Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, PD-1/PDL-1 (Programmed cell death protein 1/death ligand 1) inhibitors, ATC code: L01FF04.

Mechanism of action
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).

Clinical efficacy and safety

Merkel cell carcinoma (study EMR100070-003)
The efficacy and safety of avelumab was investigated in the single arm, multi-centre study EMR100070-003 with two parts. Part A was 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.

Study 003 Part A – previously-treated patients
The major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacy outcome measures included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

An efficacy analysis was conducted in all 88 patients after a minimum follow-up of 36 months. Patients received a median of 7 doses of avelumab (range: 1 dose to 95 doses), and the median duration of treatment was 17 weeks (range: 2 weeks to 208 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 4 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for study EMR100070-003, Part A with a minimum follow-up of 36 months. Overall survival was evaluated in an analysis with a minimum follow-up of 44 months. The median OS was 12.6 months (95% CI 7.5, 17.1).

Table 4: Response to avelumab 10 mg/kg every 2 weeks in patients with metastatic MCC in study EMR100070-003 (Part A)*

Efficacy endpoints (Part A)                            Results
(per RECIST v1.1, IERC)                               (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                                                   40.5 (95% CI)                                                 (18, not estimable) Minimum, maximum (months)                                     2.8, 41.5+ ≥ 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% (47, 82) ≥ 36 months by K-M, (95% CI)                                52% (26, 73) 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% (17, 36)
36-month PFS rate by K-M, (95% CI)                          21% (12, 32) CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier; +denotes a censored value * Efficacy data with a minimum follow-up of 36 months (cut-off date 14 September 2018) ** 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 Kaplan-Meier estimates of PFS of the 88 patients (Part A) with metastatic MCC is presented in Figure 1.

Figure 1: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC (Part A, minimum follow-up of 36 months)
Product-Limit Survival Estimate (N=88)

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Progression Free Survival by IERC (months)
# At Risk
88      43   32       30   27    24    21       20    20    20    20        17    15    14       10     10     10        8       5      2    2    2    1       0 

Tumour samples were evaluated for PD-L1 tumour cell expression, and for Merkel cell polyomavirus (MCV) using an investigational immunohistochemistry (IHC) assay. Table 5 summarises the objective response rates by the PD-L1 expression and MCV status of patients with metastatic MCC in study EMR100070-003 (Part A).

Table 5: 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) 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 * ORR (cut-off date 14 September 2018) a
Based on data from patients evaluable for PD-L1 b
Based on data from patients evaluable for MCV by immunohistochemistry (IHC) 
Study 003 Part B – patients who have not received systemic therapy in the metastatic setting 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 primary analysis for Part B included 116 patients who received at least one dose of avelumab with a minimum follow-up of 15 months at the time of the data cut-off (cut-off date 02 May 2019).

Of the 116 patients, 81 (70%) were male, the median age was 74 years (range: 41 to 93 years), 75 (65%) were white, and 72 (62%) and 44 (38%) had an ECOG performance status of 0 and 1 respectively.

Table 6 summarises the primary analysis of efficacy endpoints including an estimate of the 24-month rates by Kaplan-Meier for DOR, and PFS in patients receiving avelumab at the recommended dose for study EMR100070-003, Part B.

Table 6: Primary 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)                              Results
(per RECIST v1.1, IERC)                                (N=116)
Durable response
≥ 6 months                                                    30.2% (95% CI)                                                    (22.0, 39.4) Objective response rate (ORR)
Response rate, CR+PR** n (%)                                46 (39.7%) (95% CI)                                                    (30.7, 49.2) Confirmed best overall response (BOR)
Complete response (CR)** n (%)                              19 (16.4%) Partial response (PR)** n (%)                               27 (23.3%) Duration of response (DOR)a
Median, months                                                  18.2
(95% CI)                                                (11.3, not estimable) Minimum, maximum (months)                                     1.2, 28.3 ≥ 3 months by K-M, (95% CI)                                 89% (75, 95) ≥ 6 months by K-M, (95% CI)                                 78% (63, 87) ≥ 12 months by K-M, (95% CI)                                66% (50, 78) ≥ 18 months by K-M, (95% CI)                                52% (34, 67) ≥ 24 months by K-M, (95% CI)                                45% (25, 63) Progression-free survival (PFS)
Median PFS, months                                              4.1
(95% CI)                                                     (1.4, 6.1) 3-month PFS rate by K-M, (95% CI)                          51% (42, 60) 6-month PFS rate by K-M, (95% CI)                          41% (32, 50) 12-month PFS rate by K-M, (95% CI)                         31% (23, 40) 24-month PFS rate by K-M, (95% CI)                         20% (12, 30)
CI: Confidence interval; RECIST: Response Evaluation Criteria in Solid Tumours; IERC: Independent Endpoint Review Committee; K-M: Kaplan-Meier
* Efficacy data with a minimum follow-up of 15 months (cut-off date 02 May 2019) ** 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 estimates for PFS from the primary analysis with 116 patients enrolled into Part B with a minimum follow-up of 15 months.


Figure 2: Kaplan-Meier estimates of progression-free survival (PFS) per RECIST v1.1, IERC (Part B, N=116)
Product-Limit Survival Estimate (N=116)

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Progression Free Survival by IERC (months)
# At Risk
116       60       56   45          39              24           18         10          8             5        4        3          0 

Tumour samples were evaluated for PD-L1 tumour cell expression, and for MCV using an investigational IHC assay. Table 7 summarises the objective response rates by PD-L1 expression and MCV status of patients with metastatic MCC in study EMR100070-003 (Part B).

Table 7: Objective response rates by PD-L1 expression and MCV tumour status in patients with metastatic MCC in study EMR100070-003 (Part B)

Avelumab
ORR (95% CI)*
PD-L1 expression at cut-off of ≥ 1%                                                              N=108a Positive (n=21)                                                                         61.9% (38.4, 81.9) Negative (n=87)                                                                         33.3% (23.6, 44.3) IHC-MCV tumour status                                                                            N=107b Positive (n=70)                                                                         34.3% (23.3, 46.6) Negative (n=37)                                                                         48.6% (31.9, 65.6) IHC: Immunohistochemistry; MCV: Merkel cell polyomavirus; ORR: objective response rate * ORR (cut-off date 02 May 2019) a
Based on data from patients evaluable for PD-L1 b
Based on data from patients evaluable for MCV by IHC

Locally advanced or metastatic urothelial carcinoma (study B9991001)

First-Line Maintenance Treatment of Urothelial Carcinoma (study B9991001) The efficacy and safety of avelumab was demonstrated in study B9991001, a randomised, multi-centre, open-label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma whose disease had not progressed with 4-6 cycles of first-line platinum-based induction chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.

Randomization was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line induction chemotherapy.
Patients were randomised (1:1) to receive either avelumab 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone.


Administration of avelumab was permitted beyond Response Evaluation Criteria in Solid Tumours (RECIST) v1.1-defined progression of disease by Blinded Independent Central Review (BICR) if the patient was clinically stable and considered to be deriving clinical benefit by the investigator.
Assessment of tumour status was performed at baseline, 8 weeks after randomization, then every 8 weeks up to 12 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.

Demographic and baseline characteristics were generally well balanced between the avelumab plus BSC and the BSC alone arm. Baseline characteristics were a median age of 69 years (range: 32 to 90), 66% of patients were 65 years or older, 77% were male, 67% were White, and the ECOG PS was 0 (61%) or 1 (39%) for both arms.

For first-line induction chemotherapy, 56% of patients received cisplatin plus gemcitabine, 38% of patients received carboplatin plus gemcitabine and 6% of patients received cisplatin plus gemcitabine and carboplatin plus gemcitabine (i.e. these patients received one or more cycles of each combination).
Best response to first-line induction chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty-one percent of patients had PD-L1-positive tumours. Six percent of patients in the avelumab plus BSC arm and 44% of patients in the BSC alone arm received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment.

The primary efficacy outcome measure was overall survival (OS) in all randomized patients and in patients with PD-L1-positive tumours. Progression-free survival (PFS) based on BICR assessment per RECIST v1.1 was an additional efficacy outcome measure. Efficacy outcomes were measured from time of randomisation after 4 to 6 cycles of platinum-based induction chemotherapy.

The PD-L1 status of the tumour was assessed using the Ventana PD-L1 (SP263) assay.
PD-L1-positivity was defined as ≥ 25% of tumour cells stained for PD-L1; or ≥ 25% of immune cells stained for PD-L1 if > 1% of the tumour area contained immune cells; or 100% of immune cells stained for PD-L1 if = 1% of the tumour area contained immune cells.

At the pre-specified interim analysis (cut-off date 21 October 2019), study B9991001 met its primary endpoint for OS in both coprimary populations: in all randomized patients with a median OS of 21.4 months (95% CI: 18.9, 26.1; HR 0.69, 95% CI: 0.556, 0.863) in the avelumab plus BSC arm and with a median OS of 14.3 months (95% CI: 12.9, 17.8) in the BSC alone arm. For patients with PD-L1-positive tumours the median OS was not reached (95% CI: 20.3, not reached; HR 0.56, 95%, CI: 0.404, 0.787) in the avelumab plus BSC arm and the median OS in the BSC alone arm was 17.1 months (95% CI: 13.5, 23.7). Updated OS results with a data cut-off date of 19 January 2020 and PFS data with a cut-off date of 21 October 2019 are presented in Table 8 and in Figure 3 and Figure 4 below.


Table 8: Efficacy results by PD-L1 expression in study B9991001

Efficacy endpoints       Avelumab       BSC                Avelumab        BSC     Avelumab       BSC plus BSC                          plus BSC                plus BSC
(N=350)     (N=350)               (N=189)      (N=169)    (N=139)     (N=131) All randomized patients           PD-L1-positive tumours PD-L1-negative tumoursc Overall survival (OS)a
Events (%)             156 (44.6)      190 (54.3)            68 (36.0)      85 (50.3)      80 (57.6)      80 (61.1) Median in months          22.1            14.6                  NE            17.5           18.9           13.4 (95% CI)             (19.0, 26.1) (12.8, 17.8)              (20.6, NE) (13.5, 31.6)       (13.3, 22.1) (10.4, 17.3) Hazard ratio                       0.70                                0.60                          0.83 (95% CI)                     (0.564, 0.862)                       (0.439, 0.833)                (0.603, 1.131) 2-sided p-valued                 0.0008                               0.0019                           -
Progression-free survival (PFS)b, e, f
Events (%)             225 (64.3)      260 (74.3)           109 (57.7)      130 (76.9)    103 (74.1)      99 (75.6) Median in months           3.7             2.0                  5.7             2.1          3.0             1.9 (95% CI)                (3.5, 5.5)      (1.9, 2.7)           (3.7, 7.4)      (1.9, 3.5)   (2.0, 3.7)      (1.9, 2.1) Hazard ratio                       0.62                                 0.56                         0.63 (95% CI)                     (0.519, 0.751)                       (0.431, 0.728)               (0.474, 0.847) 2-sided p-valued                < 0.0001                             < 0.0001                          -
CI: Confidence interval; K-M: Kaplan-Meier, NE: not estimable
Note: 72 patients (22 patients on avelumab plus BSC arm and 50 patients on BSC alone arm) had a tumour with an unknown PD-L1 status a
OS cut-off date 19 January 2020 b
PFS cut-off date 21 October 2019 c
PD-L1-negative population analyses were exploratory and no formal test was performed d p-value based on stratified log-rank e
Based on BICR assessment per RECIST v1.1 f
PFS censoring reasons follow the hierarchy in sequential order: no adequate baseline assessment, start of new anti-cancer therapy, event after 2 or more missing assessments, withdrawal of consent, lost to follow-up, no adequate post-baseline tumour assessment, ongoing without an event


Figure 3: Kaplan-Meier estimates for overall survival (OS) by PD-L1 expression (cut-off date 19 January 2020) - Full analysis set



(A): All randomized patients



(B): Patients by PD-L1 expression


Figure 4: Kaplan-Meier estimates for progression-free survival (PFS) by PD-L1 expression based on BICR assessment (RECIST v1.1) (cut-off date 21 October 2019) - Full analysis set 


(A): All randomized patients



(B): Patients by PD-L1 expression
Previously-Treated Urothelial Carcinoma (study EMR100070-001)
The efficacy and safety of BAVENCIO was demonstrated in the UC cohorts of the EMR100070-001 trial, an open-label, single-arm, multi-center study that included 242 patients with locally advanced or metastatic urothelial carcinoma (UC) with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum- containing neoadjuvant or adjuvant chemotherapy regimen. Patients with active or history of central nervous system metastasis; other malignancies within the last 5 years; organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B, or hepatitis C were excluded. Patients with autoimmune disease, other than type I diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status.

Patients received BAVENCIO at a dose of 10 mg/kg intravenously every 2 weeks until radiographic or clinical progression or unacceptable toxicity. Tumor response assessments were performed every 6 weeks. Efficacy outcome measures included confirmed overall response rate (ORR), as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, and duration of response (DOR). Efficacy was evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.

Baseline demographic and disease characteristics for the 226 patients with a minimum of 13 weeks of follow-up were median age 68 years (range: 30 to 89), 72% male, 80% White, and 34% and 66% of patients had an ECOG performance status 0 and 1, respectively. Forty-four percent of patients had non- bladder urothelial carcinoma including 23% of patients with upper tract disease, and 83% of patients had visceral metastases (baseline target and/or non-target lesions present outside of the lymph nodes).
Nine (4%) patients had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin- based regimens. At baseline, 17% of patients had a hemoglobin < 10 g/dL and 34% of patients had liver metastases.

Efficacy results are presented in Table . The median time to response was 2.0 months (range: 1.3 to 11.0) among patients followed for either > 13 weeks or > 6 months. Using a clinical trial assay to assess PD-L1 staining, with 16% of patients not evaluable, there were no clear differences in response rates based on PD-L1 tumor expression. Among the total 30 responding patients followed for > 13 weeks, 22 patients (73%) had an ongoing response of 6 months or longer and 4 patients (13%) had ongoing responses of 12 months or longer. Among the total 26 responding patients followed for > 6 months, 22 patients (85%) had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 12 months or longer.


Table 9: Efficacy Results of the UC Cohorts in the EMR100070-001 Trial 

Efficacy Endpoints                   ≥ 13 Weeks Follow-Up ≥ 6 Months Follow-Up (N=226)              (N=161)
Confirmed Overall Response Rate (ORR)
Overall Response Rate n (%)                          30 (13.3%)                26 (16.1%) (95% CI)                                             (9.1, 18.4)               (10.8, 22.8) Complete Response (CR) n (%)                          9 (4.0%)                   9 (5.6%) Partial Response (PR) n (%)                          21 (9.3%)                 17 (10.6%) Duration of Response (DOR)
Median, months (range)                            NE (1.4+ to 17.4+)       NE (1.4+ to 17.4+) CI: Confidence interval; NE: Not estimable; + denotes a censored value.

Renal cell carcinoma (study B9991003)
The efficacy and safety of avelumab in combination with axitinib was demonstrated in study B9991003, a randomised, multicentre, open-label study of avelumab in combination with axitinib in 886 patients with untreated advanced or metastatic RCC with a clear-cell component.


Patients were included irrespective of prognostic risk groups or tumour PD-L1 expression and had to have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 that was not been previously irradiated. Patients with prior systemic therapy directed at advanced or metastatic RCC; prior systemic immunotherapy treatment with IL-2, IFN-α, anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies, or active brain metastasis; active autoimmune disease that might deteriorate when receiving an immunostimulatory agents; a history of other malignancies within the last 5 years; organ transplant were ineligible.

Randomization was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomised (1:1) to one of the following treatment arms:
•     Avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily orally (N=442). Patients who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
•     Sunitinib 50 mg once daily orally for 4 weeks followed by 2 weeks off (N=444) until radiographic or clinical progression or unacceptable toxicity.

Treatment with avelumab and axitinib continued until RECIST v1.1-defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of avelumab and axitinib was permitted beyond RECIST-defined disease progression based on investigator’s assessment of the patient’s benefit-risk and clinical condition, including performance status, clinical symptoms, adverse events and laboratory data. The majority (n=160, 71.4%) of the patients with progressive disease continued treatment with both medicinal products after progression.
Assessment of tumour status was performed at baseline, after randomisation at 6 weeks, then every 6 weeks thereafter up to 18 months after randomisation, and every 12 weeks thereafter until documented confirmed disease progression by BICR.

The primary efficacy endpoints were progression-free survival (PFS), as assessed by BICR using RECIST v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who have PD-L1-positive tumours (PD-L1 expression level ≥ 1%). The key secondary endpoints were PFS based on BICR assessment per RECIST v1.1 and OS irrespective of PD-L1 expression. PD-L1 status was determined by immunohistochemistry. Additional secondary endpoints included objective response (OR), time to response (TTR) and duration of response (DOR).

Study population characteristics: median age of 61 years (range: 27.0 to 88.0), 38% of patients were 65 years or older, 75% were male, 75% were White, and the ECOG performance score was 0 (63%) or 1 (37%).

Patient distribution by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups was 21% favourable, 62% intermediate, and 16% poor. Patient distribution by Memorial Sloan–Kettering Cancer Center (MSKCC) risk groups was 22% favourable, 65% intermediate, and 11% poor.

Efficacy results are presented in Table 10 and Figure 5 based on a data cut-off date of 28 January 2019. With a median OS follow-up of 19 months, OS data were immature with 27% deaths. The observed hazard ratio (HR) for OS was 0.80 (95% CI: 0.616, 1.027) for avelumab in combination with axitinib compared to sunitinib.


Table 10: Efficacy results from study B9991003 in patients irrespective of PD-L1 expression 
Efficacy endpoints                    Avelumab plus axitinib             Sunitinib (Based on BICR assessment)                        (N=442)                      (N=444) Progression-free survival (PFS)
Events (%)                                              229 (52)                   258 (58) Median in months (95% CI)                           13.3 (11.1, 15.3)            8.0 (6.7, 9.8) Hazard ratio (95% CI)                                           0.69 (0.574, 0.825) p-value*                                                              < 0.0001 12-month PFS rate by K-M, (95% CI)**               52.4% (47.4, 57.2)         39.2% (34.1, 44.2) 18-month PFS rate by K-M, (95% CI)**               43.9% (38.8, 49.0)         29.3% (24.2, 34.6) Confirmed objective response rate (ORR)
Objective response rate (ORR) n (%)                    232 (52.5)                121 (27.3) (95% CI)                                               47.7, 57.2                23.2, 31.6 Complete response (CR) n (%)                            17 (3.8)                   9 (2.0) Partial response (PR) n (%)                            215 (48.6)                112 (25.2) Time to response (TTR)
Median, months (range)                               2.7 (1.2, 20.7)           4.0 (1.2, 18.0) Duration of response (DOR)
Median, months (95% CI)                             18.5 (17.8, NE)            NE (16.4, NE) BICR: Blinded Independent Central Review; CI: Confidence interval; K-M: Kaplan-Meier; NE: Not estimable * 1-sided p-value based on stratified log-rank
** CIs are derived using the log-log transformation with back transformation to untransformed scale 
Figure 5: Kaplan-Meier estimates for progression-free survival based on BICR assessment in patients irrespective of PD-L1 expression



Improvement of PFS was observed across pre-specified subgroups.
Figure 6: Forest plot of progression-free survival based on BICR assessment in patients irrespective of PD-L1 expression

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Avelumab pharmacokinetics (PK) was assessed using a population PK approach for avelumab as monotherapy and avelumab in combination with axitinib.

Based on a population PK analysis for avelumab as monotherapy and in combination with axitinib, there are no expected clinically meaningful differences in exposure of avelumab between settings administered every 2 weeks at 800 mg or 10 mg/kg.

Distribution
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.


Elimination
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.

Linearity/non-linearity
The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg every 2 weeks.

When avelumab 10 mg/kg was administered in combination with axitinib 5 mg, the respective exposures of avelumab and axitinib were unchanged compared to the single agents. There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.

Special populations
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.

Renal impairment
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).

Hepatic impairment
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).