Malignant Melanoma: Drug Therapy

Therapeutic targets

  • Improvement of prognosis
  • Palliative

Therapy recommendations [S3 guideline]

  • First-line therapy: excision in toto (surgical removal of the tumor in its entirety, i.e., maintaining a safe distance).
  • Therapy for locoregional metastasis (stage III) [S3 guideline].
    • Satellite and in-transit metastases (regional tumor metastases formed at a distance of more than 2 cm from the primary tumor and located in the draining lymphatic ducts): if possibility of R0 resection (no residual tumor) exists → surgical treatment of satellite and in-transit metastases.
    • Lymph node metastases: Infestation of the sentinel lymph node with maximum metastasis diameter of 0.1 mm can, from 1.0 mm should be offered lymph node dissectionNote:melanoma-specific survival remains unaffected (si. u. “Surgical therapy“).
  • Stage II (IIA, IIB, IIC): adjuvant systemic therapy.
  • Stage III (IIIA, IIIB, IIIC, IIID): drugs previously used successfully in stage IV have now received approval for the adjuvant situation in stage III (as adjuvant/supplemental or supportive system therapy):
    • Patients in AJCC 2017 tumor stage III A-D should be offered adjuvant therapy with an anti-PD1 antibody.
    • Patients in AJCC 2017 tumor stage III A-D with a BRAF V600E or V600K mutation should be offered adjuvant therapy with a BRAF and MEK inhibitor.
      • Dabrafenib + trametinib
      • Nivolumab
      • Pembrolizumab
  • Stage IV (distant metastases present): surgery, radiotherapy (radiatio), adjuvant nivolumab, chemotherapy, combined chemo-immunotherapy and the “Targeted Therapy”.
    • Patients with AJCC 2017 stage IV tumor (NED) should be offered adjuvant therapy with an anti-PD1 antibody.
    • For BRAF V600 mutation, therapy with a BRAF inhibitor in combination with a MEK inhibitor or checkpoint inhibitor therapy (PD-1 monotherapy or PD1+CTLA-4 antibody therapy) should be provided. Currently, no data are available on the best sequential therapy of BRAF/MEK inhibitors and checkpoint inhibitors.
    • In c-KIT inhibitor-sensitive c-KIT mutation, a c-KIT kinase inhibitor4 is an option for targeted therapy after unsuccessful immunotherapy with checkpoint inhibitors.
    • In melanoma patients with unresectable metastases (daughter tumors that cannot be surgically removed), the option of immunotherapy with checkpoint inhibitors should be evaluated. In this context, PD-1 antibodies or their combination with ipilimumab are superior to monotherapy with ipilimumab in terms of progression-free survival (survival without disease progression). In addition, PD-1 antibodies in monotherapy are superior to ipilimumab in overall survival.
      • Complete remission occurs in approximately three out of four melanoma patients on PD-1 inhibitor therapy, meaning that they remain free of recurrence after 3 years, i.e., the patient has beaten the cancer with a high probability. When recurrence (recurrence of disease) occurred, the rate for complete remission was approximately 4-fold lower than with the first attempt at therapy.
    • If superior therapeutic regimens (BRAF/MEK inhibitors or PD-1 antibodies) are not an option, monochemotherapy with dacarbazine may be offered as an established system therapy to melanoma patients with unresectable metastases.
  • Inoperability: system therapy with (see below):
    • Nivolumab
    • Pembrolizumab
    • Ipilimumab
    • Dabrafenib + trametinib
    • Encorafenib + binimetinib
    • Nivolumab + ipilimumab
    • Vemurafenib + cobimetinib
    • (T-VEC)*

* Intratumoral (into the tumor “) injection can induce a secondary systemic effect. Cytostatic agents are administered in malignant melanoma for the following indications:

  • Inoperable recurrent tumors (recurrence of the tumor).
  • Inoperable regional metastases (daughter tumors).
  • Distant metastases

The following regimens are used in advanced malignant melanoma:

  • BHD regimen with BCNU, hydroxyurea and DTIC.
  • BOLD regimen with bleomycin, vincristine, CCNU, DTIC
  • DVP regimen with DTIC, vindesine and cisplatin.
  • CarboTax regimen with carboplatin and paclitaxel.
  • GemTreo regimen with gemcitabine and treosulfan

Furthermore, the following are used: Dacarbazine, temozolomide (TMZ), fotemustine.

Patients with advanced malignant melanoma (stage IV) benefit equally from first-line treatment with target therapy (see below) or immunotherapy compared with chemotherapy (see above). There was significantly better overall survival with BRAF/MEK or checkpoint inhibitors (31% higher survival.). No detailed information on active ingredients and dosages is provided here, as therapy regimens are constantly being modified. Other therapeutic approaches (“targeted therapy”).

  • BRaf inhibitors, CTLA-4 antibodies:
    • Vemurafenib (selective inhibitor of the oncogene B-Raf, a serine/threonine kinase) – the drug interferes with signaling pathways of melanomas. Half of all melanomas have a mutation in the BRAF gene. This turns on a signaling pathway that causes the cell to divide unchecked. “Vemurafenib targets this mutation and switches off the signaling pathway [active ingredient approved in the EU since February 2012]. Dabrafenib is another agent available Warning about vemurafenib:
      • May promote the onset of chronic lymphocytic leukemia (CLL).
      • Cases of severe radiation injury in patients who received radiotherapy before, during, or immediately after treatment with vemurafenib
    • Dabrafenib (BRAF kinase inhibitor; in patients in whom a specific genetic alteration (B-RAF mutation) is present in the melanoma cell) – Indication: non-resectable or metastatic melanoma.
    • Ipilimumab (blocks the protein CTLA-4 (cytotoxic T-lymphocyte antigen-4), which downregulates T-cell activity) – Indication: advanced (non-resectable or metastatic) melanoma.
    • MAPK pathway inhibitor trametinib is used in advanced or metastatic melanoma with BRAF V600 mutation as monotherapy or in combination with dabrafenib.
    • Cobimetinib (kinase inhibitor from the MEK inhibitor group) has been approved since November 2015 in combination with vemurafenib for the treatment of advanced malignant melanoma, in adults with metastatic or inoperable melanoma with a BRAF V600 mutation.Red-hand letter: Evidence of major bleeding events (including intracranial and gastrointestinal bleeding) and increased creatine phosphokinase (CPK) levels and rhabdomyolysis with treatment with cobimetinib.
  • PD-1 immune checkpoint inhibitors (anti-PD-1 therapy):
    • Nivolumab – Indications:
      • Adult patients with advanced (non-resectable or metastatic) melanoma regardless of BRAF mutation status.Non-pretreated patients with a BRAF V600 wild-type tumor have substantial additional benefit when treated with nivolumab.
      • Adjuvant treatment of melanoma with lymph node involvement or metastasis after complete resection in adults.
    • Side effects: Fatigue (24.8%), pruritus (17%), diarrhea (13%), exanthema (13%), nausea (12%).
    • Pembrolizumab – patients older than 60 years respond better than younger – indications:
      • For therapy of advanced, non-resectable or already metastatic malignant melanoma.
      • For monotherapy for adjuvant treatment of melanoma in tumor stage III with lymph node involvement after complete resection in adults.
      • As a clinical marker for the success of therapy has so far established only vitiligo / white spot disease (possibly in combination with leukotrichia / whitening of the hair on the face, head and body).
  • The combination of PD-1 (“programmed cell death 1 protein”) antibody therapy with the CTLA4(“cytotoxic T-lymphocyte-associated protein 4”) inhibitor ipilimumab has been shown to be superior in terms of progression-free survival.
  • See also under “Further Therapy.

Side effects of BRAF inhibition: arthralgias (joint pain), alopecia (hair loss), exanthema (rash), fatigue (tiredness), photosensitivity, nausea and itching; papillomas and squamous cell carcinomas.

Other indications

  • 25-month administration of interferon α-2b (IFN) is superior to only 13-month administration at higher doses in patients with cutaneous melanoma (especially ulcerated melanoma)
  • Melanoma patients (stage 4) with brain metastases: Patients who received checkpoint blockade immunotherapy survived on average more than twice as long as those who did not receive immunotherapy (12.4 versus 5.2 months); also better was their 5-year survival rate, 28.1% versus 11.1% in those without immunotherapy.
  • Combined treatment with the checkpoint inhibitors nivolumab and ipilimumab is also effective against brain metastases in patients with malignant melanoma. Nivolumab binds to the PD-1 receptor, and ipilimumab binds to the protein CTLA-4; thus, both prevent tumor cells from escaping T-cell attack. Therapy was initially given up to 4 cycles with nivolumab and ipilimumab in combination, and then therapy was continued with nivolumab until tumor progression recurred.Results: After 6 months, 64% and after 9 months, 60% of patients were without recurrence. Survival rates were 92 and 83%, respectively, and the authors estimated that 1-year survival could be as high as 82%. At the time of publication, the median follow-up time was 14 months.
  • Institute for Quality and Efficiency in Health Care (IQWiG): dabrafenib and trametinib is associated with longer survival and fewer or later recurrences.Dabrafenib plus trametinib is approved for the adjuvant treatment of adults with stage III melanoma with BRAF V600 mutation after complete resection, the surgical removal of diseased tissue.
  • KEYNOTE-001: The 5-year data confirm the long-term antitumor activity and tolerability of pembrolizumab in advanced melanoma. In the overall population, 16% had achieved a complete response and 24% a partial response; treatment-naïve patients achieved a complete response in 25% of cases and a partial response in 27%. In 89 and 92% of patients with complete response, respectively, it was still ongoing at the time of evaluation.