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Exclusion criteria vs reality: dual BRAF/MEK inhibition and radiotherapy in a patient with melanoma metastatic to the brain and ECOG 3

Abstract

Background

Prognosis of metastatic melanoma is changing due to advances in immunotherapy and targeted therapy. However, management of patients with brain metastases in day-to-day practice continues to be a challenge.

Case report

We describe a 40-year-old woman diagnosed with symptomatic brain metastases from cutaneous melanoma and Eastern Cooperative Oncology Group 3. She was treated, off label, with BRAF inhibitor (dabrafenib) + MEK inhibitor (trametinib) and radiotherapy. There was significant, long-lasting, response (17 months), no clinically relevant toxicity, and clear improvement in quality of life.

Conclusions

This case is an example of real-life application of advances in targeted therapy.

Tumori 2016; 102(Suppl. 2): e54 - e56

Article Type: CASE REPORT

DOI:10.5301/tj.5000408

Authors

Iván Márquez-Rodas, Jose-Antonio Avilés-Izquierdo, Verónica Parra, Ana Álvarez-González, Pedro Borrego, Pilar Fernández-García, Juan-Adan Guzmán-de-Villoria, Yolanda Jerez, Miguel Martin

Article History

Disclosures

Financial support: The study was funded by Fondo de Investigaciones Sanitarias grant (FIS) PI13/01454.
Conflict of interest: None.

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Introduction

The prognosis of metastatic melanoma has been changing since 2010, when breakthrough biological therapies entered the melanoma landscape, as demonstrated by recent phase III clinical trials. However, most clinical trials with these new treatments exclude patients with active brain metastases, despite melanoma being one of the tumors that metastasize to the brain with the highest frequency (1). The same happens to patients with Eastern Cooperative Oncology Group (ECOG) >1. Therefore, outside of specific clinical trials, implementation of the new therapies for this clinical condition is a challenge in day-to-day practice. Melanoma with brain metastases represents an unmet medical need, although melanoma may be the solid tumor with the most paradigm-changing advances in the past 5 years.

We present a case report of a 40-year-old woman with symptomatic brain metastases from a BRAF mutant melanoma and ECOG 3, successfully treated with dual BRAF/MEK inhibition and whole-brain radiotherapy (WBRT). We highlight that limiting our practice to what is described in clinical trials is often outside the real-world scenario.

Case report

The patient was diagnosed in April 2009 with cutaneous melanoma in the right arm (stage T3aN2aM0), treated with surgery and adjuvant high-dose α2b interferon for 1 year. In July 2013, the patient presented with left gluteal and thigh pain. An MRI revealed a 42-mm mass in the left sacrum wing, confirmed as metastatic melanoma, with BRAF V600E mutation.

The patient was referred to our Medical Oncology service in August 2013 to evaluate treatment alternatives. On arrival at our hospital, the patient had an ECOG 0, and no symptoms, but mild pain in the metastatic site, which was controlled with nonopioid analgesics. On physical examination, pathologic lymph nodes in left axilla, right cervical, and submammary subcutaneous metastases were detected. No significant abnormalities (including lactate dehydrogenase [LDH]) were present in the blood analysis.

With the diagnosis of a stage IV (M1c) melanoma, the patient was invited to participate in a clinical trial involving immune-checkpoint inhibitors, reserving the possibility of BRAF inhibitors to treat any eventual disease progression.

During screening, multiple, bilateral brain metastases were detected in the computed tomography (CT) scan, the largest being in the left cingulate cortex (28 × 26 mm) (Fig. 1A). Lymphadenopathies in both axillar regions, mediastinum, and extra-abdominal subcutaneous metastases, and a lytic metastasis in left iliac bone, were detected in the rest of the body. No other visceral or lung metastases were detected. A deep venous thrombosis was diagnosed in the common iliac and the left hypogastric veins. Due to the brain metastases, the patient was withdrawn from the clinical trial and rescheduled for outpatient treatment. Following discussions of risk/benefits of anticoagulation to prevent pulmonary embolism, ambulatory anticoagulation with low molecular weight heparin was initiated. Before any treatment of the melanoma could be implemented, the patient presented to the emergency department with gait instability, dizziness, right hemiparesis, and a simple motor seizure. The brain CT scan revealed that the left cingulated metastasis had grown to 42 × 33 mm in diameter, with radiologic signs of bleeding and perilesional edema (Fig. 1B). The LDH at this time was 302 IU/L (laboratory upper limit: 200).

Imaging of melanoma brain metastases. (A) Postcontrast computed tomography (CT) performed in August 2013 shows brain metastases centered in the cingulate cortex of the left frontal lobe surrounded by vasogenic edema (white arrow) and the right caudate head (yellow arrow). (B) Enlargement of both metastatic sites was demonstrated on postcontrast CT performed 1 week later. (C) Axial T1-weighted postgadolinium MRI performed in January 2014 (3 months after treatment) shows improvement due to the decreased size of both brain metastases. (D) This tendency to improvement was confirmed on magnetic resonance imaging, performed 17 months after treatment was started.

The patient was admitted and treated, initially, with high-dose steroids and inferior vena cava filter to prevent pulmonary embolism; anticoagulation was withdrawn. An ECOG 3 level due to hemiparesis was recorded at this time.

Since the combination of dabrafenib and trametinib were available for use on compassionate grounds, we decided to treat the patient with this combination. Because of the patient’s symptoms, and since a minimum of 1 week was necessary to solicit approval for this nonlabel treatment, we proceeded with WBRT with standard dose (30 Gy in 10 fractions). The patient began oral dabrafenib (150 mg/12 h) and trametinib (2 mg/24 h) a week after WBRT started. No toxicity was noted. Patient ECOG improved to 2, with an improvement in hemiparesis that allowed her to walk with help. We decided to continue the outpatient treatment, with close monitoring.

The patient continued treatment with dabrafenib and trametinib without relevant toxicity, and continued improving, walking without help, and had almost complete remission of hemiparesis; ECOG was 1 at the first follow-up visit (October 2014). Cervical and axillar lymph node metastases were not palpable in the physical examination.

In January 2014, brain magnetic resonance imaging (MRI) and a body CT scan were performed. The results revealed a major partial response of brain metastases (Fig. 1C) as well as axillar, mediastinum, and bone lesions. The patient continued treatment, with almost no toxicity (one grade I pyrexia episode, one grade I episode of transaminase elevation). The last evaluation was in February 2015, which confirmed a substantial and maintained response in the brain metastases (Fig. 1D), but progressive disease in the rest of the body (ganglionar, peritoneal, and intramuscular in left gluteus). Total duration of the response was 17 months. However, the patient’s ECOG was still 0, and therefore she was referred to another center in order to participate in a clinical trial involving immunotherapy. In April 2015, brain MRI was performed, which showed new right frontal brain metastases (images not shown), the rest of the lesions being stable. Extracranial disease remained stable, and the patient continued with immunotherapy outside our institution. The patient is alive and has good performance at the time of this writing.

Discussion

A combination of BRAF and MEK inhibition has demonstrated improvement in survival in metastatic BRAF mutant melanoma in 3 recent phase III clinical trials when compared to BRAF inhibition alone (2, 3), but at the time of patient treatment, no evidence of improved survival with these combinations was communicated. Before our patient was diagnosed with brain metastases, we initially offered a clinical trial involving immune-checkpoint inhibitors, instead of BRAF inhibitors, for the following reasons: the tumor burden was not high; the patient’s ECOG was 0; and plasma LDH was within the laboratory reference range. Hence, reserving BRAF inhibition to treat disease progression was considered an appropriate option. In addition, at the time of first evaluation of the patient (August 2013), there had been some evidence that the sequence of immune-checkpoint inhibition followed by BRAF inhibition could be an even better option than the reverse sequence for patients with BRAF mutation, especially for those with low tumor burden (4).

When brain metastases were diagnosed, neither vemurafenib nor dabrafenib was fully accessible in Spain for patients with melanoma and brain metastases. Since compassionate use was available for the dabrafenib and trametinib combination, we decided to treat the patient with this regimen.

No evidence supported this treatment decision at that time. This combination had not been explored for patients with symptomatic brain metastases without previous treatment, and ECOG >2, since these patients were excluded from these studies and usually from most clinical trials. Recently, a clinical trial was begun to explore the efficacy of dabrafenib and trametinib in previously treated (surgery and/or radiotherapy) and nontreated patients with melanoma and brain metastases, but this was not available at the time (recruitment commenced in February 2014) (5).

With respect to ECOG, phase III clinical trials with vemurafenib, dabrafenib, and its combination excluded patients with ECOG >1 (2, 3, 6, 7). The same applied to phase II clinical trials of vemurafenib (8) and dabrafenib (9) in patients with brain metastases. The ongoing phase II clinical trial for brain metastases excludes patients with ECOG >2 (5). As such, the present case also would have been excluded for this reason even if clinical trials would have been available.

Finally, although WBRT may produce clinical response, and frequently palliates symptoms, it is unlikely to eradicate brain metastases. A median overall survival of 2-4 months has been described for patients receiving radiotherapy alone (10). In our case, we decided to commence with this treatment to offer some treatment while our request for compassionate use of dabrafenib and trametinib was being considered. This treatment option became available 7 days later. The good outcomes we observed could be a synergistic effect of both treatments. Indeed, this synergy is being explored in some clinical trials with BRAF inhibitors + WBRT (11).

The present case provides insight into management of ­patients who have an extremely poor prognosis if not treated.

Acknowledgment

Editorial assistance was provided by Peter R. Turner of Tscimed.com.

Disclosures

Financial support: The study was funded by Fondo de Investigaciones Sanitarias grant (FIS) PI13/01454.
Conflict of interest: None.
References
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Authors

Affiliations

  • The Service of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid - Spain
  • The Service of Dermatology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid - Spain
  • The Service of Anatomo-Pathology, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid - Spain
  • The Service of Oncology-Radiotherapy, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid - Spain
  • The Service of Radio-diagnostics, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid - Spain

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