FormalPara Key Summary Points

BRAFV600E is the most common genetic mutation in melanoma, and its early identification is essential for disease management, so that targeted therapy can be implemented and overall survival improved.

This article gives clinicians a unique insight into a patient’s perspective of living with BRAFV600E metastatic melanoma, enriched by details of his treatment experience, which has lasted for over 10 years.

The patient’s oncologist adds his clinical perspective to this story and describes how the therapeutic partnership that evolved between him and his patient enabled them to balance acceptable adverse effects against treatment efficacy.

This partnership encouraged the patient to stay on treatment, enjoy a good quality of life, care for his family, and ultimately enter complete remission.

This personal account enriches the treatment landscape for BRAFV600E-mutant metastatic melanoma and will not only help other patients and physicians plan for appropriate treatment, but also improve our understanding of how to cope with treatment-related adverse effects and to remain on treatment.

Introduction

This article was co-authored by Mr. Carsten Finke, a patient diagnosed with BRAFV600E metastatic melanoma, and his treating oncologist, Dr. med. Peter Mohr, Head of the Skin Cancer Unit at the Clinic of Dermatology and Oncology in Buxtehude, Germany.

Cutaneous melanoma poses a significant threat as the most lethal type of skin cancer, primarily due to its elevated tendency to metastasise. Although most primary melanomas can be cured with surgical intervention, the risk of spreading to other areas in the body is high. After spreading, melanoma is much more difficult to treat [1]. BRAFV600E is the most common genetic mutation in melanoma, appearing in almost half of cutaneous melanomas [2]. Early identification of the BRAFV600E mutation is essential for disease management, so that targeted therapy can be implemented and overall survival improved [3].

Until recently, the therapeutic approach for advanced and metastatic melanomas was predominantly palliative, with a median survival ranging from 6 to 12 months [4]. Encouragingly, the emergence of immunotherapy and molecular targeted therapy over the last decade has transformed the prognosis of patients with metastatic melanoma [5]. Nowadays, 1 in 2 patients with metastatic melanoma are alive 5 years after diagnosis when treated with combination immunotherapy [6] which has markedly prolonged the survival of patients treated with combination BRAF/MEK targeted therapy [7] or monotherapy with a programmed death-1 (PD-1) inhibitor [8]. Combination BRAF/MEK inhibitor therapy is now a standard of care in the treatment of metastatic BRAFV600E-mutated melanoma [9].

This article gives a unique insight into the treatment experience of an individual patient who has lived with BRAFV600E metastatic melanoma for over 10 years. His narrative is enriched by the clinical perspective of his treating oncologist, who has closely collaborated with the patient from the beginning of his treatment journey. Together, the patient and oncologist discuss the therapeutic successes and challenges that have arisen during this journey. The article ends with an evaluation of current treatments and future therapeutic approaches.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Carsten Finke provided written informed consent for identifying his personal data in this case report.

Case Presentation

Carsten: I am a 55-year-old man residing in Bremen, Germany, working in a manual profession. I live with my wife and we have a 10-year-old daughter. I first noticed an uncomfortable itchy mole on my right shoulder blade in 2009. I was worried about it and so I consulted a dermatologist in Bremen. The dermatologist sent me for a biopsy at the Bremen hospital, and the results of the analysis came back with the diagnosis of melanoma. The melanoma was removed surgically at the hospital in Bremen in January 2010. I was told that the operation was successful, and that the prognosis was good. I was advised to undergo regular examinations with my dermatologist, just as a check-up. I felt quite relieved and was not worried about any further developments.

Dr. Mohr: The treatment received at the time was in perfect adherence with the guidelines for the management of melanoma [3]. A 1-cm-deep excision was made, and the local dermatologist conducted the postoperative follow-up. In this particular case, I would have considered a cure rate for Carsten of 95–98% [10].

Carsten: Three years later, in 2013, I noticed a bulging of the skin on the left side of my groin that appeared when I stood up. As I had undergone an inguinal hernia in 2010, I went back to my orthopaedic specialist to investigate. At the time, I really thought I had a hernia again, and the idea of this being related to skin cancer did not occur to me, especially given the physical distance from the primary melanoma, which had been on the right shoulder blade.

Of course, the orthopaedic specialist found no damage to the groin, and sent me for further examinations in the hospital in Bremen. Ultrasound examination revealed an enlarged lymph node in the left groin, confirmed as a metastasis from the primary melanoma on my right shoulder; it was only then that I realised the gravity of the diagnosis.

I felt very alone with this diagnosis at the time, and rather desperate. The next meeting with the medical team was planned several weeks later, while what I really needed was a comprehensive consultation with an oncologist as soon as possible, to obtain answers to my questions, clear solutions, and a treatment plan. The emotional difficulty of the diagnosis was exacerbated by the fact that my wife was pregnant with our first child, and I felt terrified about a negative prognosis and the impact of treatment on me and my family. My wife practices alternative medicine and was a great support in finding a specialised dermatological oncology clinic for my therapy. I wanted to start treatment as quickly as possible, reasoning that this was crucial to combat the progression of metastatic melanoma.

Dr. Mohr: I initially met Carsten in my clinic in Buxtehude in April 2013, just over 10 years ago. I would like to comment on Carsten’s initial reaction of associating the new lump with a previous condition of his inguinal hernia. This is perfectly normal and something we see quite often.

In our first meeting, Carsten decided that I would be his treating doctor. My first reaction was to arrange for an immediate removal of lymph nodes in the inguinal region. I would have preferred to do surgery within 2 weeks after our first meeting, but Carsten wanted to postpone the procedure so that he could be present at the birth of his daughter.

In late May 2013, we removed 6 lymph nodes, 2 of which were metastases. We were working according to guideline recommendations and removed all visible lymph nodes during the intervention [3]. Postoperative radiotherapy was scheduled to prevent lymph node recurrence, which has around a 50% probability of occurring [11]. The radiotherapy began in July 2013 at the hospital in Bremen and was planned to continue until the end of September. We also scheduled follow-up appointments every 3 months in the Buxtehude clinic to monitor the course of disease. An efficient adjuvant therapy for Carsten's situation was not available in 2013. After about 8 weeks, the radiotherapy had induced skin reactions and Carsten was having difficulty swallowing; he was severely fatigued and there were bulges appearing in his neck. As he was feeling worse and worse each day, he asked for an earlier appointment in Buxtehude (early October).

At this point, I performed extensive staging, including computed tomography (CT) and magnetic resonance imaging (MRI) scans of the head [12] and abdominal region [13], and we identified lymph node metastasis at various body locations, but fortunately no organ involvement. Enlarged lymph nodes were diagnosed near the trachea, in the stomach and neck area, the para-aortic region, and repeated groin involvement. This kind of accelerated disease course occurring within 16 weeks postoperatively is not very common and indicated rapidly progressive organ metastases.

As dabrafenib, a BRAF inhibitor, had been available as monotherapy for stage IV BRAF-positive melanoma since late summer 2013, I undertook polymerase chain reaction genetic testing [14], which revealed BRAF mutations in the primary tumour and the lymph node metastases. The only other therapeutic option was chemotherapy, which has a very poor outcome for first-line stage IV melanoma. The accelerated disease progression and stage IV status with distant metastases mandated swift action.

I like to keep myself updated on ongoing studies through conferences and regular communication with colleagues in dermatological oncology in Germany, Austria, and Switzerland. PD-1 inhibitors such as pembrolizumab [15,16,17], and nivolumab [18, 19] were not yet approved, but had already shown promising results with low adverse effects, particularly in patients with melanoma with lymphatic metastases and no organ metastases. There was even talk of a revolution in cancer therapy [20]. I therefore proposed to include Carsten in a study involving PD-1 inhibitors and patients with BRAF gene mutations.

Carsten: After a discussion with Dr. Mohr, who explained the situation to me, I agreed to enter the trial and commence nivolumab in early November 2013. The treatment was given as 3 mg/kg intravenous (IV) 60-min infusions every 2 weeks. Initially, the treatment led to stabilisation or even reduction in lymph node growth, and I started to feel better. It was easier for me to swallow, and the swollen lymph nodes subsided slightly. However, it only lasted about 6 months and, in April 2014, there was renewed growth of lymph nodes, especially the one near the trachea. I also experienced an adverse effect of nivolumab, which was a skin reaction, with psoriasis affecting my entire body. I was given phototherapy to alleviate the adverse effects [21].

Dr. Mohr: This renewed lymph node growth was an unexpected development. Patients who respond to PD-1 inhibitors usually profit from the therapy for a prolonged period of time, with a median response of 2 years [8, 22].

We needed to consider alternative solutions or trials. I proposed the COLUMBUS trial, the first study of a BRAF/MEK inhibitor combination therapy (encorafenib and binimetinib) for BRAFV600-mutated stage IV melanoma [23,24,25]. BRAF inhibitors target the mitogen-activated protein kinase (MAPK) signalling pathway, and thus hinder the uncontrolled division of melanoma cells by kinase inhibition [26]. Subsequently, the results from part 2 of the COLUMBUS trial have shown that combining a BRAF inhibitor with a MEK inhibitor blocks the MAPK pathway more efficiently than single-agent BRAF inhibitor therapy, and not only improves progression-free survival (PFS) and overall survival (OS) but also mitigates BRAF inhibitor-associated toxicity, enabling patients to receive a higher dose of encorafenib compared with single-agent encorafenib [26, 27]. In part 1 of the COLUMBUS trial, patients were randomised to BRAF inhibitor monotherapy with either encorafenib or vemurafenib, or encorafenib combined with the MEK inhibitor binimetinib [23]. After accepting and entering part 1 of the COLUMBUS trial in May 2014, Carsten was randomly allocated to oral monotherapy with encorafenib 300 mg/day. Although we were both blinded to treatment allocation, I suspected he was in the monotherapy group quite early on, as he had pronounced hand–foot syndrome, which is more frequent on encorafenib monotherapy.

Carsten: The adverse effects started just 3 h after the initial intake of the study drug. I had pain in my feet that prevented me from walking even small distances. I also had intensely painful photosensitivity: my skin hurt and felt as if it was burning, which made wearing clothes unbearable and it was even difficult to sleep. After 2 weeks in the trial, I called Dr Mohr and asked him if I could leave the study as the adverse effects were unbearable. With these adverse effects, life was not worth living for me.

Dr. Mohr: The study protocol allowed for a dose reduction, and so I managed to convince Carsten to carry on at a lower dose, with 4 tablets (200 mg/day) instead of 6 (300 mg/day); two-thirds of the original dose. Even this dose was unbearable, and Carsten was back in my office 2 weeks later saying he wanted to be able to resume a normal daily life. We further reduced the dose to 2 tablets daily (100 mg/day), one-third of the initially planned dosage [23].

The severe skin reaction that Carsten suffered was unpredictable. The primary issue was the pain in his feet, due to the formation of thick calloused layers which partially cracked, causing intense pain and making movement nearly impossible. Treating the feet via a podiatrist was not a long-term solution, as it only provided temporary relief. Moreover, it was not reimbursed by health insurance in Germany at the time and would have been a financial burden.

Carsten: At the new lower dosage, I could endure the treatment and I managed to continue with the therapy. Normal social life and meetings with friends were almost impossible for me, although I did manage to work, with reduced hours. I was glad that my boss was understanding and allowed me to adjust my working hours. On the other hand, the results of the therapy were indeed very positive and encouraging! The study administrators could see the reduction in the size of the lymph nodes at the first examination after the administration of the study drug.

Dr. Mohr: Carsten stayed on the lower dose of encorafenib for 4 years until 2018 as part of the study. He visited the clinic in Buxtehude monthly at the beginning of the study for blood tests, electrocardiograms and eye examinations, and regularly for CT and MRI scans. He also filled out a questionnaire at regular intervals in the clinic regarding his physical and mental well-being. This was part of the study, but all our oncology patients are closely monitored so that we can quickly respond to any potential adverse effects. Since we noticed that Carsten was well-adjusted to the medication, we reduced the frequency of his visits to once every 4 months. He responded exceptionally well to the treatment, and clinical examination showed a large reduction in size and number of the metastases with encorafenib, followed by stabilisation.

I recall seeing Carsten in the corridor of the clinic one day and I was delighted to see that he had developed vitiligo on his skin. For me, this was positive evidence of the effectiveness of the encorafenib therapy. It is a sign of an immunological reaction where the body's defence cells dissolve the melanocytes [28].

Carsten: At that time, I avoided the support groups and patient information. Personally, I found the group discussions about adverse effects and tumours more of a burden than a help. However, I was interested in learning about new medications and clinical trials; I often asked the nurses about these aspects when I went into the clinic, to stay updated.

Dr. Mohr: Yes, there was a change in 2018, when the combination therapy of encorafenib with binimetinib was approved in Europe. I asked the trial managers to unblind Carsten’s treatment allocation and we finally got confirmation that he was indeed on monotherapy with encorafenib. Together, we took the decision to stop the monotherapy and switch to the combination therapy, which we hoped would be better tolerated. I decided to keep the same dosage of encorafenib with 100 mg/day and add in a reduced dose of binimetinib at 30 mg/day (2 tablets). This differs from the recommended dose of encorafenib (450 mg/day) in combination with binimetinib (45 mg/day) for BRAFV600E-mutated metastatic melanoma [29, 30].

Carsten: You can imagine that I was quite nervous about leaving the study! I was used to being so intensively cared for by Dr. Mohr and his team, including three assistants in the clinic. Dr. Mohr used to organise weekly team meetings lasting 2 or 3 h to discuss all patient records, and so all team members were always up-to-date on the current status of my treatment. I was afraid of getting less attention, but my fears were unfounded. I really had nothing to worry about.

Dr. Mohr: Once we had initiated the combination therapy, the adverse effects almost simultaneously disappeared, allowing Carsten to regain a good quality of life and return to full-time employment. In a follow-up examination in 2020, we were able to confirm a further reduction of lymph node metastases and the complete disappearance of the previously larger pretracheal lymph node metastasis.

Around this time, Carsten volunteered to participate in the COLUMBUS rollover study [25, 31]. This was an observational study of patients from the original trial undergoing long-term therapy. It did not require a specific therapy regimen, and so we were happy for him to do so, as he could maintain his treatment [25, 31]. The trial confirmed what we saw with Carsten: long-term follow-up showed no new safety concerns, and the results were consistent with the known tolerability profile of encorafenib plus binimetinib. The study showed that median PFS was prolonged in patients with BRAFV600E−mutated advanced melanoma given the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib and the combination achieved a better 7-year PFS rate than encorafenib alone (21.2 vs 15.8 months; the data are currently only available as a conference abstract) [32].

At the present time, Carsten is in complete remission. Statistically, the combination therapy of encorafenib with binimetinib achieves good effectiveness in almost all patients, with confirmed response rates from part 2 of the COLUMBUS trial of 67.8% for overall response (i.e. complete response plus partial response), 22.9% for disease stabilisation, and 9.3% for progressive disease [27], but eventually leads to treatment resistance in many cases [33]. Notably, the treatment response rates from part 2 of COLUMBUS were observed at median durations of follow-up of 57.1 months for PFS and of 67.6 months for OS, which suggests that some patients treated with BRAF/MEK inhibitor combination therapy may remain progression-free for many years [27], as with Carsten’s experience.

Carsten: After discussing the situation with Dr. Mohr, my decision was the same at every visit: to continue the therapy at the same dose of encorafenib with binimetinib. I understand that there may still be a 50% risk of recurrence if I discontinue therapy and that is unthinkable for me after all I have been through.

During the last almost 10 years, I have been subjected to different treatments [surgery, PD-1 inhibitors, encorafenib monotherapy, and finally encorafenib (morning) combined with binimetinib (morning and evening)], which has given me a good quality of life. I am able to work full-time in my job. I still experience some adverse effects, especially pain in the soles of my feet. However, I regularly go to the podiatrist since it is now reimbursed by German health insurance, and it does provide me with significant relief. I wear shoes with soft soles and special insoles, allowing me comfortable walking. I remember Dr Mohr noticing the first day I came to the hospital with closed shoes instead of the open shoes that I had to wear for so long.

Dr. Mohr: It is a huge success for us that Carsten is stable in complete remission! An awful lot happened in research in dermatology between 2011 and 2017, especially regarding the approval of new therapies, namely the approval of PD-1 inhibitors, BRAF inhibitors, and MEK inhibitors [1, 34, 35]. These therapies can also now be used earlier in adjuvant therapy.

Discussion

Dr. Mohr: I do think that we are now on the verge of the next major leap in research. There is currently a study on the adjuvant treatment of malignant melanoma through vaccination therapy; indeed, vaccination treatment trials are ongoing in all stages of melanoma [36,37,38]. Importantly, the use of next-generation sequencing has given scientists the opportunity to design personalised vaccines that can target tumour-specific antigens (neoantigens) in individual melanoma tumours, with preliminary clinical evidence suggesting that this approach has promising antitumour activity and good safety and tolerability [39]. Clinical trials have now been launched to evaluate whether the clinical activity and efficacy of these new, precise and personalised vaccination therapies improve when they are administered with other immunotherapies [39]. Another concept is to combine more immunological agents [40] and treat patients with 3 or 4 agents concomitantly, although these trials are still in phase II with only 40–50 patients [41]. Genetic biomarkers will most likely also play an increased role in deciding which patients need prophylactic tumour therapy [42, 43]. Therapies will also most likely be better personalised [44], and it may be possible to decide which therapy scheme offers the greatest benefit for each patient. I would expect to see new treatment concepts that will revolutionise melanoma therapy in the next 3 years.

Conclusions

In this article, oncologist Dr. Mohr and Carsten have described the treatment journey from the initial diagnosis in 2010 to the present day, highlighting the challenges of identifying the most suitable therapeutic options for individual patients. Notably, no therapeutic options existed for BRAFV600E metastatic melanoma in 2010; PD-1 inhibitors and BRAF/MEK inhibitors were yet to be approved in Europe, and it was only in 2013 that some therapeutic options appeared on the market. Dr. Mohr’s decision to include his patient in clinical trials quite early in the treatment pathway led to long-term survival of more than 10 years. At the time of writing this report, Carsten remains in complete remission, stable on treatment, and optimistic for the future.

Finding the appropriate therapeutic dosage to balance acceptable adverse effects against efficacy is a constant challenge for oncologists. Importantly, Carsten’s determined resilience and large capacity for endurance ensured that he remained enrolled on the clinical trials and persevered with the BRAF/MEK inhibitors, despite experiencing marked treatment-related adverse effects. The quality of life resulting from this treatment has enabled Carsten to continue working full-time and to care for his family. He is clearly a major player in his treatment decisions.