Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Merck Europe B.V., Gustav Mahlerplein 102, 1082 MA Amsterdam, The Netherlands
Pharmacotherapeutic group: Other antineoplastic agents, monoclonal antibodies
ATC code: L01XC31
Avelumab is a human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the programmed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses.
Avelumab has also shown to induce natural killer (NK) cell-mediated direct tumour cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC).
The efficacy and safety of avelumab was investigated in the study EMR100070-003 with two parts. Part A was a single-arm, multi-centre study conducted in patients with histologically confirmed metastatic MCC, whose disease had progressed on or after chemotherapy administered for distant metastatic disease, with a life expectancy of more than 3 months. Part B included patients with histologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in the metastatic setting.
Patients with active or a history of central nervous system (CNS) metastasis; active or a history of autoimmune disease; a history of other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C were excluded.
Patients received avelumab at a dose of 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than two weeks, and no need for salvage therapy could continue treatment.
Tumour response assessments were performed every 6 weeks, as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.
For Part A, the major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacy outcome measures included duration of response (DOR), and progression-free survival (PFS).
For Part A, an updated efficacy analysis was conducted in all 88 patients after a minimum follow-up of 24 months. Patients received a median of 7 doses of avelumab (range: 1 dose to 72 doses), and the median duration of treatment was 17 weeks (range: 2 weeks to 158 weeks).
Of the 88 patients, 65 (74%) were male, the median age was 73 years (range 33 years to 88 years), 81 (92%) patients were Caucasian, and 49 (56%) patients and 39 (44%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status 0 and 1, respectively.
Overall, 52 (59%) patients were reported to have had 1 prior anti-cancer therapy for MCC, 26 (30%) with 2 prior therapies, and 10 (11%) with 3 or more prior therapies. Forty-seven (53%) of the patients had visceral metastases.
Table 3 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for study EMR100070-003, Part A, updated with a minimum follow-up of 24 months.
Table 3. Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study EMR100070-003 (Part A)*:
| Efficacy endpoints (Part A) (per RECIST v1.1, IERC) | Results (N=88) |
|---|---|
| Objective response rate (ORR) | |
| Response rate, CR+PR** n (%) | 29 (33,0%) |
| (95% CI) | (23,3-43,8) |
| Confirmed best overall response (BOR) | |
| Complete response (CR)** n (%) | 10 (11,4%) |
| Partial response (PR)** n (%) | 19 (21,6%) |
| Duration of response (DOR)a | |
| Median, months | NR |
| (95% CI) | (18, δεν ήταν δυνατόν να εκτιμηθεί) |
| Minimum, maximum (months) | 2,8-31,8+ |
| ≥6 months by K-M, (95% CI) | 93% (75-98) |
| ≥12 months by K-M, (95% CI) | 71% (51-85) |
| ≥24 months by K-M, (95% CI) | 67% (46-81) |
| Progression-free survival (PFS) | |
| Median PFS, months | 2,7 |
| (95% CI) | (1,4-6,9) |
| 6-month PFS rate by K-M, (95% CI) | 40% (29-50) |
| 12-month PFS rate by K-M, (95% CI) | 29% (19-39) |
| 24-month PFS rate by K-M, (95% CI) | 26% (16-36) |
CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier; NR: Not reached; +denotes a censored value
* Efficacy data updated with a minimum follow-up of 24 months (cut-off date 26 September 2017)
** CR or PR was confirmed at a subsequent tumour assessment
a Based on number of patients with confirmed response (CR or PR)
The median time to response was 6 weeks (range: 6 weeks to 36 weeks) after the first dose of avelumab. Twenty-two out of 29 (76%) patients with response were reported to have responded within 7 weeks after the first dose of avelumab.
The updated Kaplan-Meier curve of PFS of the 88 patients (Part A) with metastatic MCC is presented in Figure 1.
Figure 1. Updated Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC (Part A, minimum follow-up of 24 months):
Tumour samples were evaluated for PD-L1 tumour cell expression, and for Merkel cell polyomavirus (MCV) using an investigational immunohistochemistry (IHC) assay. Table 4 summarises the PD-L1 expression and MCV status of patients with metastatic MCC in study EMR100070-003 (Part A).
Table 4. Objective response rates by PD-L1 expression and MCV tumour status in patients with metastatic MCC in study EMR100070-003 (Part A):
| Avelumab ORR (95% CI) | |
|---|---|
| PD-L1 expression at cut-off of 1% | N=74a |
| Positive (n=58) | 36,2% (24,0-49,9) |
| Negative (n=16) | 18,8% (4,0-45,6) |
| PD-L1 expression at cut-off of 5% | N=74a |
| Positive (n=19) | 57,9% (33,5-79,7) |
| Negative (n=55) | 23,6% (13,2-37,0) |
| IHC-MCV tumour status | N=77b |
| Positive (n=46) | 28,3% (16,0-43,5) |
| Negative (n=31) | 35,5% (19,2-54,6) |
IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate
a Based on data from patients evaluable for PD-L1
b Based on data from patients evaluable for MCV by immunohistochemistry (IHC)
The clinical utility of PD-L1 as a predictive biomarker in MCC has not been established.
For Part B, the major efficacy outcome measure was durable response, defined as objective response (complete response (CR) or partial response (PR)) with a duration of at least 6 months; secondary outcome measures included BOR, DOR, PFS, and OS.
The prespecified interim analysis for Part B included 39 patients who received at least one dose of avelumab and 29 patients with a minimum 13 weeks of follow-up at the time of the data cut-off (cut-off date 24 March 2017).
Of the 39 patients, 30 (77%) were male, the median age was 75 years (range: 47 to 88 years), 33 (85%) were Caucasian, and 31 (79%) and 8 (21%) had an ECOG performance status of 0 and 1 respectively. The efficacy endpoints were based on 29 patients with 13 weeks of follow-up. The objective response rate (ORR) was 62.1% (95% CI: 42.3, 79.3) with 4 (14%) of patients reported to have a complete response and 14 (48%) to have a partial response. The median duration of response was not estimable (95% CI: 4 months, not estimable) with a minimum of 1.2 months to a maximum of 8.3 months duration. Analysis of progression-free survival (PFS) was based on 39 patients who received at least one dose of avelumab, with median PFS of 9.1 months (95% CI: 1.9, not estimable) and estimated 3-month PFS rate by Kaplan-Meier of 67% (95% CI: 48, 80).
A subsequent interim analysis for Part B was conducted with 74 patients who received at least one dose of avelumab and 39 patients with at least 6 months of follow-up at the time of the data cut-off (cut-off date 26 September 2017). Of the 74 patients, 51 (69%) were male, the median age was 74 years (range: 47 to 89 years), 49 (66%) were Caucasian, and 51 (69%) and 23 (31%) had an ECOG performance status of 0 and 1, respectively.
Table 5 summarises the subsequent interim analysis of efficacy endpoints including an estimate of the 6-month rates by Kaplan-Meier for DOR and PFS, in patients receiving avelumab at the recommended dose for study EMR100070-003, Part B.
Table 5. Subsequent interim analysis of response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study EMR100070-003 (Part B)*:
| Efficacy endpoints (Part B) (per RECIST v1.1, IERC) | Results |
|---|---|
| Objective response rate (ORR) | (N=39) |
| Response rate, CR+PR** n (%) | 20 (51,3%) |
| (95% CI) | (34,8-67,6) |
| Confirmed best overall response (BOR) | (N=39) |
| Complete response (CR)** n (%) | 7 (17,9%) |
| Partial response (PR)** n (%) | 13 (33,3%) |
| Duration of response (DOR)a | (N=39) |
| Median, months | 11,3 |
| (95% CI) | (5,6, δεν ήταν δυνατόν να εκτιμηθεί) |
| Minimum, maximum (months) | 1,2-13,8 |
| ≥3 months by K-M, (95% CI) | 84% (59-95) |
| ≥6 months by K-M, (95% CI) | 73% (46-88) |
| Progression-free survival (PFS) | (N=74) |
| Median PFS, months | 4,2 |
| (95% CI) | (2,9-12,7) |
| 3-month PFS rate by K-M, (95% CI) | 61% (48-73) |
| 6-month PFS rate by K-M, (95% CI) | 46% (32-59) |
CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier
* Efficacy data (cut-off date 26 September 2017) included 39 patients with a minimum follow-up of 6 months for ORR, BOR and DOR analyses, and 74 patients included in the PFS analysis.
** CR or PR was confirmed at a subsequent tumour assessment a Based on number of patients with confirmed response (CR or PR)
Figure 2 presents the Kaplan-Meier curve for PFS from the subsequent interim analysis with 74 patients enrolled into Part B who received at least one dose of avelumab prior to the data cut-off.
Figure 2. Updated Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC (Part B, N=74)*:
The European Medicines Agency has waived the obligation to submit the results of studies with Bavencio in all subsets of the paediatric population for the treatment of Merkel cell carcinoma (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.
Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in the extracellular space. The volume of distribution at steady state was 4.72 L.
Consistent with a limited extravascular distribution, the volume of distribution of avelumab at steady state is small. As expected for an antibody, avelumab does not bind to plasma proteins in a specific manner.
Based on a population pharmacokinetic analysis from 1,629 patients, the value of total systemic clearance (CL) is 0.59 L/day. In the supplemental analysis, avelumab CL was found to decrease over time: the largest mean maximal reduction (% coefficient of variation [CV%]) from baseline value with different tumour types was approximately 32.1% (CV 36.2%).
Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing at 10 mg/kg every 2 weeks, and systemic accumulation was approximately 1.25-fold.
The elimination half-life (t½) at the recommended dose is 6.1 days based on the population PK analysis.
The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg every 2 weeks.
A population pharmacokinetic analysis suggested no difference in the total systemic clearance of avelumab based on age, gender, race, PD-L1 status, tumour burden, renal impairment and mild or moderate hepatic impairment.
Total systemic clearance increases with body weight. Steady-state exposure was approximately uniform over a wide range of body weights (30 to 204 kg) for body weight normalised dosing.
No clinically important differences in the clearance of avelumab were found between patients with mild (glomerular filtration rate (GFR) 60 to 89 mL/min, Cockcroft-Gault Creatinine Clearance (CrCL); n=623), moderate (GFR 30 to 59 mL/min, n=320) and patients with normal (GFR ≥90 mL/min, n=671) renal function.
Avelumab has not been studied in patients with severe renal impairment (GFR 15 to 29 mL/min).
No clinically important differences in the clearance of avelumab were found between patients with mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin between 1 and 1.5 times ULN, n=217) and normal hepatic function (bilirubin and AST ≤ ULN, n=1,388) in a population PK analysis. Hepatic impairment was defined by National Cancer Institute (NCI) criteria of hepatic dysfunction.
Avelumab has not been studied in patients with moderate hepatic impairment (bilirubin between 1.5 and 3 times ULN) or severe hepatic impairment (bilirubin >3 times ULN).
Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity in Cynomolgus monkeys administered intravenously doses of 20, 60 or 140 mg/kg once a week for1 month and 3 months, followed by a 2-month recovery period after the 3-month dosing period. Perivascular mononuclear cell cuffing was observed in the brain and spinal cord of monkeys treated with avelumab at ≥20 mg/kg for 3 months. Although there was no clear dose-response relationship, it cannot be excluded that this finding was related to avelumab treatment.
Animal reproduction studies have not been conducted with avelumab. The PD-1/PD-L1 pathway is thought to be involved in maintaining tolerance to the foetus throughout pregnancy. Blockade of PD-L1 signalling has been shown in murine models of pregnancy to disrupt tolerance to the foetus and to result in an increase in foetal loss. These results indicate a potential risk that administration of avelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
No studies have been conducted to assess the potential of avelumab for carcinogenicity or genotoxicity.
Fertility studies have not been conducted with avelumab. In 1-month and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the female reproductive organs. Many of the male monkeys used in these studies were sexually immature and thus no explicit conclusions regarding effects on male reproductive organs can be made.
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