ated dose was established as vemurafenib 960 mg not yet available. BID in combination with cobimetinib 60 mg for 21 days on, 7 days off. The ORR rate was 87% in the 63 BRAF inhibitor naïve patients, with a Encorafenib and binimetinib median PFS of 13.7 months (95% CI: 10·1– The third BRAF and MEK inhibitor combina- 17·5). Comparable with the ORR and PFS results tion in clinical trials is encorafenib and bin- in the dabrafenib/trametinib patients after they imetinib. In a phase Ib/II trial (CMEK162X2110) had progressed on dabrafenib alone, the ORR of patients with advanced BRAFV600 melanoma, was only 15% in the 66 patients who had already patients were treated with 400, 450 or 600 mg http://tam.sagepub.com 51 Therapeutic Advances in Medical Oncology 8(1) QD of encorafenib and 45 mg BID of binimetinib with a 5 weeks on, 3 weeks off schedule [Algazi [Sullivan et al. 2015]. For the 55 patients without et al. 2015]. Serial biopsies are used to determine prior BRAF inhibitor therapy, the combined mechanisms associated with disease progression. ORR was 74.5%, with a median PFS of 11.3 months (95% CI: 7.4–14.6) for all of the BRAF inhibitor naïve patients. A 64% frequency of BRAF and MEK inhibitors in combination grade 3/4 toxicities was observed in patients with other targeted therapies treated with 600 mg encorafenib, such as Besides intermittent therapy, other drugs have increased alanine aminotransferase (ALT) (18%), been combined with BRAF and MEK inhibitors lipase (15%), aspartate transaminase (AST) in an attempt to overcome acquired resistance. (13%), and creatine phosphokinase (13%). A Preclinical studies have demonstrated that heat phase III trial (COLUMBUS) is ongoing with 3 shock protein 90 (HSP90) inhibitors such as arms: encorafenib 450 mg daily with 45 mg BID XL888 can overcome the onset of BRAF inhibi- of binimetinib, encorafenib alone at 300 mg daily, tor resistance [Paraiso et  al. 2012]. HSP90 is a and vemurafenib alone [ClinicalTrials.gov identi- chaperone protein involved in resistance mecha- fier: NCT01909453]. nisms to BRAF targeted therapies and inhibition of HSP90 was shown to degrade proteins critical for vemurafenib resistance such as IGF1R, Intermittent dosing and sequencing of PDGFRβ, CRAF and cyclin D1 and to inhibit therapies AKT, extracellular-signal-regulated kinase Preclinical studies have demonstrated that inter- (ERK) and S6 signaling. There is an ongoing mittent as opposed to continuous therapy with a phase I study of vemurafenib with XL888 in BRAF inhibitor may delay the development of patients with advanced BRAF V600-mutant mel- acquired resistance [Thakur and Stuart, 2013]. anoma [ClinicalTrials.gov identifier: Acquired resistance to BRAF and MEK inhibitor NCT01657591], with plans for a triple combina- therapy combination is also of significant concern tion with BRAF and MEK inhibitor therapy. with these drugs, and resistance mechanism are PI3K–PTEN–AKT–upregulating genetic altera- similar to mechanisms of resistance to BRAF tions have also been observed as a resistance inhibitors alone, except in greater magnitudes or mechanism to BRAF targeted therapies [Shi et al. in combinations such as BRAF ultra-amplifica- 2014] and AKT inhibitors are undergoing clinical tion [Long et al. 2014a]. Melanoma clones resist- trials including in a triple combination of ant to BRAF and MEK inhibitor therapy also GSK2141795 with dabrafenib and trametinib in appear to display increased drug addiction com- the SWOG study S1221 [ClinicalTrials.gov iden- pared with those resistant to BRAF inhibitors tifier: NCT01902173]. MDM2 is an oncogene alone [Moriceau et al. 2015]. that is a major negative regulator of the tumor suppressor p53; AMG 232 is a small molecule Therefore, studies examining sequential or inter- inhibitor of MDM2 designed to block the mittent dosing of BRAF and MEK inhibitors MDM2–p53 interaction and is currently under are ongoing. In the phase II randomized investigation in a phase I/II trial with dabrafenib COMBAT study [ClinicalTrials.gov identifier: and trametinib [ClinicalTrials.gov identifier: NCT02224781], patients are randomized to the NCT02110355]. combination of dabrafenib and trametinib versus their combination after 8 weeks of monotherapy with dabrafenib or trametinib. Biopsies are taken BRAF and MEK inhibitors in combination at randomization, week 2, week 8, week 10, and with immunotherapy at progression to assess biomarkers linked to While response rates up to 70% have been treatment response and resistance [Mateus et  al. observed with BRAF and MEK inhibitors in clini- 2014]. The SWOG study S1320 [ClinicalTrials. cal trials, given the limited durability of responses, gov identifier: NCT02196181] is looking at an there has been interest in combination with check- intermittent dosing schedule, with patients point inhibitors such as anti-cytotoxic T lympho- treated with dabrafenib at 150 mg BID and cyte antigen-4 (anti-CTLA-4) and anti-programed trametinib 2 mg QD during an 8-week lead in death 1 (anti-PD-1)/programmed death-ligand 1 period, and randomizing patients without disease (PD-L1) antibodies. These therapies offer less fre- progression at the end of the lead in period to quent objective responses compared with targeted either continuous dosing or to intermittent dosing therapies (10–15% range with the anti-CTLA-4 52 http://tam.sagepub.com Z Eroglu and A Ribas antibodies ipilimumab or tremelimumab, up to importantly, further follow up will determine how 30–40% with the anti-PD-1 antibodies nivolumab durable the tumor responses of these patients or pembrolizumab in patients with advanced mel- will be. Another ongoing phase I/II trial anoma), but with significant durability of responses KEYNOTE-022 [ClinicalTrials.gov identifier: compared with BRAF and MEK inhibitor thera- NCT02130466] is looking at the combination of pies; a 2-year OS rate of 60% with first-line pem- pembrolizumab with dabrafenib and trametinib. brolizumab and 4-year OS rate of 32% with first-line nivolumab have been reported [Schadendorf et  al. 2015; Robert et  al. 2015b; Patients with brain metastases Ribas et  al. 2013; Hodi et  al. 2010, 2014; Daud There has been a special focus in patients with et  al. 2015a]. BRAF and MEK inhibition have brain metastases in metastatic melanoma. While been shown in tumor biopsies to modulate the animal studies have suggested that BRAF inhibi- immune microenvironment and increase CD8 tors may have limited brain distribution due to positive T cells and melanoma differentiation efflux from transporters such as P-glycoprotein, antigens like MART-1 and gp100, which may activity has been seen clinical trials [Mittapalli have role in T-cell recognition [Frederick et  al. et  al. 2013]. In the BREAK-MB trial of 171 2013; Wilmott et al. 2012; Wargo et al. 2014] and patients with at least one asymptomatic brain animal studies have demonstrated improved sur- metastasis treated with 150 mg dabrafenib BID, vival with BRAF/MEK inhibitors when combined there was an ORR of 39.2% in patients with mel- with anti-PD1 therapy [Hu-Lieskovan et al. 2015]. anoma brain metastases without previous local Subsequently clinical trials have been undertaken (brain) therapy, with a 39.2% intracranial to determine if the combination of BRAF and response rate which went down to 30.8% in MEK targeted therapies with immunotherapy patients with prior local therapy [Long et  al. would indeed result in higher frequency of long- 2012]. In a small study of 24 patients with unre- lasting responses in patients with advanced BRAF sectable and previously treated brain metastases, mutated melanoma. a 42% ORR was observed at both intracranial and extracranial sies of disease with vemurafenib In a study undertaken to determine the safety of treatment [Dummer et  al. 2014]. Limited data dabrafenib with and without trametinib and ipili- have been reported on low cerebrospinal fluid mumab at the doses of dabrafenib 100 mg BID, (CSF) concentrations of vemurafenib in patients, trametinib 1 mg QD and ipilimumab at the FDA- although CSF drug concentration may not neces- approved dose of 3 mg/kg every 3 weeks for 4 sarily be the optimum surrogate marker for con- doses, 2 out of 7 advanced melanoma patients centration of a drug in brain tumor tissue developed grade 3 colitis complicated by perfora- [Sakji-Dupré et  al. 2015]; there have also been tion [Puzanov, 2015]. Therefore, enrollment to case reports of melanoma patients with leptome- the triple combination arm was stopped, although ningeal disease who have had responses to vemu- the dabrafenib and ipilimumab combination arm rafenib [Schäfer et  al. 2013; Kim et  al. 2015]. is ongoing. Another ongoing trial is looking at the There is an ongoing phase II study of the dab- combination of the anti-PD-L1 antibody rafenib and trametinib combination in patients MEDI4736 at 10 mg/kg every 2 weeks, together with BRAF mutation-positive melanoma that has with dabrafenib 150 mg BID and trametinib 2 mg metastasized to the brain; cohorts will include QD [Ribas et al. 2015]. Tumor biopsies from the patients with symptomatic and asymptomatic patients have revealed evidence of immune acti- brain metastases, and with or without prior ther- vation post-treatment, with frequency of tumor- apy to the brain [Davies et  al. 2014]. Another infiltrating CD8+ T cells and levels of interferon-γ study, coBRIM-B, is focusing on vemurafenib increased post-treatment. For the 26 BRAF and cobimetinib therapy in patients with active mutated advanced melanoma patients treated melanoma brain metastases with the primary with the triple combination, an ORR of 69% was objective of determining the objective intracranial obtained and 16 out of 18 patients have ongoing response rate [Yee et al. 2015]. responses. There was no exacerbation of immune- related AEs. While an ORR of 69% does not appear to be higher than the ORR of BRAF and Conclusion MEK inhibitor combinations alone, some of the In comparison with single agent BRAF inhibitors, responses may not have declared yet during the the combination of BRAF and MEK inhibitors short follow up presented for this study; more have shown significant improvement in response http://tam.sagepub.com 53 Therapeutic Advances in Medical Oncology 8(1) rates, PFS and OS in addition to fewer side effects Funding related to paradoxical activation of the MAPK The author(s) received no financial support for pathway; the combination has now become the the research, authorship, and/or publication of standard of care in patients with BRAFV600 this article. mutated advanced melanoma for whom targeted therapy is used. While there has not yet been Conflict of interest statement direct comparison of the three different BRAF– The author(s) declared the following potential MEK inhibitor combinations in clinical trials, conflicts of interest with respect to the research, they have shown similar clinical efficacy. There authorship, and/or publication of this article: are some differences in the toxicity profiles of the A.R.: consultant or advisory role with Merck combinations, such as much more frequent Sharp & Dohme Corp., Amgen, Astellas, Daiichi- pyrexia with dabrafenib and trametinib compared Sankyo, GlaxoSmithKline, Genentech-Roche, with vemurafenib/cobimetinib and encorafenib/ Novartis, Pierre Fabre; DSMB member for binimetinib, and vice versa with photosensitivity MedImmune/AstraZeneca and Novartis; stock much more common with vemurafenib/cobi- or ownership interests from Kite Pharma, metinib; hepatic enzyme elevations were reported Compugen. 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J Clin SAGE journals in patients treated for brain metastatic BRAF-V600 Oncol 33: TPS9088. 56 http://tam.sagepub.com

Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 18, 2015

Keywords: BRAF inhibitors; MEK inhibitors; melanoma

References