"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.
Mechanism Of Action
CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that 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, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T cell responsiveness, including the anti-tumor immune response.
The pharmacokinetics (PK) of ipilimumab was 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. The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent coefficient of variation) based on population PK analysis for the terminal half-life (t½) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%).
The effects of various covariates on the PK of ipilimumab were assessed in population PK analyses. The CL of ipilimumab increased with increasing body weight supporting the recommended body weight (mg/kg) based dosing. The following factors had no clinically important effect on the CL of ipilimumab: age (range: 23 to 88 years), sex, 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 PK 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 (n=76) compared to patients with normal hepatic function (n=708) in the population PK analyses, and no clinically important differences in the CL of ipilimumab were found. YERVOY has not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations].
Unresectable Or Metastatic Melanoma
The safety and efficacy of YERVOY were investigated in a randomized (3:1:1), double-blind, double-dummy trial (Trial 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 as a single agent. The trial enrolled only patients with HLA-A2*0201 genotype; this HLA genotype facilitates the immune presentation of the investigational peptide vaccine. The trial 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 plus gp100 arm compared to that in the single-agent gp100 arm. Secondary efficacy outcome measures were OS in the YERVOY plus 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 trial arms, and duration of response.
Of the randomized patients, 61%, 59%, and 54% in the YERVOY plus 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 7 and Figure 1.
Table 7: Overall Survival Results
|Hazard Ratio (vs. gp100)||0.66||0.68|
|(95% CI)||(0.51, 0.87)||(0.55, 0.85)|
|Hazard Ratio (vs. YERVOY)||1.04|
|(95% CI)||(0.83, 1.30)|
|(95% CI)||(8.0, 13.8)||(8.5, 11.5)||(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 plus 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 plus gp100 arm and has not been reached in the YERVOY or gp100 arm.
Adjuvant Treatment Of Melanoma
The safety and efficacy of YERVOY for the adjuvant treatment of melanoma were investigated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in patients with resected Stage IIIA ( > 1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) histologically confirmed cutaneous melanoma. Patients were randomized to receive YERVOY 10 mg/kg or placebo as an intravenous infusion every 3 weeks for 4 doses, followed by YERVOY 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (3 years) or until documented disease recurrence or unacceptable toxicity. Enrollment required complete resection of melanoma with full lymphadenectomy within 12 weeks prior to randomization. Patients with prior therapy for melanoma, autoimmune disease, and prior or concomitant use of immunosuppressive agents were ineligible. Randomization was stratified by stage according to American Joint Committee on Cancer (AJCC) 2002 classification (Stage IIIA > 1 mm nodal involvement, Stage IIIB, Stage IIIC with 1 to 3 involved lymph nodes, and Stage IIIC with ≥ 4 involved lymph nodes) and by region (North America, Europe, and Australia). The major efficacy outcome measures were recurrence-free survival (RFS) defined as the time between the date of randomization and the date of first recurrence (local, regional, or distant metastasis) or death, whichever occurs first and assessed by an independent review committee and overall survival. Tumor assessment was conducted every 12 weeks for the first 3 years then every 24 weeks until distant recurrence.
Among 951 patients enrolled, 475 were randomized to receive YERVOY and 476 to placebo. Median age was 51 years old (range: 18 to 84), 62% were male, 99% were white, 94% had ECOG performance status of 0. With regard to disease stage, 20% had Stage IIIA with lymph nodes > 1 mm, 44% had Stage IIIB, and 36% had Stage IIIC (with no in-transit metastases). Other disease characteristics of the trial population were: clinically palpable lymph nodes (58%), 2 or more positive lymph nodes (54%), and ulcerated primary lesions (42%).
The RFS results are in Table 8 and Figure 2. Based on the observation of 282 deaths at the time of the RFS analysis, the final analysis of overall survival has not occurred (planned at the time of 491 deaths).
Table 8: Efficacy Results in Trial 2
|Number of Events, n (%)||234 (49%)||294 (62%)|
|(95% CI)||(19, 39)||(13, 22)|
|(95% CI)||(0.64, 0.90)|
|p-value (stratified log-ranka)||p < 0.002|
|a Stratified by disease stage.|
Figure 2: Recurrence-Free Survival
Last reviewed on RxList: 11/5/2015
This monograph has been modified to include the generic and brand name in many instances.
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