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Upstream mitogen-activated protein kinase (MAPK) pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients

European Journal of Cancer

Abstract

BRAF-mutant melanoma can be successfully treated by BRAF kinase inhibitors (BRAFi) and MEK kinase inhibitors (MEKi). However, the administration of BRAFi followed by MEKi did not generate promising response rate (RR). The purpose of this investigation was to evaluate the time to progression (TTP) with a mitogen-activated protein kinase (MAPK) pathway upstream inhibition strategy in BRAF mutated melanoma patients.

BRAF mutation positive metastatic melanoma patients were identified within the Dermatology Cooperative Oncology Group (DeCOG) network and were treated first with a MEKi and upon progression with a selective BRAFi.

A total of 23 melanoma patients (six females, 17 males, aged 47–80 years) were retrospectively analysed for TTP. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2–23.2) and subsequent for BRAFi 4.5 (1.2–15.7) months, respectively. A higher RR for MEKi (39%, nine partial responses and 0 complete responses) than previously reported was observed.

Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in BRAF mutated melanoma. The median TTP (8.9 months) is close to the promising BRAF- and MEKi combination therapy (median progression-free survival (PFS) 9.4 months). The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi. This approach is feasible with reasonable tolerability. This clinical investigation encourages further studies in prospective clinical trials to define the optimal treatment schedule for the MAPK pathway inhibition and should be accompanied by molecular monitoring using repeated biopsies.

Keywords: BRAF inhibitor, MEK inhibitor, Melanoma, MAPK pathway, Upstream inhibition, Downstream inhibition, Sequenced administration.

1. Introduction

Melanoma is a common and aggressive skin cancer which often represents a challenge for surgeons, oncologists and dermatooncologists.

There is a plethora of oncogenic events including activating mutations and loss of cell cycle control mechanism that contributes to increased proliferation, resistance to apoptosis and metastatic spread [1] .

The mitogen-activated protein kinase (MAPK) pathway is a key regulator for proliferation, expression of genes that drive melanocytic gene differentiation such as MITF, cell survival by suppressing apoptotic pathways and plays an important role in oncogenic signalling in the majority of the patients with melanoma [2] . It consists of serine/threonine-specific kinases including RAS (rat sarcoma), RAF (rapidly accelerated fibrosarcoma), MEK (mitogen-activated protein kinase kinase) and ERK (extracellular signal-related kinase).

These kinases have received considerable scientific attention, in particular RAF and MEK [3], [4], and [5]. In these, BRAF, one member of the RAF kinase family, can present a mutation in codon V600, previously called V599 [6] . The presence of activating BRAF mutations in about 50% of all melanomas has provided new successful therapeutic opportunities [7] . In vitro studies have shown that MEK inhibitors (MEKi) suppress the growth of most BRAF mutated, some NRAS mutated melanoma cell lines, but do not affect the growth of NRAS–BRAF wildtype (wt) cells [4] .

Hence, this led to the development of selective inhibitors targeting the RAF and MEK kinases for the melanoma patients harbouring BRAF mutations [5] and [8]. In particular, the selective BRAF inhibitor (BRAFi) vemurafenib has led to improved overall survival in these melanoma patients and was FDA (Food and Drug Administration) approved in August 2011 [9] . Dabrafenib and LGX818 are also highly specific and potent BRAFi which are improving the standard of care of melanoma patients [10] and [11]. In addition, MEK-targeted inhibition increases apoptosis in NRAS- and BRAF-mutant melanoma [12] and is clinically active in BRAFi-naïve patients previously treated with chemotherapy and/or immunotherapy as well as in patients previously treated with a BRAFi [13] . MEK is the downstream effector of BRAF. The optimal blockage of the MAPK pathway with BRAFi and MEKi is yet to be determined, in particular because of the limited duration of benefit of the treatment due to the development of resistance mechanisms [14] and [15].

Tumour resistance evolves in most patients. This treatment failure is associated with a reconstitution of phosphorylated MEK and ERK (downstream targets of BRAF) as Trunzer et al. have demonstrated [16] . One therapeutic option is the combination of selective BRAF blockade and MEKi which demonstrated first promising activity [17] . An alternative logical consequence of this observation would be the blockade of MEK1/2 with selected inhibitors such as trametinib, selumetinib or MEK 162 [18], [19], and [20]. However, the administration of BRAFi followed by MEKi did not generate promising response rates [18] . An upstream inhibition in which melanoma treatment is initiated with a MEKi followed by a BRAFi has not yet been clinically explored.

In this paper we retrospectively analysed the outcome of the inverse sequential therapy (MEKi followed by BRAFi in case of progression) and observed surprisingly long disease control rates [21] .

2. Patients and methods

2.1. Patient selection

Patients with BRAF V600 mutation positive metastatic melanoma were identified within the network of Dermatology Cooperative Oncology Group (DeCOG) centres who participated in MEKi trials. Patients who were treated first with a MEKi inside various clinical trials [22] and [23] and who upon progression received a selective BRAFi were selected from hospital trial data bases. Data were retrospectively analysed for survival. All patients gave their informed consent before treatment initiation.

2.2. Medication

Eligible patients with BRAF-mutant melanoma received one of the following MEKi: selumetinib (100 mg twice daily (bid)) (AZD6244) (n = 1); trametinib (2 mg once daily (qd)) (GSK1120212, recently approved as Mekinist® by the FDA) (n = 15); or MEK 162 (45 mg bid) (ARRY-438162) (n = 7). After progression patients were treated with vemurafenib 960 mg bid (approved as Zelboraf®) (n = 22), dabrafenib 300 mg bid (FDA-approved as Tafinlar®) (n = 1) and/or LGX 818 45 mg qd (n = 1). The treatment was administered regularly according the study protocols or package insert and its efficacy was evaluated radiologically using response evaluation criteria in solid tumours (RECIST-criteria) 1.1 [24] and/or clinically based on investigator’s judgment.

Time to progression (TTP) was defined as the interval between the initiation of treatment and treatment discontinuation due to disease progression or toxicity and was determined in months (rounded up to a decimal). The median TTP of this cohort was evaluated and compared to the available phase II data that show progression-free survival (PFS) when MAPK inhibition is initiated with a BRAFi followed by a MEKi.

3. Results

A total of 23 melanoma patients (six females, 17 males, aged 47–80 years) harbouring a BRAF mutation were identified within six centres of the DeCOG network and evaluated. The total median TTP was 8.9 months. The median TTP for MEKi was 4.8 (1.2–23.2) and subsequent for BRAFi 4.5 (1.2–15.7) months, respectively ( Table 1 ). There was no apparent change in the previously described tolerability during BRAFi therapy after MEKi treatment. In addition, a higher response rate for MEKi (39%, nine partial responses and 0 complete responses) than previously reported [18] was observed.

Table 1 Time to progression (TTP): 23 advanced BRAF mutated melanoma patients were treated with selective BRAF kinase inhibitors (BRAFi) after mitogen-activated protein kinase kinase inhibitors (MEKi) progression. TTP is defined as the interval in months between the initiation of treatment and treatment discontinuation due to disease progression or toxicity. The median TTP for MEKi was 4.8 months (red) and for BRAFi 4.5 months (blue), respectively. 9/23 patients experienced partial response (PR) under the treatment with a selective MEKi. 10/23 patients showed PR when treated with a selective BRAFi after disease progression or toxicity with MEKi. In total, 5/23 patients had PR with both kinase inhibitors.

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Most patients died after progression upon MAPK inhibition, but a few exceptions were observed. Four patients were treated with immunotherapy (all progressive disease) and four other patients had chemotherapy (two with partial response) after progression upon MAPK pathway inhibition.

4. Discussion

The purpose of this investigation was to evaluate the time to progression with a MAPK pathway upstream inhibition treatment strategy in advanced melanoma patients.

Clinical studies investigating selective BRAFi as first-line treatment report a median progression-free survival (PFS) of 5.3 months for vemurafenib in 275 patients and 5.1 months for dabrafenib in 187 patients [9] and [25], respectively. These results led to FDA approval of the two compounds. Some patients received MEKi after BRAF progression. Ascierto et al. and Kim et al. reported a PFS of 1.7 and 1.8 months in BRAF progressors, respectively [20] and [26].

We were interested in investigating the TTP of BRAFi after MEKi failure. We did not use PFS, as the retrospective analysis setting would have led to inaccurate data. However TTP, defined as the interval between the initiation of treatment and treatment discontinuation due to disease progression or toxicity can approximately be compared to PFS that describes the length of time during and after treatment during which the disease being treated does not get worse. TTP is therefore a time period of PFS, as in TTP the time after treatment discontinuation is not considered.

Our analysis suggests that the reversed inhibition of the MAPK pathway is feasible in melanoma patients harbouring a V600 BRAF mutation. The median TTP (8.9 months) is close to the promising clinical phase II BRAFi and MEKi combination therapy (median PFS 9.4 months) [17] . Certainly, the combination therapy has an encouraging tolerability with e.g. less neoplastic cutaneous eruptions. However, there are real life situations where an oncologist has to decide for a single agent therapy because of various reasons including potential reimbursement limitations.

The total treatment duration of the MAPK inhibition when a MEKi is administered first is similar compared to the reversed sequence, but TTP shifts in favour to the MEKi [21] .

Our data indicate that a MEKi–BRAFi sequence is promising. This approach is feasible and has reasonable tolerability. Furthermore, the TTP seems to favour this order when compared to the reversed sequence (median PFS 5.3 months for BRAFi first-line [9] and median PFS 1.8 months for MEKi that were pretreated with a BRAFi [26] ). Besides the sequenced administration analysed here, an intermittent administration should be investigated [15] and [27]. This might point out that the resistance mechanisms upon RAF and MEK are different. Furthermore, we observed in the analysed cohort some benefit using chemotherapy after BRAF- and MEK-inhibition progression. This indicates that chemotherapy has still a role in the melanoma treatment and is not to be completely abolished. Limitations of the current report certainly are the retrospective analysis setting and the small cohort number. However, it seems important to be aware that the treatment strategy in BRAF mutated melanoma should be optimised. This clinical investigation encourages further studies in prospective clinical trial settings to define the optimal treatment schedule for the MAPK pathway inhibition that should be accompanied with a molecular monitoring of using repeated biopsies as reported by McArthur et al. [28] .

Conflict of interest statement

 

  • Dr. Goldinger reports personal fees and non-financial support from Bristol-Myers Squibb, outside the submitted work.
  • Dr. Zimmer reports personal fees and other from Bristol-Myers Squibb, personal fees and other from Roche, personal fees from Amgen, personal fees from Boehringer Ingelheim, other from Merck Sharp & Dohme, outside the submitted work.
  • Dr. Schulz has nothing to disclose.
  • Dr. Ugurel has nothing to disclose.
  • Dr. Hoeller has nothing to disclose.
  • Dr. Kähler has nothing to disclose.
  • Dr. Schadendorf reports personal fees and other from Bristol-Myers Squibb, personal fees and other from Roche, grants and other from Merck Sharp & Dhome, personal fees and other from GSK, personal fees and other from Novartis, personal fees and other from Amgen, personal fees and other from Delcath, outside the submitted work.
  • Dr. Hassel has nothing to disclose.
  • Dr. Becker reports personal fees from GSK, personal fees from Roche outside the submitted work.
  • Dr. Hauschild reports personal fees and other from Roche, personal fees and other from GSK, personal fees and other from Novartis, outside the submitted work.
  • Dr. Dummer reports grants from Astra Zeneca, Novartis, Cephalon, MSD, Transgene, BMS, Roche, GSK, Bayer, grants and personal fees from Astra Zeneca, Novartis, Cephalon, MSD, Transgene, Genta, Bayer, BMS, Roche, GSK, Spirig, outside the submitted work.

Acknowledgement

None.

References

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Footnotes

a Department of Dermatology, University Hospital Zürich, Gloriastrasse 31, 8091 Zürich, Switzerland

b Department of Dermatology, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany

c Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, 69120 Heidelberg, Germany

d Department of Dermatology, University Hospital Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany

e Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria

f Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstrasse 7, 24105 Kiel, Germany

g Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, 8036 Graz, Austria

lowast Corresponding author: Tel.: +41 44 255 25 07; fax: +41 44 255 11 90.

Partially presented at ASCO Annual Meeting 2013.