Nivolumab in melanoma

Introduction: The treatment of melanoma is evolving rapidly over the past few years.

Areas covered: We conducted a comprehensive review of the literature on the role of nivolumab in melanoma

Expert commentary: Nivolumab is approved by FDA and EMA for the treatment of patients with metastatic melanoma. Nivolumab is superior to chemotherapy and to ipilimumab in previously untreated patients and to chemotherapy in ipilimumab pre-treated patients. The addition ipilimumab to nivolumab is associated with a higher response rate and a better PFS, particularly in patients with PD-L1 negative tumors, albeit at the cost of an increase in grade 3–4 adverse event rate. Definitive survival data on this combination are pending and the selection of patients most likely to benefit from this combination and its pharmacoeconomics are to be elucidated. Prospectively validated predictive markers are lacking. Of particular interest are immune-related adverse events which should be managed according to published guidelines.     

Ipilimumab in melanoma

Ipilimumab is a fully human monoclonal antibody directed against the cytotoxic T-lymphocyte antigen-4 receptor. Blocking cytotoxic T-lymphocyte antigen-4 signaling has been shown to enhance T-cell activation and to amplify T-cell-mediated immunity. Ipilimumab, either as a single agent or in combination with gp100 vaccination, significantly prolonged overall survival in a randomized Phase III trial in patients with disease progression after prior treatment when compared with gp100 alone. In previously untreated patients, the addition of ipilimumab to dacarbazine also significantly prolonged overall survival. The most common adverse events are immune related. Adherence to established treatment algorithms in patients with immune-related adverse events is advocated. Predictive factors for the activity of ipilimumab have not been identified but would be of great value in the selection of patients who are most likely to benefit from this innovative immunotherapy. Outstanding issues include the role of ipilimumab in the adjuvant treatment of patients who are at high risk for relapse, and the optimal treatment sequence for patients with BRAFV600 mutant melanoma, as small-molecule BRAF inhibitors have also been shown to improve the survival for this subgroup of patients.     

Ipilimumab for Patients With Advanced Mucosal Melanoma

The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer‐testis antigens and other antigens. By the immune‐related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune‐related complete response, 1 immune‐related partial response, 6 immune‐related stable disease, and 22 immune‐related progressive disease. By the modified World Health Organization criteria, there were 1 immune‐related complete response, 1 immune‐related partial response, 5 immune‐related stable disease, and 23 immune‐related progressive disease. Immune‐related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8–26.7 months). Several patients demonstrated serologic responses to cancer‐testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma.     

Ipilimumab alone or in combination with nivolumab after progression on anti-PD-1 therapy in advanced melanoma

BackgroundThe anti-programmed cell death-1 (PD-1) inhibitors pembrolizumab and nivolumab alone or in combination with ipilimumab have shown improved objective response rates and progression-free survival compared to ipilimumab only in advanced melanoma patients. Anti-PD-1 therapy demonstrated nearly equal clinical efficacy in patients who had progressed after ipilimumab or were treatment-naïve. However, only limited evidence exists regarding the efficacy of ipilimumab alone or in combination with nivolumab after treatment failure to anti-PD-therapy.Patients and methodsA multicenter retrospective study in advanced melanoma patients who were treated with nivolumab (1 or 3 mg/kg) and ipilimumab (1 mg or 3 mg/kg) or ipilimumab (3 mg/kg) alone after treatment failure to anti-PD-1 therapy was performed. Patient, tumour, pre- and post-treatment characteristics were analysed.ResultsIn total, 47 patients were treated with ipilimumab (ipi-group) and 37 patients with ipilimumab and nivolumab (combination-group) after treatment failure to anti-PD-1 therapy. Overall response rates for the ipi- and the combination-group were 16% and 21%, respectively. Disease control rate was 42% for the ipi-group and 33% for the combination-group. One-year overall survival rates for the ipi- and the combination-group were 54% and 55%, respectively.ConclusionsIpilimumab should be considered as a viable treatment option for patients with failure to prior anti-PD-1 therapy, including those with progressive disease as best response to prior anti-PD-1. In contrast, the combination of ipilimumab and nivolumab appears significantly less effective in this setting compared to treatment-naïve patients.     

Updates in adjuvant systemic therapy for melanoma

There has been a rapid increase in adjuvant therapies approved for treatment following surgical resection of stages III/IV melanoma. We review current indications for adjuvant therapy, which currently includes a heterogenous group of stages III and IV patients with melanoma. We describe several pivotal clinical trials of systemic immune therapies, targeted immune therapies, and adjuvant vaccine strategies. Finally, we discuss the evidence for selecting the most appropriate treatment regimen(s) for the individual patient.     

Adjuvant immunotherapy for melanoma

Adjuvant immunotherapy was administered to 84 lymph-node-negative and 25 lymph-node-positive melanoma patients. This active specific homologous cell protein preparation was given after aggressive surgery and given over 2 years. Projected and observed survival rates are presented as well as other clinical and pathologic characteristics such as female-to-male ratio, site of primary, level and depth of invasion. The projected 5-year survival rates are 90% for all stage I with 89% for females and 94% for males. Lower extremity stage I projected 5-year survival rate was 88% for all, 87% for females, and 100% for males. The projected 5-year survival rate for stage II was 68% overall and 100% for lower extremity. Only two of five patients with an unknown primary have expired. All of these results are improved over expected survival. Hopefully a randomized prospective study will be stimulated to ascertain the basis for this improvement.     

Bronchial malignant melanoma

We describe a case of malignant melanoma presenting initially as an endobronchial lesion located in the left main bronchus causing total atelectasis. This resolved with radiation therapy. Widespread metastases developed shortly thereafter. The differential diagnosis of primary and metastatic bronchial malignant melanoma is discussed. Other isolated case reports are reviewed.     

Uveal melanoma

Uveal melanoma, which arises from melanocytes residing in the stroma, is the most common primary intraocular tumor in adults. Up to 50% of patients with primary uveal melanoma will ultimately develop distant metastasis, the liver being involved in up to 90% of individuals and the median survival reported to be 4-5 months. The current treatment of metastatic uveal melanoma is limited by the lack of effective systemic therapy. The intrinsic resistance of uveal melanoma to conventional systemic chemotherapy has led researchers to evaluate new approaches. Molecular biology and a better knowledge of cancer cells allowed the development of target therapies: these refer to drugs designed to interact with a specific molecular pathway known to have a critical role in tumor growth or progression. Several drugs, such as bevacizumab, imatinib and MEK-inhibitors, are currently under investigation as single agents or in combination with chemotherapeutic drugs for the treatment of metastatic uveal melanoma. Finally, ipilimumab, which targets the immune compartment, was reported to increase overall survival in cutaneous melanoma patients, with preliminary evidence of similar activity in ocular melanoma.     

Extensive screening for primary tumor is redundant in melanoma of unknown primary

For decades, patients in our institution with metastastic melanoma of unknown primary have been subjected to extensive examinations in search of the primary tumor. This retrospective study questions the results, and thus the feasibility of these examinations. Of 103 patients diagnosed with unknown primary tumor during the period 1986-2006, 39 (38%) presented primarily with a cutaneous or a subcutaneous metastasis, and 63 (61%) with a lymph node metastasis. One patient presented with a bone metastasis (1%). Eighty-seven patients (84%) were examined by an ophthalmologist. A choroidal melanoma was suspected as the primary tumor in one patient. Eighty-four patients (82%) were examined by an oto-rhino-laryngologist, whereby no primary tumor was found. Ninety-five patients (92%) were examined by sigmoideoscopy/rectoscopy. No primary tumor was found. Of the 36 women, 32 had a gynecological examination (89%), revealing no primary tumor. We conclude, that only one possible (but not verified) primary tumor was disclosed by various specialists examinations of 103 patients referred with the diagnosis metastatic melanoma with no primary tumor. Special screenings can thus be considered as redundant. Thus, for patients referred with metastastic melanoma of unknown primary, we recommend that a detailed history is obtained, and a standard physical examination performed, in addition to a histopathological review and CT/PET for staging.     

Immune toxicities and long remission duration after ipilimumab therapy for metastatic melanoma: two illustrative cases

New antitumour immunotherapy strategies for stage iv metastatic melanoma include ipilimumab, a monoclonal antibody against ctla-4. Patterns of response with cancer immunotherapy differ from those with cytotoxic chemotherapy. We present two cases of long-duration immune-related responses with ipilimumab in a phase ii trial.A 66-year-old woman with multiple lung metastases from a scalp primary melanoma received 4 doses of ipilimumab with mixed clinical response. However, after the first maintenance dose, she developed severe ileitis and colitis that responded to steroid therapy. Four months later, she had surgery and radiotherapy for a single brain metastasis. Radiologically, stable disease continued for 36 months after the last ipilimumab dose, and partial response for 5 years after ipilimumab start.A 54-year-old man with cervical lymph node and pulmonary metastases from a scalp primary melanoma received three induction doses of ipilimumab. He developed alopecia universalis and widespread vitiligo, and he discontinued treatment because of hypophysitis. Maintenance ipilimumab was started after a 6-month drug-free interval, with no further adverse events over 15 cycles. At week 12, computed tomography imaging showed no lung metastases and partial response in a supraclavicular lymph node, which was positive on positron-emission tomography. Five years after starting ipilimumab, the supraclavicular lymph node was calcified, and the patient was off steroid therapy and asymptomatic.The foregoing patients demonstrate long responses with ipilimumab (in association with delayed severe colitis in one case, and a constellation of immune events, including alopecia universalis in another). Re-treatment with ipilimumab may be possible even after significant immune adverse events.     

Radiotherapy for metastatic melanoma presenting in pregnancy

We describe the study of a patient with metastatic melanoma to axillary nodes presenting during pregnancy. The factors considered in her management are discussed, including issues related to staging, the decision not to terminate the pregnancy and the relative efficacy and fetal toxicity of the available treatment options. An overview of the known effects of radiotherapy on the fetus is presented and the technical alterations that were used to decrease the toxicity of radiotherapy are discussed.     

Intermediate dose interferon alpha in adjuvant treatment for high-risk melanoma

Interferon is widely used as the most effective agent in the adjuvant therapy of patients with melanoma. However, little is known about the effect of intermediate dose interferon (IDI) in adjuvant therapy. We conducted this study to determine whether intermediate doses of interferon-alpha 2 could be beneficial for these patients. A series of 84 melanoma patients with high-risk relapse potential (stage II–III) after excisional biopsy were enrolled for adjuvant therapy with IDIs, either IFN-alpha 2a, 9 MU or IFN alpha 2b, 10 MU per day, subcutaneously, for 1 yr consisted of an induction period (5 d/wk for 4 wk) followed by 48 wk of same dose administered three times per week. The median follow-up was 25.9 mo, with range 4−90.4 mo. Thirty-three (39%) patients had progressed; 18 (55%) of them while on treatment. The median (range) time of the failure occurrence was 9.1 mo (1.7−47.3 mo). Distribution of failure site was identical and the majority of the recurrences were found as single metastasis. For distant metastasis-free interval, mean (±SE) value was 28.8±3.6 mo; 1− and 2−yr survival rates were 87.8±5.7% and 61.6±9.3%, respectively. Twenty-two deaths were observed. Five-year survival rates of progression-free survival and overall survival were 50% and 60%, respectively. Generally, the treatment was found well-tolerated; drug-induced dose reduction or treatment discontinuation due to toxicity was minimal. Severe toxicity was rare. In conclusion, the small number of patients and the short follow-up does not permit any conclusion. However, the preliminary data seem to show that treatment with IDI was usually well tolerated with low toxicity of the patients during the adjuvant therapy.     

The natural course of cutaneous melanoma

The natural course of cutaneous melanoma (CM) is determined by its metastatic spread and depends on tumor thickness, ulceration, gender, localization, and the histologic subtype of the primary tumor. CM metastasis develops via three main metastatic pathways and occurs as satellite or in-transit metastasis, as regional lymph node metastasis or as distant metastasis at the time of primary recurrence. About 50% of all CM patients with tumor progression firstly develop regional lymph node metastases. In the other 50% the first metastases are satellite or in-transit metastases (about 20%), or immediately distant metastases (about 30%). Development of distant metastasis appears to be an early event in metastatic spread and may in the majority of cases originate from the primary tumor, only few cases may develop secondarily to locoregional metastasis. Reporting of organ involvement in distant metastasis greatly differs between the results of imaging techniques and autopsy results in respect to the metastatic patterns detected, pointing out that there is a need of improved imaging systems. Proliferation, neovascularization, lymphangiogenesis, invasion, circulation, and embolism are important steps in the pathogenesis of CM metastasis, with tumor vascularity as an important independent significant prognostic factor. The expression of chemokine receptors in cancer cells associated with the expression of the respective chemokine receptor ligands in the target sites of the metastasis is an interesting observation which may stimulate the development of new therapeutic strategies.     

Interleukin-2 improves tumour response to DNP-modified autologous vaccine for the treatment of metastatic malignant melanoma

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.     

Biochemotherapy with low doses of subcutaneous interleukin-2 in patients with melanoma: results of a phase II trial

Introduction Metastatic melanoma has an ominous prognosis. Bio-chemotherapy regimens can increase the response rate but with a high degree of toxicity due, mainly, to the use of high-dose intravenous interleukin-2. Objectives To test the feasibility and activity profile of a bio-chemotherapy regimen of low-dose subcutaneous interleukin-2. Material and methods Administration scheme: dacarbazine at 200 mg/m²/d on days 1–4, cisplatin at 20 mg/m²/d intravenous on days 1–4, vinblastine at 1.5 mg/m²/d on days 1–4, IL-2 at 4.5 MUI/m²/d subcutaneous on days 5–8, IFN-alpha at 5 MU subcutaneous on days 5–9, 11, 13, 15 of every 21-day cycle. Results Objective response was obtained in 11 patients (39.3%; 95%CI: 21–59) including 4 with complete response (14.5%; 95%CI: 4–33). With an extended follow-up of 49 months and 60 months, respectively, 2 patients continue with complete response. The main toxicities were haematological: grade 3–4 neutropenia in 8.2% of cycles, thrombocytopenia in 1.2% and anaemia in 3.2%. Conclusions The regimen is safe and has a good activity profile. The presence of long-term survivors, despite the use of lower doses and subcutaneous IL-2, is encouraging.