"The U.S. Food and Drug Administration today approved Zelboraf (vemurafenib), a drug to treat patients with late-stage (metastatic) or unresectable (cannot be removed by surgery) melanoma, the most dangerous type of skin cancer.
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Mechanism Of Action
CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab's effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
The pharmacokinetics of ipilimumab were studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. Peak concentration (Cmax ), trough concentration (C min ), and area under the plasma concentration versus time curve (AUC) of ipilimumab increased dose proportionally within the dose range examined. Upon repeated dosing every 3 weeks, the clearance (CL) of ipilimumab was found to be time-invariant, and systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean C min at steady-state was 19.4 mcg/mL following repeated doses of 3 mg/kg. The mean value (% coefficient of variation) generated through population pharmacokinetic analysis for the terminal half-life (t 1/2 ) was 15.4 days (34%) and for CL was 16.8 mL/h (38%).
The effects of various covariates on the pharmacokinetics of ipilimumab were assessed in population pharmacokinetic analyses. The CL of ipilimumab increased with increasing body weight; however, no dose adjustment is recommended for body weight after administration on a mg/kg basis. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23–88 years), gender, performance status, renal impairment, mild hepatic impairment, previous cancer therapy, and baseline lactate dehydrogenase (LDH) levels. The effect of race was not examined due to limited data available in non-Caucasian ethnic groups.
The effect of renal impairment on the CL of ipilimumab was evaluated in patients with mild (GFR < 90 and ≥ 60 mL/min/1.73 m²; n=349), moderate (GFR < 60 and ≥ 30 mL/min/1.73 m²; n=82), or severe (GFR < 30 and ≥ 15 mL/min/1.73 m²; n=4) renal impairment compared to patients with normal renal function (GFR ≥ 90 mL/min/1.73 m²; n=350) in population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with renal impairment and patients with normal renal function. [See Use in Specific Populations]
The effect of hepatic impairment on the CL of ipilimumab was evaluated in patients with mild hepatic impairment (TB 1.0 × to 1.5 × ULN or AST > ULN as defined using the National Cancer Institute criteria of hepatic dysfunction; n=76) compared to patients with normal hepatic function (TB and AST ≤ ULN; n=708) in the population pharmacokinetic analyses. No clinically important differences in the CL of ipilimumab were found between patients with mild hepatic impairment and normal hepatic function. YERVOY has not been studied in patients with moderate (TB > 1.5 × to 3 × ULN and any AST) or severe hepatic impairment (TB > 3 × ULN and any AST). [See Use in Specific Populations]
Animal Toxicology And/Or Pharmacology
In addition to the severe findings of abortion, stillbirths, and postnatal deaths observed in pregnant cynomolgus monkeys that received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition [see Use In Specific Populations], developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the clinically recommended dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/- heterozygous offspring. Mated CTLA-4+/- heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-). The CTLA-4-/- homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3–4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind, double-dummy study (Study 1) that included 676 randomized patients with unresectable or metastatic melanoma previously treated with one or more of the following: aldesleukin, dacarbazine, temozolomide, fotemustine, or carboplatin. Of these 676 patients, 403 were randomized to receive YERVOY at 3 mg/kg in combination with an investigational peptide vaccine with incomplete Freund's adjuvant (gp100), 137 were randomized to receive YERVOY at 3 mg/kg, and 136 were randomized to receive gp100 alone. The study enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The study excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. YERVOY/placebo was administered at 3 mg/kg as an intravenous infusion every 3 weeks for 4 doses. Gp100/placebo was administered at a dose of 2 mg peptide by deep subcutaneous injection every 3 weeks for 4 doses. Assessment of tumor response was conducted at weeks 12 and 24, and every 3 months thereafter. Patients with evidence of objective tumor response at 12 or 24 weeks had assessment for confirmation of durability of response at 16 or 28 weeks, respectively.
The major efficacy outcome measure was overall survival (OS) in the YERVOY+gp100 arm compared to that in the gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY+gp100 arm compared to the YERVOY arm, OS in the YERVOY arm compared to the gp100 arm, best overall response rate (BORR) at week 24 between each of the study arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the YERVOY+gp100, YERVOY, and gp100 arms, respectively, were men. Twenty-nine percent were ≥ 65 years of age, the median age was 57 years, 71% had M1c stage, 12% had a history of previously treated brain metastasis, 98% had ECOG performance status of 0 and 1, 23% had received aldesleukin, and 38% had elevated LDH level. Sixty-one percent of patients randomized to either YERVOY-containing arm received all 4 planned doses. The median duration of follow-up was 8.9 months.
The OS results are shown in Table 3 and Figure 1.
Table 3: Overall Survival Results
|YERVOY + gp100
|Hazard Ratio (vs. gp100) (95% CI)||0.66 (0.51, 0.87)||0.68 (0.55, 0.85)|
|Hazard Ratio (vs. YERVOY) (95% CI)||1.04 (0.83, 1.30)|
|Median (months) (95% CI)||10 (8.0, 13.8)||10 (8.5, 11.5)||6 (5.5, 8.7)|
|a Not adjusted for multiple comparisons.|
Figure 1: Overall Survival
The best overall response rate (BORR) as assessed by the investigator was 5.7% (95% CI: 3.7%, 8.4%) in the YERVOY+gp100 arm, 10.9% (95% CI: 6.3%, 17.4%) in the YERVOY arm, and 1.5% (95% CI: 0.2%, 5.2%) in the gp100 arm. The median duration of response was 11.5 months in the YERVOY+gp100 arm and has not been reached in the YERVOY or gp100 arm.
Last reviewed on RxList: 12/17/2013
This monograph has been modified to include the generic and brand name in many instances.
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