SUMMARY:Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody. The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. The anti–PD-1 antibody by blocking the PD-1 receptor essentially unleashes the immune system to fight off cancer cells. One hundred and thirty five patients with advanced melanoma regardless of their prior therapy with YERVOY® (Ipilimumab) received IV Lambrolizumab every 2-3 weeks. There was no difference in the response rates between patients who had prior therapy with YERVOY® and those who did not (38%). Majority of these patients had a rapid and durable response. The median progression-free survival was more than 7 months. The most common adverse events, mostly low grade were, fatigue, rash, pruritus, and diarrhea. The authors concluded that Lambrolizumab can significantly benefit patients with advanced Malignant Melanoma, regardless of their prior therapy with anti-CTLA 4 antibody, YERVOY® and with minimal toxicity. Hamid O, Robert C, Daud A, et al. N Engl J Med 2013; 369:134-144
Tag: Malignant Melanoma of the Skin
MEKINIST® (Trametinib)
MEKINIST® (Trametinib): The FDA on May 29, 2013 approved the use of MEKINIST® tablet for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutation, as detected by an FDA-approved test. The FDA also approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E and V600K mutations. MEKINIST® is not indicated for treatment of patients who had received prior BRAF inhibitor therapy. MEKINIST® is a product of GlaxoSmithKline, LLC.
TAFINLAR® (Dabrafenib)
TAFINLAR® (Dabrafenib): The FDA on May 29, 2013 approved the use of TAFINLAR® capsule for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. TAFINLAR® is not indicated for the treatment of patients with wild-type BRAF melanoma because of the potential risk of tumor proliferation. The FDA also approved the THxID BRAF assay (bioMerieux, Inc.) for detection of BRAF V600E mutations. TAFINLAR® is a product of GlaxoSmithKline, LLC.
Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma
SUMMARY:The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is an important signaling pathway which enables the cell to respond to external stimuli. There are a number of MAP kinase pathways, which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS 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 site and is detected in approximately 50% of melanomas.The BREAK-3 trial is a randomized phase III trial, with the study design similar to that of the Vemurafenib BRIM-3 trial. Dabrafenib is a selective oral BRAF inhibitor. Patients with advanced BRAFV600E mutated melanoma were randomized to receive either Dabrafenib or Dacarbazine (DTIC). Primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and duration of response. The median PFS was 5.1 months for Dabrafenib and 2.7 months for DTIC (hazard ratio = 0.30; P< 0.0001). RR was 53% for Dabrafenib and 19% for DTIC. OS data was not mature for analysis. Squamous cell carcinomas were seen in 6% of the patients. Hauschild A, Grob JJ, Demidov LV, et al. J Clin Oncol. 2012:30(suppl; abstr LBA8500).
METRIC phase III study Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAFV600E/K mutant advanced or metastatic melanoma (MM)
SUMMARY: The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is an important signaling pathway which enables the cell to respond to external stimuli. There are a number of MAP kinase pathways, which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS 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 site and is detected in approximately 50% of melanomas. Vemurafenib is a novel oral inhibitor of mutated BRAF. However, Vemurafenib may increase the risk of developing a secondary malignancy (squamous cell carcinoma). Trametinib is a very potent and selective inhibitor of MEK gene and by seeking out this mechanism of action, there is probably a lower risk of another activated event ie. secondary malignancies. This is because MEK is downstream from RAF in the MAP Kinase pathway. In a phase III trial, patients with advanced melanoma with BRAF V600E/K mutations and without brain metastases were randomized to receive Trametinib or chemotherapy (either dacarbazine or paclitaxel). Patients receiving chemotherapy were allowed to crossover to receive Trametinib if they had documented progression. Primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The outcomes were in favor of Trametinib with a PFS of 4.8 months vs 1.4 months (HR =0.44; P<0.0001), RR of 24% vs 7%, with a 47% reduction in the risk of death compared to chemotherapy. Robert C, Flaherty KT, Hersey P, et al. J Clin Oncol. 2012:30(suppl; abstr LBA8509).
Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600E BRAF-mutated melanoma
SUMMARY: The Mitogen- Activated Protein kinase pathway (MAP kinase pathway) is a key signaling pathway which enables the cell to respond external stimuli. There are a number of MAP kinase pathways which share different proteins at each step. The MAP kinase pathway plays a dual role regulating cytokine production and participating in cytokine dependent signaling cascade. The MAP kinase pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAS 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 mutations in melanoma is at the V600E site and is detected in approximately 50% of melanomas. Vemurafenib is a novel oral inhibitor of mutated BRAF. Based on the impressive phase I and phase II data, BRIM 3, a randomized, open-label, multicenter, phase III trial was conducted, in treatment naïve patients with unresectable Stage IIIC or Stage IV melanoma with V600E BRAF mutation. Patients in this trial received either Vemurafenib or Dacarbazine. The primary end points were progression- free survival and overall survival . There was a statistically significant improvement both in progression free survival and overall survival in the Vemurafenib group compared to those in the Dacarbazine group.This is a major advance in the field of personalized medicine and molecular targeted therapy. J Clin Oncol 29: 2011 (suppl; abstr LBA4)
Improving Survival in Metastatic Melanoma
Approximately 50% of the patients with melanoma have an activating BRAF mutation, V600E. Vemurafenib is an oral BRAF kinase inhibitor. In a randomized phase III study involving treatment naive patients with unresectable stage III or stage IV melanoma patients with BRAF mutation V600E, Vemurafenib significantly improved progression free survival (PFS) and overall survival (OS) compared to Dacarbazine (DTIC). This is a major advance in the field of personalized medicine and molecular targeted therapy. This information was presented at the 2011 ASCO meeting.
Improved Survival with Ipilimumab in Patients with Metastatic Melanoma
SUMMARY: T lymphocytes play an important role in cell mediated immunity. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4) also known as CD 152 is a protein expressed on the surface of T lymphocytes and has an inhibitory role in T cell function. Ipilimumab (YERVOY®) is a CTLA-4 targeted monoclonal antibody which was studied in metastatic malignant melanoma. MDX010-20 is a large double blind placebo controlled trial in which 676 HLA-A*0201–positive patients, with pretreated advanced melanoma, were randomly assigned to one of the three treatment groups- YERVOY® along with a placebo (137 patients), YERVOY® administered along with a peptide vaccine gp 100 (403 patients) or peptide vaccine gp 100 along with a placebo (136 patients). Patients receiving YERVOY® along with a peptide vaccine had a median survival of 10.1 months compared to 6.4 months for those who received the vaccine alone. This survival benefit for YERVOY® plus vaccine compared to vaccine alone was seen at 12 months (46% vs 25% ) and 24 months (24% vs 14%) respectively. Approximately 10-15% of the patients treated with YERVOY® experienced Grade 3 or 4 immune-related adverse events compared to 3% when treated with gp100 alone. This landmark study is a significant advance in the treatment of metastatic malignant melanoma, with an overall survival benefit. N Engl J Med 2010; 363:711-723
Oncoprescribe Blog Improving Survival in Advanced Malignant Melanoma
Advanced malignant melanoma has been an elusive disease with very few treatment options. There has been no treatment available to improve survival. That changed in June 2010 following the presentation of results from a landmark study.
Ipilimumab is an antibody that targets an antigen called CTLA-4 (Cytotoxic T- Lymphocyte-associated Antigen 4) present on the surface of T cells. T cells or T lymphocytes play a key role in cell mediated immunity. CTLA-4 which is present on the surface of T cells has a negative effect on T cell activation. By blocking CTLA-4, T cells are activated to attack and kill melanoma cells.
Ipilimumab in a randomized phase III trial doubled the survival rates compared to the control group. Studies are underway combining this agent with BRAF inhibitors. Stay tuned.
Oncoprescribe Blog Malignant Melanoma – An Elusive Disease?
Not anymore. A point mutation in the BRAF proto-oncogene has now been identified. This is detected in approximately 60% of the patients with metastatic melanoma. This mutation appears to be one of the key genetic drivers responsible of the initiation and progression of malignant melanoma. Several selective BRAF inhibitors are in development and these agents have demonstrated significantly high overall response rates. In addition to the anti-CTLA-4 monoclonal antibodies we may soon have a new player with a different mechanism of action to combat this deadly disease.