Molecularly targeted therapies for melanoma

Systemic and topical targeted therapies are emerging as a rational approach to the management of skin cancers. In this article, we review the molecular pathways critical to the development of melanoma and the novel pharmacologic agents that have been rationally designed to target it. Included is a review of vemurafenib, imatinib, and ipilimumab for metastatic or unresectable melanoma.     

Targeted therapies for metastatic melanoma

The next few years may show that when the novel therapeutics reviewed in this article are used in thoughtful combinations, a new standard of care for the treatment of advanced melanoma will emerge. As more understanding is gained on the different signaling pathways for tumor cell growth and mechanisms of action of the different classes of drugs, the ability to identify different subsets of patients with differentially dysregulated oncogenic signaling pathways may allow for more individualized treatments of advanced melanoma in the near future, which will ultimately translate into improved survival.     

Cutaneous adverse effects during ipilimumab treatment for metastatic melanoma: a prospective study

Background

Ipilimumab is an immunomodulatory antibody directed against cytotoxicT-lymphocyte-associated antigen 4 (CTLA-4), which is administered to patients with advanced melanoma, with a proven positive effect on overall survival. The cutaneous adverse effects (AEs) of ipilimumab are relatively frequent, although described as usually mild and rarely life threatening.

Objectives

To describe a three-year experience of a single institute in detecting and managing cutaneous AEs.

Materials & Methods

A cohort of patients (n = 41) treated with ipilimumab (3 mg/kg/three weeks) for metastatic melanoma, from 2013 to 2016,was investigated for adverse cutaneous events.

Results

On dermatological evaluation, 34.1% of the patients in our series developed cutaneous AEs: rash (7.3%; n = 3), folliculitis (7.3%; n = 3), mucositis (2.4%; n = 1), rosacea (2.4%; n = 1), eczema (2.4%; n = 1), acneiform eruption (2.4%; n = 1), syringometaplasia mucinosa (2.4%; n = 1), Stevens-Johnson syndrome (2.4%; n = 1), and vitiligo (4.9%; n = 2). These were all Grade 1 and 2 AEs, except for the case of Stevens-Johnson syndrome (Grade 4). On a patient-reported scale, 4.9% (n = 2) and 9.8% (n = 4) of the patients complained of severe xerosis and pruritus, respectively.

Conclusion

Ipilimumab was relatively well tolerated in our series, mainly causing mild cutaneous AEs, which, in our experience, responded satisfactorily to conventional therapies. Only in one case was the treatment discontinued, due to Grade 4 side effects.

     

Cutaneous adverse events in patients treated with BRAF inhibitor‐based therapies for metastatic melanoma for longer than 52 weeks

Generalized pustular psoriasis (GPP) is a severe, potentially life‐threatening inflammatory dermatosis, which is traditionally difficult to manage. Recent evidence suggests that interleukin (IL)‐1 plays a central role in the disease pathogenesis, and thus makes the use of IL‐1 inhibitors potentially effective. Two patients with severe, recalcitrant GPP were enrolled in an open‐label, expanded access study to receive a new IL‐1β inhibitor, gevokizumab. The two patients had a respective 79% and 65% reduction in GPP area and severity index scores at weeks 4 and 12, with some improvements in quality‐of‐life instruments. There were no significant adverse events related to the study medication, although one patient developed an abscess in a haematoma secondary to an injury. Both patients showed substantial initial clinical response to gevokizumab, with no significant laboratory abnormalities noted. These cases illustrate the growing need for targeted, efficacious therapies for this severe, debilitating disease. Prospective randomized control studies are required to further assess the safety and efficacy of IL‐1β inhibitors for the treatment of GPP.     

Severe de‐novo palmoplantar and nail psoriasis complicating Nivolumab treatment for metastatic melanoma

Nivolumab, a fully human IgG4 immune checkpoint modulator, binds to the programmed cell death 1 (PD‐1) receptor on T cells and blocks their inhibition. Thus, it increases the anticancer host immune response by allowing T cells to attack tumor cells. Although anti‐PD‐1 immunotherapy is typically well accepted, deregulation of immune tolerance caused by nivolumab may determine immune‐related adverse events, among which skin toxicities represent the most common. We report a case of severe new‐onset palmoplantar and nail psoriasis after receiving nivolumab treatment for metastatic melanoma.     

Rechallenge of targeted therapy in metastatic melanoma

Rechallenge of targeted therapy in patients with BRAFV⁶⁰⁰‐mutated melanoma plays an important role, because of the prolonged overall survival of melanoma patients. Patients may be rechallenged after a drug‐free interval following adverse drug reactions, after radiation therapy or surgery, following disease progression on subsequent immunotherapy or chemotherapy, or after disease progression without interim therapeutic intervention. To date, only few data has been published on treatment outcomes associated with rechallenge. The articles published on this topic included a total of 238 patients. In general, it was shown that patients did respond to rechallenge, even if they had previously experienced disease progression on targeted therapy. Patient response varied from stable disease to partial response and even complete remission in some cases. Our analysis showed overall response rates to rechallenge of 47 %, with disease control rates of 67 %. While mean progression‐free survival was 6.4 months, this was shorter than after the first round of targeted therapy (mean progression‐free survival of 9.2 months). Rechallenge of targeted therapy offers another option in the management of melanoma patients who have received extensive prior treatment. In particular, it will be important to clarify whether the type of interim treatment has an impact on the response to rechallenge.     

Diffuse melanosis cutis in the setting of BRAFV600E mutant melanoma and treatment with targeted therapies

Diffuse melanosis cutis (DMC) is a rare presentation of metastatic melanoma associated with a particularly guarded prognosis. We report a case of a 35‐year‐old man with BRAF^V600E metastatic melanoma treated with dabrafenib (as well as ipilimumab and whole brain radiotherapy), who is alive, 25 months after the onset of his DMC. This is significantly longer than the reported mean survival of 4 months, highlighting the importance of BRAF mutation testing and the promising survival advantage of using targeted therapies compared with conventional chemotherapeutic regimens.     

Laser and light therapies for the treatment of nail psoriasis

Psoriatic involvement of the nail is notoriously refractory to conventional therapy. Nail psoriasis has a high incidence amongst patients with psoriasis. It remains a significant cosmetic problem and thus, has a significant impact on quality of life. More recently, light and laser therapies have emerged as modalities for treatment of nail psoriasis. In this study, the efficacies of light and laser therapies are systematically reviewed. Light therapies involve ultraviolet light (with or without photosensitizers) or intense pulsed light. Alternatively, laser therapy in nail psoriasis is primarily administered using a 595‐nm pulsed dye laser. These modalities have demonstrated significant improvement in psoriatic nail lesions, and even complete resolution in some cases. Both laser and light modalities have also been tested in combination with other systemic or topical therapeutics, with variable improvement in efficacy. Both laser and light therapies are generally well tolerated. Side‐effects of light therapies include hyperpigmentation, itching and erythema; whereas, side‐effects of laser therapy are more frequent and include pain, purpura/petechiae and hyperpigmentation. Patterns of response to therapy were also seen based on presenting characteristics of the nail lesions: subungual hyperkeratosis and onycholysis appeared to be the most responsive to therapy, while nail pitting was the most resistant. Light or laser therapies have the potential to be an efficient and cost‐effective in‐office based treatment for nail psoriasis. However, more large‐scale clinical trials are needed to assess their efficacy, particularly in combination with other therapeutic modalities.     

A prospective study of cutaneous adverse events induced by low-dose alpha-interferon treatment for malignant melanoma

INTRODUCTION: alpha-Interferon is associated with numerous cutaneous side effects, but the accurate incidence of these complications is not clearly known. OBJECTIVES: A prospective study was designed to evaluate the incidence and clinical pattern of cutaneous side effects in a cohort of patients receiving adjuvant therapy with low-dose interferon for malignant melanoma. MATERIAL AND METHODS: A cohort of 33 patients with stage IIA and IIB melanoma treated with low-dose alpha-interferon (3 MIU 3 times a week for 18 months) were prospectively enrolled in a single-center study. The patients responded to a questionnaire on their medical history and were systematically examined for any cutaneous lesions before treatment and every 3 months afterwards. RESULTS: 29/33 patients (87%) experienced 1 or more cutaneous side effects. The most frequent was hair loss and occurred in 16 cases (48.4%). Hair discoloration was noted in 6 cases (18%). Eczematous reactions at injection sites or at remote sites were observed in 13 patients (39%). Pruritus occurred in 10 cases (30%). Xerostomia, Raynaud's phenomenon or livedo reticularis were observed in 10 patients, associated with an increase in circulating autoantibody titer in 2 cases. Some rare side effects were observed: urticaria (1 case) or angioedema (1 case), worsening of preexisting seborrheic dermatitis (3 cases), herpetic recurrence (2 cases), pityriasis versicolor (1 case), worsening of recurrent buccal aphthous ulcer (1 case) and vitiligo (1 case). CONCLUSION: Cutaneous adverse events during adjuvant immunotherapy of melanoma with low-dose alpha-interferon seem to be frequent but do not result in treatment discontinuation. A good awareness of these side effects may be useful for a more accurate survey and clinical management of patients receiving this treatment.     

Upcoming strategies for the treatment of metastatic melanoma

Prognosis for advanced and metastatic melanoma is poor, with a 5-year survival of 78, 59 and 40% for patients with stage IIIA, IIIB and IIIC, respectively, and a 1-year survival of 62% for M1a, 53% for M1b and 33% for M1c. The unsatisfactory results of actual standard therapies for metastatic melanoma highlight the need for effective new therapeutic strategies. Several drugs, including BRAF, KIT and MEK inhibitors, are currently being evaluated after promising data from Phase I and Phase II studies; Vemurafenib, a BRAF-inhibitor agent, has been approved by the Food and Drug Administration (FDA) for the treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation after a significant impact on both progression-free and overall survival was demonstrated compared with dacarbazine in a Phase III trial. Ipilimumab, an immunotherapeutic drug, has proven to be capable of inducing long-lasting responses and was approved for patients with advanced melanoma in first- and second-line treatment by the FDA and in second-line treatment by the European Medicines Agency. Furthermore, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. In the near future, patients with BRAF mutations could have the chance to benefit from treatment with BRAF inhibitors; patients harboring BRAF or NRAS mutations could be treated with MEK inhibitors; finally, the subgroup of patients with acral, mucosal or chronic sun-damaged melanoma harboring a KIT mutation could benefit from KIT inhibitors. Ipilimumab could become a standard treatment for metastatic melanoma, both as a single agent and in combination; its efficacy has been proven, and researchers should now address their efforts to understanding the predictive variables of response to treatment.     

Perilesional treatment of metastatic melanoma with interferon-β

Previous trials with various treatments have not shown satisfactory therapeutic results for cutaneous metastasis of malignant melanoma (MM). We report three patients who were treated with peritumoral injection of interferon (IFN)-β for multiple skin metastases of MM. The metastatic tumours were infiltrated by significant numbers of CD8+ TIA+ cytotoxic lymphocytes, and the numbers of CD4+ cells and human leucocyte antigen-DR+ cells increased after IFN-β injection. These results suggest that the peritumoral administration of IFN-β enhanced the antitumour immune response against the MM, suggesting that it is a promising supportive treatment for skin metastasis of MM.     

Enhanced survival associated with vitiligo expression during maintenance biotherapy for metastatic melanoma

Vitiligo, an autoimmune skin disorder, was evaluated in 49 metastatic melanoma patients treated with an immunotherapy regimen of maintenance biotherapy (mBT) following induction concurrent biochemotherapy (cBCT). Patients receiving mBT demonstrated a stable or better response to cBCT. The mBT regimen consisted of outpatient subcutaneous injections of low-dose IL-2 (1 MIU/m(2)) 5/7 days weekly, GM-CSF (125 mcg/m(2)) 14 days monthly, and high-dose pulses of in-patient continuous infusion decrescendo IL-2 (54 MIU/m(2)) over 48 hours monthly for the first 6 months and every 2 months thereafter. The majority of patients had poor prognostic features. Forty-nine patients were without evidence of vitiligo at the start of mBT. Of these, 21 patients (43%) developed vitiligo during mBT and had a median overall survival from the start of mBT of 18.2 months (95% CI, 12.3-N/A) compared to 8.5 months (95%CI <6.7-12.7) for 28 non-vitiligo patients (P=0.027). Six of 21 vitiligo patients (29%) expressed IgG antibody titers to tyrosinase-related protein-2 compared to four of 28 non-vitiligo patients (14%) (P=NS). The development of vitiligo in metastatic melanoma patients on cBCT/mBT immunotherapy correlates with a better therapeutic outcome.     

Management and outcome of metastatic melanoma during pregnancy

Background Although metastatic melanoma occurrence during pregnancy challenges the physician in several ways, only a few studies have been published. Objectives Our aim was to investigate therapeutic management together with maternal and fetal outcomes in pregnant women with advanced melanoma. Methods A French national retrospective study was conducted in 34 departments of Dermatology or Oncology. All patients with American Joint Committee on Cancer (AJCC) stage III/IV melanoma diagnosed during pregnancy were included. Data regarding melanoma history, pregnancy, treatment, delivery, maternal and infant outcomes were collected. Results Twenty‐two women were included: 10 AJCC stage III and 12 stage IV. Abortion was performed in three patients. Therapeutic abstention during pregnancy was observed in three cases, 14 patients underwent surgery, four patients received chemotherapy and one patient was treated with brain radiotherapy alone. The median gestational age was 36 weeks amenorrhoea. Neither neonatal metastases nor deformities were observed. Placenta metastases were found in one case. Among 18 newborns, 17 are currently alive (median follow up, 17 months); one died of sudden infant death. The 2‐year maternal survival rates were 56% (stage III) and 17% (stage IV). Conclusions Faced with metastatic melanoma, a majority of women chose to continue with pregnancy, giving birth, based on our samples, to healthy, frequently premature infants. Except during the first trimester of pregnancy, conventional melanoma treatment was applied. No serious side effect was reported, except one case of miscarriage after surgery. Mortality rates do not suggest a worsened prognosis due to pregnancy but larger prospective controlled studies are necessary to assess this specific point.