Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, PD-1/PD-L1 (Programmed cell death protein 1/death ligand 1) inhibitors. ATC code: L01FF06

Mechanism of action
Cemiplimab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds to the programmed cell death-1 (PD-1) receptor and blocks its interaction with its ligands PD-L1 and PD-L2.
Engagement of PD-1 with its ligands PD-L1 and PD-L2, which are expressed by antigen presenting cells and may be expressed by tumour cells and/or other cells in the tumour microenvironment, results in inhibition of T cell function such as proliferation, cytokine secretion, and cytotoxic activity. Cemiplimab potentiates T cell responses, including anti-tumour responses, through blockade of PD-1 binding to PD- L1 and PD-L2 ligands.

Clinical efficacy and safety
CSCC
The efficacy and safety of cemiplimab in patients with mCSCC (nodal or distant) or laCSCC who were not candidates for curative surgery or curative radiation were studied in clinical trial R2810-ONC-1540 (Study 1540). Study 1540 was a phase 2, open-label, multi-centre study that enrolled 193 patients with mCSCC or laCSCC in Groups 1 to 3 with a combined median follow-up time of 15.7 months total.

Median duration of follow-up was 18.5 months for the mCSCC 3 mg/kg every 2 weeks (Q2W) group (Group 1), 15.5 months for the laCSCC 3 mg/kg Q2W group (Group 2) , 17.3 months for the mCSCC 350 mg Q3W group (Group 3). In an additional cohort of 165 advanced CSCC patients (mCSCC and laCSCC) dosed at 350 mg Q3W, the median duration of follow-up was
8.7 months (Group 6).

Patients with any of the following were excluded: autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; history of pneumonitis within the last 5 years; prior treatment with anti-PD-1/PD-L1 or other immune checkpoint inhibitor therapy; active infection requiring therapy, including known infection with human immunodeficiency virus, or active infection with hepatitis B or hepatitis C virus; chronic lymphocytic leukaemia (CLL); brain metastases or Eastern Cooperative Oncology Group (ECOG) performance score (PS) ≥ 2.

In Study 1540, patients received cemiplimab intravenously (IV) until progression of disease, unacceptable toxicity or completion of planned treatment [3 mg/kg Q2W for 96 weeks (Groups 1 and 2) or 350 mg Q3W for 54 weeks (Group 3)]. If patients with locally advanced disease showed sufficient response to treatment, surgery with curative intent was permitted. Tumour response assessments were performed every 8 or 9 weeks (for patients receiving 3 mg/kg Q2W or 350 mg Q3W, respectively). The primary efficacy endpoint of Study 1540 was confirmed objective response rate (ORR), as assessed by independent central review (ICR). For patients with mCSCC without externally visible target lesions, ORR was determined by Response Evaluation Criteria in Solid Tumours (RECIST 1.1). For patients with externally visible target lesions (laCSCC and mCSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria). The key secondary endpoint was duration of response (DOR) by ICR.
Other secondary endpoints included ORR and DOR by investigator assessment (IA), progression free survival (PFS) by ICR and IA, overall survival (OS), complete response rate (CR) by ICR, and change in scores in patient reported outcomes on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30).

In the efficacy analysis of 193 patients with advanced CSCC from Study 1540 Groups 1 to 3, 115 had mCSCC and 78 had laCSCC. The median age was 72 years (range: 38 to 96): Seventy-eight (40.4%) patients were 75 years or older, 66 patients (34.2%) were 65 to less than 75 years, and 49 patients (25.4%) were less than 65 years. A total of 161 (83.4 %) patients were male, and 187 (96.9%) patients were White; the ECOG PS was 0 (44.6%) and 1 (55.4%). Thirty-three and 7/10 percent (33.7%) of patients had received at least 1 prior anti-cancer systemic therapy, 81.3% of patients had received prior cancer related surgery, and 67.9% of patients had received prior radiotherapy. Among patients with mCSCC, 76.5% had distant metastases, and 22.6% had only nodal metastases.

Efficacy results based on the final analysis of Study 1540 Groups 1 to 3 are presented in Table 3.

Table 3:         Efficacy results – Study 1540 - metastatic CSCC by dosing group, locally advanced CSCC 
Efficacy endpoints                                 mCSCC                 laCSCC               mCSCC cemiplimab:           cemiplimab:          cemiplimab:
3 mg/kg every 2      3 mg/kg every 2       350 mg every 3 weeks                 weeks                weeks
(Group 1)             (Group 2)            (Group 3)
(N = 59)              (N = 78)             (N = 56)

ICR                   ICR                    ICR
Confirmed objective response rate (ORR)a

ORR                                               50.8%                 44.9%                46.4% 95% CI for ORR                                (37.5, 64.1)          (33.6, 56.6)         (33.0, 60.3) Complete response (CR)b                           20.3%                 12.8%                19.6% Partial response (PR)                             30.5%                 32.1%                26.8% Stable disease (SD)                               15.3%                 34.6%                14.3% 
Progressive disease (PD)                              16.9%                  12.8%                  25.0% Duration of response (DOR)
Medianc (months)                                       NR                      41.9                  41.3 (95% CI)                                           (20.7,NE)               (20.5, 54.6)          (40.8, 46.3) Range (months)                                       2.8-38.9                1.9-54.6              4.2-46.3 Patients with DOR ≥ 6 months, %                       93.3%                   88.6%                 96.2% Time to response (TTR)
Median (months) range (min:max)                        1.9                    2.1                    2.1 (1.7: 21.8)             (1.8: 8.8)            (2.0: 22.8)
Progression-free survival (PFS)a, c
6 months                                               66.4%                   72.4%                 60.7% (95% CI)                                         (52.5, 77.1)            (60.1, 81.5)           (46.7, 72.1) 12 months                                               53.8%                  60.8%                 53.4% (95% CI)                                          (40.0, 65.8)           (47.8, 71.5)           (39.5, 65.4) Overall survival (OS)a, c
12 months                                               81.3%                  91.8%                 72.5% (95% CI)                                         (68.7, 89.2)           (82.6, 96.2)           (58.6, 82.5) CI: Confidence interval; ICR: Independent Central Review; NR: Not reached; NE: Not evaluable.
a.
In Groups 1, 2, and 3, median durations of follow-up were 18.5, 15.5, and 17.3 months, respectively.
b.
Only includes patients with complete healing of prior cutaneous involvement; laCSCC patients in Study 1540 required biopsy to confirm CR.
c.
Based on Kaplan Meier estimates.

Efficacy and PD-L1 status
Clinical activity was observed regardless of tumour PD-L1 expression status.

BCC
The efficacy and safety of cemiplimab in patients with laBCC or mBCC who had progressed on HHI therapy, were intolerant of prior HHI therapy, or had no better than SD after 9 months on HHI therapy (exclusive of treatment breaks), were evaluated in Study 1620, an open-label, multi-centre, non-randomised study. The study excluded patients with autoimmune disease that required systemic therapy with immunosuppressant agents within 5 years; history of solid organ transplant; prior treatment with anti–PD-1/PD-L1 therapy or other immune checkpoint inhibitor therapy; infection with HIV, hepatitis B or hepatitis C; or ECOG performance score (PS) ≥ 2.

Patients received cemiplimab 350 mg intravenously (IV) every 3 weeks for 5 cycles of 9 weeks followed by 4 cycles of 12 weeks up to 93 weeks of treatment. Treatment continued until disease progression, unacceptable toxicity or completion of planned treatment. Tumour assessments were performed every 9 weeks during cycles 1 to 5 and every 12 weeks during cycles 6 to 9. The major efficacy endpoints were confirmed ORR and DOR as assessed by ICR. Secondary efficacy outcomes included ORR and DOR by IA, PFS, OS, CR by ICR, and time to response. For patients with mBCC without externally visible target lesions, ORR was determined by RECIST 1.1. For patients with externally visible target lesions (laBCC and mBCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria).

A total of 138 patients with advanced BCC were included in the efficacy analysis of Study 1620, 84 patients with laBCC and 54 patients with mBCC.

In the laBCC group, the median age was 70.0 years (range: 42 to 89): 31 (37%) patients were <65 years old and 53 (63%) were 65 years or older. A total of 56 (67%) were male and 57 (68%) were White; the ECOG PS was 0 (61%) and 1 (39%); Eighty-three per cent (83%) of patients had received at least 1 prior cancer-related surgery and 35% of patients had >3 prior cancer-related surgeries (median: 3.0 surgeries, range: 1 to 43); 50% of patients had received at least 1 prior anti-cancer radiotherapy (RT) (median: 1.0 RT, range: 1 to 6).

In the mBCC group, the median age was 63.5 years (range: 38 to 90): 27 (50%) patients were <65 years old and 27 (50%) were 65 years or older. A total of 38 (70%) were male and 47 (87%) were White; the ECOG PS was 0 (67%) and 1 (33%); Eighty-five per cent (85%) of patients had received at least 1 prior cancer-related surgery and 28% of patients had >3 prior cancer-related surgeries (median: 2.0 surgeries, range: 1 to 8); 59% of patients had received at least 1 prior anti-cancer radiotherapy (RT) (median: 1.0 RT, range: 1 to 4).

All 138 patients were previously treated with a HHI, and 12% (16/138) of patients were previously treated with both vismodegib and sonidegib (as separate lines of therapy). Of the 84 laBCC patients, 71% (60/84) of patients discontinued HHI therapy due to disease progression, 38% (32/84) of patients discontinued HHI therapy due to intolerance and 2% (2/84) discontinued solely due to lack of response.
Of the 54 mBCC patients, 76% (41/54) of patients discontinued HHI therapy due to disease progression, 33% (18/54) of patients discontinued HHI therapy due to intolerance, and 6% (3/54) discontinued solely due to lack of response. Investigators could select more than one reason for discontinuation of prior HHI therapy for an individual patient.

Efficacy results are presented in Table 4.

Table 4:              Efficacy results for Study 1620 in locally advanced and metastatic basal cell carcinoma
Efficacy endpoints                                           laBCC                               mBCC cemiplimab 350 mg every 3          cemiplimab 350 mg every 3 weeks                    weeks
N=84                                N=54
ICR                                 ICR
Best overall response (BOR)a, b, c
Objective response rate                                   27 (32.1%)                           12 (22.2%) (ORR: CR+ PR) (95% CI)                                    (22.4, 43.2)                         (12.0, 35.6) Complete response (CR) rated                                6 (7.1%)                            1 (1.9%) (95 % CI)                                                  (2.7, 14.9)                          (0.0, 9.9) Partial response (PR) rate                               21 (25.0%)                             11 (20.4%) Progressive disease (PD) rate                             9 (10.7%)                             16 (29.6%) Duration of response (DOR)                               N=27 responders                        N=12 responders Mediane (months)                                              NR                                     16.7 (95% CI)                                                  (15.5, NE)                              (9.8, NE) Range (observed) (months)                               2.1 – 36.8+                            9.0 – 25.8+ Patients with DOR ≥ 6 months, %e                            88.5%                                  100.0% (95% CI)                                                 (68.4, 96.1)                            (100,  100) Time to response (TTR)                                   N=27 responders                        N=12 responders Median (months)                                                4.3                                    3.1 (Range)                                                  (2.1 - 21.4)                           (2.0 – 10.5) CI: Confidence interval; +: Denotes ongoing at last assessment; ICR: Independent Central Review; NR: Not reached; NE: Not evaluable a.
Median duration of follow-up: laBCC: 15.9 months, mBCC: 8.4 months.
b.
Includes 2 laBCC patients who met the inclusion criteria solely on the basis of “No better than stable disease (SD) after 9 months on HHI therapy”. BOR results by ICR were SD for 1 patient and NE for 1 patient.
c.
Includes 3 mBCC patients who met the inclusion criteria solely on the basis of “No better than SD after 9 months on HHI therapy”. BOR results by ICR were PR for 1 patient and SD for 2 patients.
d.
Locally advanced BCC patients in Study 1620 required biopsy to confirm complete response.
e.
Based on Kaplan Meier estimates.

Efficacy and PD-L1 status
Clinical activity was observed regardless of tumour PD-L1 expression status.

Elderly population
Of the 1281 patients treated with cemiplimab in clinical studies, 52.2% (669/1281) were less than 65 years, 25.9% (332/1281) were 65 to less than 75 years, and 21.9% (280/1281) were 75 years or older.

No overall differences in efficacy were observed between elderly patients and younger patients. There was a trend towards a higher frequency of serious adverse events and discontinuations due to adverse events in patients 65 years and older compared with patients aged less than 65 years.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Concentration data from 1063 patients with various solid tumours who received intravenous cemiplimab were combined in a population PK analysis.
At 350 mg Q3W, the mean cemiplimab concentrations at steady-state ranged between a Ctrough of 59 mg/l and a concentration at end of infusion (Cmax) of 171 mg/l. Steady-state exposure is achieved after approximately 4 months of treatment.

Cemiplimab exposure at steady-state in patients with solid tumours is similar at 350 mg Q3W and at 3 mg/kg Q2W.

Absorption
Cemiplimab is administered via the intravenous route and hence is completely bioavailable.

Distribution
Cemiplimab is primarily distributed in the vascular system with a volume of distribution at steady-state (Vss) of 5.9 l. Median Tmax occurs at the end of the 30-minute infusion.

Biotransformation
Specific metabolism studies were not conducted because cemiplimab is a protein. Cemiplimab is expected to degrade to small peptides and individual amino acids.

Elimination
Clearance of cemiplimab is linear at doses of 1 mg/kg to 10 mg/kg every two weeks. Cemiplimab clearance after the first dose is approximately 0.25 l/day. The total clearance appears to decrease by approximately 11% over time, resulting in a steady state clearance (CLss) of 0.22 l/day; the decrease in CL is not considered clinically relevant. The within dosing interval half-life at steady state is 22 days.

Linearity/non-linearity
At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, pharmacokinetics of cemiplimab were linear and dose proportional, suggesting saturation of the systemic target-mediated pathway.

Special populations
A population PK analysis suggests that the following factors have no clinically significant effect on the exposure of cemiplimab: age, gender, body weight, race, cancer type, albumin level, renal impairment, and mild to moderate hepatic impairment.

Renal impairment
The effect of renal impairment on the exposure of cemiplimab was evaluated by a population PK analysis in patients with mild (CLcr 60 to 89 ml/min; n= 396), moderate (CLcr 30 to 59 ml/min; n= 166), or severe (CLcr 15 to 29 ml/min; n= 7) renal impairment. No clinically important differences in the exposure of cemiplimab were found between patients with renal impairment and patients with normal renal function. Cemiplimab has not been studied in patients with CLcr <21 ml/min (see section 4.2).

Hepatic impairment
The effect of hepatic impairment on the exposure of cemiplimab was evaluated by population PK analysis in patients with mild hepatic impairment (n= 22) (total bilirubin [TB] greater than 1.0 to 1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [AST]) and patients with moderate hepatic impairment (n=3) (total bilirubin >1.5 times ULN up to 3.0 times ULN) and any AST; no clinically important differences in the exposure of cemiplimab were found compared to patients with normal hepatic function. Cemiplimab has not been studied in patients with severe hepatic impairment.
There are insufficient data in patients with severe hepatic impairment for dosing recommendations (see section 4.2).