A fully human monoclonal immunoglobulin (IgG1kappa) specific for CTLA composed of four polypeptide chains, to identical heavy chains consisting of 467 amino acids, and two identical light chains with 235 amino acids.

Yervoy trade name.

Has high affinity for CTLA-4 and impedes the binding of CTLA-4 to B7 preventing down regulation of immune response.

Induces antitumor immune responses by removing a key negative regulator and T cell activation.

The first agent to demonstrate improved overall survival for patients with advanced melanoma.

Durable benefits have been noted with approximately 20% of patients surviving at least five years.

Can increase proliferation of activated T cells and increases the interactions of T cells and cancer cells, by preventing down regulation of the immune response.

A fully human monoclonal and a body that blocks cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4).

Cytotoxic T- lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint molecule that can down regulate pathways of T cell activation (Melero T).

Indicated for unresectable or metastatic melanoma.

Approved for adjuvant treatment of patients with stage III melanoma with nodal involvement following complete resection and lymphadenectomy.

In adjuvant therapy the drug reduces recurrence rate by 25% vs placebo.

Anti-CTLA-4 monoclonal antibody.

A treatment option for patients with either BRAF mutated or BRAF wild type metastatic melanoma.

While clinical response to chemotherapy is usually rapid, disease control by anti-CTLA-4 monoclonal anti-bodies can be late in onset and occur after an initial disease progression.

A decreased absolute neutrophil/lymphocyte ratio correlates with response to treatment, is an early marker of response.

Administered as 4 treatments at 3 week intervals.

90 minute infusions of 3mg/kg.

Premedications and antiemetics not needed.

In adjuvant treatment dose 10mg/kg.

Cost about $145 per mg, or about $120,000 per dose.

In patients with advanced melanoma ipilimumab10 mg per kilogram results in a significantly longer overall survival than ipilimumab 3 mg per kilogram, but with increased treatment related adverse events (Ascierto PA).

Dose adjustments for hepatic and renal dysfunction not needed.

Before each infusion AST, ALT, bilirubin, and thyroid function tests should be evaluated.

A total of 676 HLA-A0201 positive patients when unresectable stage III or IV melanoma whose disease has progressed were randomized to receive ipilimumab plus gp100, ipilimumab alone, or gp100 alone: Median survival 10 months among patients receiving ipilimubab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (Hodi FS).

In a phase 3 study with more than 70% of the patients with M1c disease indicating the presence of visceral metastases, with more than 36% with an elevated LDH, both indicating poor survival (Hodi FS).

10-25% of patients who ultimately benefited from the drug in phase II trials initially experienced tumor growth or new lesions.

In a phase III study as primary treatment of either unresectable stage III or metastatic stage IV melanoma comparing dacarbazine with dacarbazine with ipilimumab: Ipilimumab -containing regimen at a higher objective response rate of 15.2% versus 10.3%, improved progression free response of median 2.8 versus 2.6 months and overall median survival of 11.2 versus 9.1 months, and 3 year overall survival was 20.8% versus 12.2%.

In a randomized phase III study of ipilimumab plus DTIC or placebo plus DTIC, the ipilimumab/DTIC on had an overall survival rate of 47.3% at one year, 28.5% at 2 years and 20.8% at 3 years compared to overall survival rates of the DTIC alone or in of 36.3% at one year, 17.9% at 2 years and 12.2% at 3 years (Study 024).

A pooled analysis of almost 5000 patients receiving ipilimumab presented at the European Cancer Congress 2013 demonstrated a plateau in the survival curves occurred at 3 years, with about 20% of the patients achieving this, with a measurable response around 10%.

The analysis of the 1861 patients showed that the median overall survival was 11.4 months, and among these patients, 254 patients (22%) were still alive after three years.

There were no deaths among patients who survived beyond seven years.

Patients have demonstrable disease but it remains stable and does not lead to host deterioration, morbidity, and death.

Changes to the immune system triggered by the drug are sustained and not degraded with time.

One phase III clinical trial showing an overall survival rate of 18% after five years, with the plateau starting at three years and continues through ten years.

Inflammatory Tcell infiltrates can produce tissue necrosis within 12 weeks, which may be mild to life threatening: skin, gastrointestinal tract, liver and endocrine systems can be affected.

Can result in severe and fatal immune mediated adverse reactions due to T cell activation and proliferation.

Its toxic effects arise from immune dysregulation resulting in ab2242ant targeting of antigens in normal tissue.

Only a minority of patients, 27%, have an exacerbation of their autoimmune disease with therapy indicating that patients with concurrent autoimmune disease can be safely given this drug.

Immune related adverse events include colitis, hepatitis, dermatitis, hypophysitis, adrenal insufficiency, hypothyroidism, and neuropathies.

Patients with baseline autoimmune disease generally excluded from clinical trials. Margie over

Immune mediated reactions may involve any organ system but the most common severe immune mediated adverse reactions are enterocolitis, hepatitis, dermatitis, neuropathy, an endocrinopathy.

Majority of immune responses occur with treatment, and a minority can occur within weeks to months of discontinuing therapy.

Discontinuation of therapy and the use of high dose corticosteroids is the treatment for immune-mediated reactions.

Most common reactions include: fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%) and colitis (8%).

GI tract side effects occur in 10% to 35% of patients and include: colitis, nausea, vomiting, abdominal pain, increased liver function tests (LFTs), and increased bilirubin levels.

15% of patients have grade 3-4 immune related rash and colitis

Colitis generally occurs approximately 6 to 7 weeks after initiation of treatment.

Moderate colitis with <6 bowel movements per day can be managed by temporarily discontinuing Ipilimumab, and starting on anti-diarrhea medications.

If the symptoms persist for more than 1 week, then oral prednisone can be started at a dose of 0.5 mg/kg/day and slowly tapered.

Persistence of diarrhea, with high fever, peritoneal signs and >7 bowel movements per day is considered severe colitis, and prednisone 1-2 mg/kg/day should be started and ipilimubab permanently withdrawn.

Once the diarrhea has subsided, the steroids should be tapered over at least a 1-month to pevent rebound symptoms.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma and the addition of GM-CSF results on longer overall survival and lower toxicity, but no difference in progression free survival.

The addition of GM-CSF to ipilimubab resulted in 69% survival of patients at 1 year, with metastatic melanoma compared to 53% of those that got ipilimubab alone, for a 35% reduction in risk of death (Hodi SF et al).

Adjuvant ipilimumab for patients with lymph node positive stage III melanoma randomized to ipilimumab vs placebo decreased recurrence by 25% after median follow up at 2.7 years (Eggermont et al).

Combining Nivolumab and Ipilimumab for the treatment of advanced melanoma: ipilimumab was held at a fixed dose of 3 mg/kg while nivolumab was escalated from 0.3 mg/kg to 3 mg/kg. The drugs were given together every 3 weeks for a total of 4 doses demonstrated an objective response rate of 40% and an 80% survival rate at 1 year.

In the above study there was a 1-year survival of 85%, 2-year survival rate of 79%, and median survival of 40 months in the first 53 patients.

Survival curve plateaus at about 3 years, with 20-30% of patients surviving at that time.

The extended use of Ipilimumab approval was based in the results from the international, double-blind phase 3 EORTC 18071 trial involving 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes.

In the above study patients were randomized in a 1:1 ratio to receive ipilimumab ( 10 mg/kg IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years.

The median relapse free survival (RFS) was 26.1 versus 17.1 months with ipilimumab versus placebo, respectively, and the 3-year RFS rate was 46.5% in the ipilimumab arm compared with 34.8% in the placebo group.

Nivolumab and ipilimubab in metastatic renal cell cancer decrease risk of death by 32% compared with sunitinib with a median overall survival that has not been reached versus 32.9 months with sunitinib (Checkmate 214 study).

In the above study the combination of ipilimumab and nivolumab had an objective response rate of 39% vs 32% for sunitinib.

The above combination approved as treatment for renal cell cancer.

The addition of ipilmubab increases the response rate of nivolumab from 50% to 80% in miscrosatellite instability-high patients, and the combination is approved by FDA.

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