Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Regeneron Ireland Designated Activity Company (DAC), Europa House, Harcourt Centre, Harcourt Street, Dublin 2, Ireland
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies
ATC code: not yet assigned
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.
The efficacy and safety of cemiplimab in patients with metastatic (nodal or distant) CSCC (mCSCC) or locally advanced CSCC (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 had enrolled 193 patients with mCSCC or laCSCC with a combined median follow-up time of 9.4 months total. Median follow-up was 16.5 months for the mCSCC 3 mg/kg every 2 weeks group, 9.3 months for the laCSCC 3 mg/kg every 2 weeks group and 8.1 months for the mCSCC 350 mg every 3 weeks group.
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 ≥2.
In Study 1540, patients received cemiplimab until progression of disease, unacceptable toxicity or completion of planned treatment [3 mg/kg every 2 weeks for 96 weeks or 350 mg every 3 weeks for 54 weeks]. 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 every 2 weeks or 350 mg every 3 weeks, respectively). The primary endpoint of Study 1540 was confirmed objective response rate (ORR), as assessed by independent central review (ICR). For patients with metastatic CSCC 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 (locally advanced CSCC and metastatic CSCC), ORR was determined by a composite endpoint that integrated ICR assessments of radiologic data (RECIST 1.1) and digital medical photography (WHO criteria). Secondary endpoints were duration of response (DOR) by ICR and by investigator assessment (IA), ORR by IA, progression free survival (PFS) by ICR and IA, overall survival (OS), complete response rate (CRR) 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).
Results are presented from 193 patients in Study 1540. Of these 193 patients, 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 performance score was 0 (44.6%) or 1 (55.4%). Thirty-three and 7/10 per cent (33.7%) of patients had received at least 1 prior anti-cancer systemic therapy, 90.2% 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 for Study 1540 are presented in Table 3.
Table 3. Efficacy results – Study 1540 – metastatic CSCC by dosing group, locally advanced CSCC:
| mCSCC cemiplimab: 3 mg/kg Q2W ((Group 1) (N=59) | laCSCC cemiplimab: 3 mg/kg Q2W ((Group 2) (N=78) | mCSCC cemiplimab: 350 mg Q3W ((Group 3) (N=56) | |
|---|---|---|---|
| ICR | ICR | ICR | |
| Confirmed objective response rate (ORR)a | |||
| ORR | 49,20% | 43,60% | 39,30% |
| 95% CI for ORR | (35,9, 62,5) | (32,4, 55,3) | (26,5, 53,2) |
| Complete response (CR)b | 16,90% | 12,80% | 3,60% |
| Partial response (PR) | 32,20% | 30,80% | 35,70% |
| Stable disease (SD) | 15,30% | 35,90% | 14,30% |
| Progressive disease (PD) | 16,90% | 11,50% | 26,80% |
| ICR | ICR | ICR | |
| Duration of response (DOR)a | |||
| Median (range) (months) | NR (2,8-21,6+) | NR (1,9 – 24,2+) | NR (2,1-11,1+) |
| Patients with DOR ≥6 months, % | 93,10% | 67,60% | 63,60% |
| Time to response | |||
| Median (months) range (min:max) | 1,9 | 1,9 | 2,1 |
| (1,7: 9,1) | (1,8: 8,8) | (2,0: 8,3) | |
| Progression free survival (PFS)a,c | |||
| 6 months | 66,00% | 71,50% | 59,30% |
| (52,0, 76,8) | (58,9, 80,9) | (45,0, 71,0) | |
| 12 months | 53,10% | 58,10% | 44,60% |
| (39,1, 65,2) | (43,7, 70,0) | (26,5, 61,3) | |
| Overall survivala,c,d | |||
| 12 months | 81,3% | 93,2% | 76,1% |
| (68,7, 89,2) | (84,4, 97,1) | (56,9, 87,6) | |
Data cut-off was Sep 20, 2018 for Groups 1 and 3 patients, and Oct 10, 2018 for Group 2 patients.
CI: confidence interval; ICR: Independent Central Review; NR: Not Reached; +: Denotes ongoing at last assessment
a In Groups 1, 2, and 3, median durations of follow-up were 16.5, 9.3, and 8.1 months, respectively.
b Only includes patients with complete healing of prior cutaneous involvement; locally advanced CSCC patients in Study 1540 required biopsy to confirm complete response.
c Based on Kaplan Meier estimates
d Overall survival does not require central review.
Clinical activity was observed regardless of tumour PD-L1 expression status. The relationship between PD-L1 status and efficacy was analysed post-hoc in patients with available tissue samples. Overall in Studies 1423 and 1540, PD-L1 IHC results were available for 75 advanced CSCC patients. Among 22 advanced CSCC patients with PD-L1 <1%, ORR per independent central review was 40.9% (9/22). Among 53 advanced CSCC patients with PD-L1 ≥1%, ORR was 54.7% (29/53). Among 21 mCSCC patients, ORR was 60% (3/5) in patients with PD-L1 <1% and 56.3% (9/16) among patients with PD-L1 ≥1%. Among 54 patients with laCSCC, ORR was 35.3% (6/17) in patients with PD-L1 <1% and 54.1% (20/37) among patients with PD-L1 ≥1%.
Of the 219 patients with mCSCC and laCSCC treated with cemiplimab, 25.1% (55/219) were less than 65 years, 34.2% (75/219) were 65 to less than 75 years, and 40.6% (89/219) were 75 years or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
In the 193 patients in the efficacy analysis, the objective response rate by ICR (95% CI) was 40.8% (27.0%, 55.8%) in patients less than 65 years, 48.5% (36.0%, 61.1%) in patients 65 to less than 75 years, and 42.3% (31.2%, 54.0%) in patients 75 years or older.
The European Medicines Agency has deferred the obligation to submit the results of studies with cemiplimab in all subsets of the paediatric population in the treatment of all conditions included in the category of malignant neoplasms, except haematopoietic and lymphoid tissue (see section 4.2 for information on paediatric use).
This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.
Concentration data were collected in 548 patients with various solid tumours, including 178 patients with CSCC, who received cemiplimab. At dosing regimens of 1 mg/kg to 10 mg/kg every 2 weeks and 350 mg every 3 weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the target-mediated pathway over the dosing interval. Similar exposures to cemiplimab are achieved with the doses of 350 mg every 3 weeks and 3 mg/kg every 2 weeks. With 350 mg every 3 weeks, the mean steady-state concentration of cemiplimab ranged between Cmax of 168 mg/l and a C trough of 61 mg/l. Steady-state exposure is achieved after approximately 4 months of treatment.
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) is 5.2 l.
Specific metabolism studies were not conducted because cemiplimab is a protein. Cemiplimab is expected to degrade to small peptides and individual amino acids.
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 0.33 l/day. The total clearance appears to decrease by approximately 35% over time, resulting in a steady state clearance (CLss) of 0.21 l/day; the decrease in CL is not considered clinically relevant. The within dosing interval half-life at steady state is 19.4 days.
At the dosing regimens of 1 mg/kg to 10 mg/kg every two weeks, kinetics of cemiplimab were observed to be linear and dose proportional, suggesting saturation of the 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, mild hepatic impairment and renal 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=197), moderate (CLcr 30 to <60 ml/min; n=90), or severe (CLcr <30 ml/min; n=4) 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 <25 ml/min (see section 4.2).
The effect of hepatic impairment on the exposure of cemiplimab was evaluated by population PK analysis. In patients with mild hepatic impairment (n=5) (total bilirubin [TB] greater than 1.0 to 1.5 times the upper limit of normal [ULN] and any aspartate aminotransferase [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 moderate or severe hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations (see section 4.2).
No studies have been performed to test the potential of cemiplimab for carcinogenicity or genotoxicity. Animal reproduction studies have not been conducted with cemiplimab (see section 4.6). As reported in the literature, PD-1/PD-L1 signalling pathway plays a role in sustaining pregnancy by maintaining immunological tolerance and studies have shown that PD-1 receptor blockade results in early termination of pregnancy. The increase of spontaneous abortion and/or resorption in animals with restricted PD-L1 expression (knock-out or anti-PD1/PD-L1 monoclonal antibodies) has been shown in both mice and monkeys. These animal species have similar maternal-foetal interface to that in humans.
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