Tag: Malignant Melanoma of the Skin

SUMMARY: It is estimated that in the US, approximately 100,350 new cases of melanoma will be diagnosed in 2020 and approximately 6,850 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Stage III malignant melanoma is a heterogeneous disease and the risk of recurrence is dependent on the number of positive nodes as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death, than those with a metastasis of 1 mm or less. Patients with Stage IIIA disease have a disease-specific survival rate of 78%, whereas those with Stage IIIB and Stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.
Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system, prevent uncontrolled immune reactions and suppress antitumor immunity. Antibodies that target these membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), PD-1 (Programmed cell Death-1) and PD-L1 (Programmed cell Death-Ligand1) block the Immune checkpoint proteins and ligands, unleash T cells, resulting in T cell proliferation, activation and a therapeutic response. Several agents are presently approved by the FDA for the adjuvant treatment of high-risk Melanoma and they include YERVOY® (Ipilimumab), OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), high-dose Interferon alfa-2b, as well as TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib) combination for BRAF-mutant Melanoma.
YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. Overall Survival however has only been established for adjuvant high-dose Interferon alfa-2b or high dose YERVOY® given at 10 mg/kg. However, the use of YERVOY® at 10mg/kg as adjuvant therapy in clinical practice has been limited by the high incidence of severe toxicities. YERVOY® at 3 mg/kg was approved in 2011 for unresectable metastatic melanoma. To further address the relative efficacy and safety of YERVOY® at the 2 dose levels, the authors in the present study compared high-dose Interferon (HDI), a standard adjuvant treatment for high-risk melanoma available since 1996, with YERVOY® given at 3 mg/kg (Ipi3) and YERVOY® given at a dose of 10 mg/kg (Ipi10). Adjuvant high dose Interferon has been shown to improve Relapse Free Survival (RFS) and Overall Survival (OS) in ECOG and several intergroup trials. 
Intergroup trial E1609 is an open-label, multicenter, multinational, 3-arm, Phase III study in which 1,670 adult patients were randomly assigned 1:1:1 to receive Ipi3 (N = 523), HDI (N = 636), or Ipi10 (N = 511). Eligible patients had completely resected Stage IIIB, IIIC, or IV (M1a or M1b) cutaneous malignant melanoma, and patients with Stage IIIB or IIIC disease were required to have complete lymph node dissection. Both Ipi3 or Ipi10 were administered IV every 3 weeks for 4 doses (induction), followed by the same dose every 12 weeks for up to 4 additional doses (maintenance). HDI was administered IV at 20 million units/m2 daily, 5 days a week, for 4 weeks (induction), followed by 10 million units/m2 subcutaneously every other day, 3 days per week, for 48 weeks (maintenance). Treatment was continued for a maximum of 60 weeks with YERVOY® or 52 weeks with HDI, or until unacceptable toxicities or disease progression. The two Coprimary end points were Overall Survival (OS) and Relapse Free Survival (RFS) of patients in the Ipi3 or Ipi10 group, each compared with outcomes of those patients in the HDI group. Secondary end points were Safety and tolerability of adjuvant YERVOY® and Quality of Life assessments.
Patients in the Ipi3 (YERVOY® 3 mg/kg) group had superior Overall Survival compared with patients in the HDI (high dose Interferon) group (HR=0.78; P=0.044). The 5 year Overall Survival rate was 72% with ipi3 and 67% with HDI. For RFS, the HR was 0.85 (P=0.065), with a median RFS of 4.5 years for Ipi3 and 2.5 years for HDI, and these study outcomes were positive and favored Ipi3, based on the protocol criteria.
When Ipi10 (YERVOY® 10 mg/kg) was compared with HDI, there were trends toward improvement in OS and RFS in favor of Ipi10, but these findings were not statistically significant. More patients in the HDI group required salvage therapy with YERVOY® or YERVOY®/PD-1 combination, compared to the Ipi3 and Ipi10 groups (P<0.001).
It was concluded that adjuvant therapy with YERVOY®, given at a dose of 3 mg/kg, was significantly less toxic and demonstrated a significant improvement in OS against an active control regimen (high dose Interferon), among patients with high-risk resected melanoma. The authors added that the current approved adjuvant YERVOY® dose of 10 mg/kg was more toxic and not superior in efficacy to high dose Interferon. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. Tarhini AA, Lee SJ, Hodi FS, et al. DOI: 10.1200/JCO.19.01381 Journal of Clinical Oncology 38, no. 6 (February 20, 2020) 567-575.

SUMMARY: It is estimated that in the US, approximately 91,270 new cases of melanoma will be diagnosed in 2018 and about 9,320 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Brain metastases are a frequent complication of solid tumors and these patients tend to have a very poor prognosis with a median survival of a few weeks to months. Malignant melanoma has the highest propensity to metastasize to the brain. More than one third of patients with advanced melanoma have brain metastases at the time of diagnosis, and up to 75% of patients have brain metastases at the time of death. Prognosis of patients with melanoma who have brain metastases is poor, with a median Overall Survival of 4-5 months and a 5 year survival of 5%. This is because systemic chemotherapy has minimal antitumor activity in the brain, does not decrease the risk of development of new brain metastases, does not control of extracranial disease and does not improve Overall Survival.

Immune checkpoint inhibitors by blocking immune checkpoint proteins unleash T cells, resulting in T cell proliferation, activation and a therapeutic response. YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks immune checkpoint protein/receptor CTLA-4, and has been shown to have activity against brain metastases from melanoma when used individually as monotherapy. OPDIVO® (Nivolumab) is a fully human, Immunoglobulin G4, anti PD-1 targeted monoclonal antibody. It binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. OPDIVO® when combined with YERVOY® significantly improved Overall Survival in patients with previously untreated advanced melanoma, compared with YERVOY® alone, in phase II and III studies. These studies however excluded patients with untreated brain metastases.

CheckMate 204 is an open-label, multicenter, phase II study, conducted at 28 sites in the United States and the authors in this study evaluated the efficacy and safety of OPDIVO® plus YERVOY® in patients with melanoma who had untreated brain metastases. This study enrolled 101 patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter 0.5-3 cm) and no neurologic symptoms. Patients received OPDIVO® 1 mg/kg plus YERVOY® 3 mg/kg every 3 weeks for up to four doses, followed by OPDIVO® 3 mg/kg every 2 weeks until progression or unacceptable toxic effects. The median age was 59 years, 44% of patients had PD-L1 expression of 1% or more, 22% of the patients had 3 or more target lesions and 17% had received previous systemic anticancer therapy, with BRAF inhibitor being the most common (11%), a MEK inhibitor (9%), or both. Patients with known leptomeningeal involvement, those with metastases larger than 3 cm in diameter, and those patients receiving glucocorticoid therapy, were excluded from the study. The Primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, Complete Response, or Partial Response. Of the 101 patients enrolled, 94 patients had a minimum follow up of 6 months (median follow up 14.0 months), and could be evaluated for the Primary end point.

With a median follow up of 14 months, the rate of intracranial clinical benefit was 57%, with a Complete Response rate of 26%, Partial Response rate of 30%, and 2% of the patients had stable disease for at least 6 months. Similar rates of Objective Response Rate (50%) and Clinical Benefit (56%) were observed for extracranial lesions. The median time to intracranial response was 2.3 months. The safety profile of the regimen was similar to that reported in patients with melanoma who did not have brain metastases, and treatment-related grade 3/ 4 Adverse Events were reported in 55% of patients.

It was concluded that OPDIVO® combined with YERVOY® is an effective treatment for metastatic melanoma patients with asymptomatic, untreated brain metastases. In this study, patients had clinically meaningful intracranial efficacy, concordant with extracranial activity. The safety profile in this population was similar to that reported in studies involving patients without brain metastases. This regimen should be considered as first-line therapy for all eligible metastatic melanoma patients, with brain metastases. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. Tawbi HA, Forsyth PA, Algazi A, et al. N Engl J Med 2018; 379:789-790

SUMMARY: The FDA on April 30, 2018, granted regular approval to TAFINLAR® (Dabrafenib) and MEKINIST® (Trametinib), in combination, for the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection. It is estimated that in the US, approximately 91,270 new cases of melanoma will be diagnosed in 2018 and about 9,320 patients are expected to die of the disease. The incidence of melanoma has been on the rise for the past three decades. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma, with a 5-year survival rate of 98% for stage I disease and 90% for stage II disease. Stage III malignant melanoma however is a heterogeneous disease, and the risk of recurrence is dependent on the number of positive nodes, as well as presence of palpable versus microscopic nodal disease. Further, patients with a metastatic focus of more than 1 mm in greatest dimension in the affected lymph node, have a significantly higher risk of recurrence or death than those with a metastasis of 1 mm or less. Patients with stage IIIA disease have a disease-specific survival rate of 78% whereas those patients with stage IIIB and stage IIIC disease have disease-specific survival rates of 59% and 40% respectively.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been demonstrated in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas and result in constitutive activation of the MAPK pathway.

TAFINLAR®,is a selective oral BRAF inhibitor and MEKINIST® is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with stage III melanoma, with BRAFV600E or V600K mutations, after complete surgical resection.

This FDA approval was based on COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, phase III trial, in which 870 patients with completely resected, stage III melanoma and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had stage IIIA disease, 41% had stage IIIB disease, and 40% had stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant metastasis-free survival, Freedom from relapse, and Safety.

At a median follow up of 2.8 years, the estimated 3-year RFS rate was 58% in the combination therapy group and 39% in the placebo group (HR=0.47; P<0.001), and this represented a 53% lower risk of relapse. At the time of this analysis, median RFS rate had not yet been reached in the combination therapy group and was 16.6 months in the placebo group. The improved RFS benefit with the combination therapy was consistent across patient subgroups, regardless of lymph node involvement or primary tumor ulceration. The risk of distant metastases or death was reduced by 49% with the combination therapy versus placebo (HR=0.51; P<0.001). The safety profile of TAFINLAR® plus MEKINIST® was consistent with that observed with the combination, in patients with metastatic melanoma, and the common side effects were pyrexia, fatigue, nausea, vomiting, diarrhea, headache, rash, arthralgia, and myalgia.

It was concluded that adjuvant combination therapy with TAFINLAR® plus MEKINIST® in patients with stage III melanoma with BRAF V600E or V600K mutations, resulted in a significantly lower risk of recurrence, compared to placebo, with no new adverse events. With more than half the patients with stage III melanoma having a recurrence after surgery, this first effective oral targeted combination therapy, will be an important adjuvant treatment option. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. Long GV, Hauschild A, Santinami M, et al. N Engl J Med 2017; 377:1813-1823