Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FY02.

Mechanism of action
Opdualag is a fixed-dose combination (FDC) of nivolumab, a programmed death-1 inhibitor (anti-PD-1) and relatlimab, a lymphocyte-activation gene-3 inhibitor (anti-LAG-3).

Binding of the PD-1 ligands, PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumours, and signalling through this pathway can contribute to inhibition of active T cell immune surveillance of tumours. Nivolumab is a human IgG4 monoclonal antibody that binds to the PD-1 receptor, blocks interaction with its ligands PD-L1 and PD-L2 and reduces PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response. In syngeneic mouse tumour models, blocking PD-1 activity resulted in decreased tumour growth.

Relatlimab is a human IgG4 monoclonal antibody that binds to the LAG-3 receptor, blocks its interaction with ligands, including MHC II, and reduces LAG-3 pathway-mediated inhibition of the immune response. Antagonism of this pathway promotes T cell proliferation and cytokine secretion.

The combination of nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) results in increased T-cell activation compared to the activity of either antibody alone. In murine syngeneic tumour models, LAG-3 blockade potentiates the anti-tumour activity of PD-1 blockage, inhibiting tumour growth and promoting tumour regression.

Cliniacl studies
The efficacy of OPDUALAG was investigated in RELATIVITY-047 (NCT03470922), a randomized (1:1), double-blinded trial in 714 patients with previously untreated metastatic or unresectable Stage III or IV melanoma. Patients were allowed to have received prior adjuvant or neoadjuvant melanoma therapy: anti-PD-1, anti-CTLA-4, or BRAF-MEK inhibitors were allowed if received at least 6 months between the last dose of therapy and date of recurrence; interferon therapy was allowed if the last dose was at least 6 weeks prior to randomization. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. Patients were randomized to receive OPDUALAG (nivolumab 480 mg and relatlimab 160 mg) by intravenous infusion every 4 weeks (n=355) or nivolumab 480 mg by intravenous infusion every 4 weeks (n=359) until disease progression or unacceptable toxicity. Randomization was stratified by tumor PD-L1 expression (1% vs. <1%) using PD-L1 IHC 28-8 pharmDx test, LAG-3 expression (1% vs. <1%) using a clinical trial assay, BRAF V600 mutation status (V600 mutation positive vs. wild type), and M stage per the American Joint Committee on Cancer (AJCC) version 8 staging system (M0/M1any[0] vs. M1any[1]).
The major efficacy outcome measure was progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR) determined by BICR using RECIST v1.1. Tumor assessments were conducted 12 weeks after randomization and continued every 8 weeks up to week 52 and then every 12 weeks.
The trial population characteristics were: median age 63 years (range: 20 to 94); 58% male; 97% White 0.7% African American, and American Indian/Alaskan Native 0.1%; Hispanic 7%; and ECOG performance score was 0 (67%) or 1 (33%). Disease characteristics were: PD-L1 expression ≥1% (41%), LAG-3 expression ≥1% (75%), AJCC Stage IV disease (92%), M1c disease (39%); M1d disease (2.4%), elevated LDH (36%), and BRAF V600 mutation-positive melanoma (39%).
The trial demonstrated a statistically significant improvement in PFS for patients randomized to the OPDUALAG arm compared with the nivolumab arm. The final analysis of OS was not statistically significant. Efficacy results are shown in Table 3 and Figure 1.

Table 3:           Efficacy Results in RELATIVITY-047

OPDUALAG                              Nivolumab
N=355                                 N=359
Progression-free Survivala,b
Disease progression or death (%)                  180 (51)                             211 (59) 
Median (months)c (95% CI)                     10.1 (6.4, 15.7)                       4.6 (3.4, 5.6) 
Hazard ratiod (95% CI)                                           0.75 (0.62, 0.92)  p-valuee                                                              0.0055 
Overall Survivalf

Deaths (%)                                        137 (39)                             160 (45) 
Median in months (95% CI)                      NR (34.2, NR)                    34.10 (25.2, NR) 
Hazard ratiod (95% CI)                                           0.80 (0.64, 1.01)  p-valuee                                                               NSg Overall Response Ratea,f, h, n (%)                153 (43)                             117 (33) (95% CI)                                          (38, 48)                             (28, 38) Complete response rate (%)                         58 (16)                              51 (14) 
Partial response rate (%)                          95 (27)                              66 (18) a
Assessed by BICR.
b
Final PFS analysis.
c
Kaplan-Meier estimate.
d
Based on stratified Cox proportional hazard model.
e
Based on stratified log-rank test.
f
At the time of the final OS analysis, which was event-driven and occurred after the final PFS analysis.
g
Not Significant at alpha level 0.04302.
h
Not formally tested based on the testing hierarchy.
NR = Not reached.

Figure 1:        Progression-free Survival - RELATIVITY-047



In exploratory analyses, hazard ratio (HR) point estimates for PFS favoured OPDUALAG across pre- specified subgroups, including those defined by the study stratification factors (PD-L1, LAG-3 and BRAF status, and M-stage per AJCC version 8), and key clinical subgroups including baseline ECOG performance status, age, history of brain metastases, and baseline LDH level.

In the PD-L1 <1% subgroup, the HR (95% CI) for PFS was 0.66 (0.51, 0.84) with median PFS of 6.4 and 2.9 months for the OPDUALAG and nivolumab arms, respectively. In the PD-L1 ≥1% subgroup, the HR for PFS was 0.95 (95% CI: 0.68, 1.33) with median PFS of 15.7 and 14.7 months for the OPDUALAG and nivolumab arms, respectively.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

The pharmacokinetics (PK) of relatlimab following the administration of nivolumab in combination with relatlimab was characterised in patients with various cancers who received relatlimab doses of 20 to 800 mg every 2 weeks and 160 to 1440 mg every 4 weeks either as a monotherapy or in combination with nivolumab doses of 80 or 240 mg every 2 weeks or 480 mg every 4 weeks.

Steady-state concentrations of relatlimab were reached by 16 weeks with an every 4-week regimen and the systemic accumulation was 1.9-fold. The average concentration (Cavg) of relatlimab after the first dose increased dose proportionally at doses ≥ 160 mg every 4 weeks.


Table 4:        Geometric mean (CV%) of nivolumab and relatlimab steady-state exposures following 480 mg nivolumab and 160 mg relatlimab fixed-dose combination every 4 weeks
Cmax (μg/mL)           Cmin (μg/mL)           Cavg (μg/mL)
Relatlimab      62.2 (30.1)            15.3 (64.3)            28.8 (44.8) Nivolumab       187 (32.9)             59.7 (58.6)            94.4 (43.3) 
Based on population PK analyses, the nivolumab and relatlimab FDC infusion duration of 30 min and 60 min were predicted to produce similar (< 1% different) exposures of nivolumab and relatlimab.

In CA224047, the nivolumab geometric mean Cmin at steady state in the nivolumab in combination with relatlimab arm was similar to the nivolumab arm with a geometric mean ratio of 0.931 (95% CI: 0.855-1.013).

Distribution
The geometric mean value (CV%) for nivolumab volume of distribution at steady state is 6.65 L (19.2%) and relatlimab is 6.65 L (19.8%).

Biotransformation
Nivolumab and relatlimab are therapeutic mAb IgG4 that are expected to be catabolised into small peptides, amino acids, and small carbohydrates by lysosome or receptor-mediated endocytosis.

Elimination
Nivolumab clearance is 21.1% lower [geometric mean (CV%), 7.57 mL/h (40.1%)] at steady state than that after the first dose [9.59 mL/h (40.3%)] and the terminal half-life (t1/2) is 26.5 days (36.4%).

Relatlimab clearance is 9.7% lower [geometric mean (CV%), 5.48 mL/h (41.3%)] at steady state than that after the first dose [6.06 mL/h (38.9%)]. Following administration of relatlimab 160 mg and nivolumab 480 mg administered every 4 weeks, the geometric mean (CV%) effective half-life (t1/2) of relatlimab is 26.2 days (37%).

Special populations
A population PK analysis suggested that the following factors had no clinically important effect on the clearance of nivolumab and relatlimab: age (range: 17 to 92 years), sex, [male (1056) and female (657)], or race [Caucasian (1655), African American (167) and Asian (41)]. The body weight (range: 37 to 170 kg) was a significant covariate on the nivolumab and relatlimab PK, however, there is no clinically relevant impact based on exposure-response analysis.

Paediatric population
Limited data suggest that nivolumab clearance and volume of distribution in adolescent subjects with solid tumours were 36% and 16% lower, respectively, than those of adult reference patients. It is unknown if the same holds for melanoma patients and if relatlimab clearance and volume of distribution are also lower in adolescents than adults. However, based on population PK simulations, the exposure of nivolumab and relatlimab in adolescents weighing at least 30 kg are expected to result in similar safety and efficacy to that of adults of the same weight, at the same recommended dose.

Renal impairment
The effect of renal impairment on the clearance of nivolumab and relatlimab was evaluated by a population PK analysis in patients with mild or moderate renal impairment compared to patients with normal renal function. No clinically important differences in the clearance of nivolumab or relatlimab were found between patients with renal impairment and patients with normal renal function.

Hepatic impairment
The effect of hepatic impairment on the clearance of nivolumab and relatlimab was evaluated by population PK analysis in patients with mild hepatic impairment (total bilirubin [TB] less than or equal to upper limit of normal [ULN] and AST greater than ULN or TB greater than 1 to 1.5 times ULN and any AST) or moderate hepatic impairment (TB greater than 1.5 to 3 times ULN and any AST) compared to patients with normal hepatic function. No clinically important differences in the clearance of nivolumab or relatlimab were found between patients with hepatic impairment and patients with normal hepatic function.

Immunogenicity
The observed low incidence rate of treatment emergent anti-nivolumab antibody and treatment emergent anti-relatlimab antibody had no effects on PK of nivolumab and relatlimab.