Phase I/Ib dose-escalation study of avelumab in Chinese patients with advanced solid tumors

Figures & data

Table 1. Baseline characteristics.

Characteristic	Avelumab dose
	3 mg/kg Q2W (n = 3)	10 mg/kg Q2W (n = 7)	20 mg/kg Q2W (n = 6)	10 mg/kg QW→Q2W (n = 8)	Total (n = 24)
Sex, n (%)
Male	3 (100.0)	5 (71.4)	2 (33.3)	4 (50.0)	14 (58.3)
Female	0	2 (28.6)	4 (66.7)	4 (50.0)	10 (41.7)
Age, years
Median	50	59	56	58	57
Range	38–73	27–67	24–65	44–77	24–77
Race, n (%)
Asian	3 (100.0)	7 (100.0)	6 (100.0)	8 (100.0)	24 (100.0)
ECOG PS, n (%)
0	0	1 (14.3)	0	0	1 (4.2)
1	3 (100.0)	6 (85.7)	6 (100.0)	8 (100.0)	23 (95.8)
Site of primary tumor, n (%)
Abdomen, NOS^†	1 (33.3)	0	0	0	1 (4.2)
Body of pancreas	0	1 (14.3)	0	0	1 (4.2)
Breast	0	1 (14.3)	1 (16.7)	1 (12.5)	3 (12.5)
Cervix uteri	0	0	1 (16.7)	0	1 (4.2)
Soft tissues, lower limb and hip^‡	0	1 (14.3)	0	0	1 (4.2)
Duodenum	1 (33.3)	0	0	0	1 (4.2)
Kidney, NOS	0	0	1 (16.7)	0	1 (4.2)
Renal pelvis	0	0	0	1 (12.5)	1 (4.2)
Liver	0	0	0	1 (12.5)	1 (4.2)
Bronchus and lung	0	2 (28.6)	3 (50.0)	4 (50.0)	9 (37.5)
Nasopharynx, NOS	0	0	0	1 (12.5)	1 (4.2)
Parotid gland	1 (33.3)	1 (14.3)	0	0	2 (8.3)
Thoracic esophagus	0	1 (14.3)	0	0	1 (4.2)
Median time since initial cancer diagnosis (range), months	46.19 (17.3–118.7)	15.34 (8.5–138.6)	20.37 (11.1–159.8)	37.65 (19.6–74.9)	24.57 (8.5–159.8)
Median time since documented locally advanced/metastatic disease (range), months	16.69 (10.2–100.2)	10.25 (2.8–42.4)	18.66 (11.1–65.0)	19.65 (7.0–49.2)	16.69 (2.8–100.2)
Prior anticancer surgery, n (%)	3 (100.0)	4 (57.1)	2 (33.3)	6 (75.0)	15 (62.5)
Prior anticancer radiotherapy, n (%)	2 (66.7)	3 (42.9)	3 (50.0)	2 (25.0)	10 (41.7)
Prior systemic anticancer treatment, n (%)	2 (66.7)	7 (100.0)	6 (100.0)	8 (100.0)	23 (95.8)
Type of prior systemic therapy, n (%)
Cytotoxic therapy	2 (66.7)	6 (85.7)	5 (83.3)	8 (100.0)	21 (87.5)
Endocrine therapy	0	0	1 (16.7)	1 (12.5)	2 (8.3)
Monoclonal antibodies	0	2 (28.6)	1 (16.7)	0	3 (12.5)
Molecular-targeted therapy	1 (33.3)	1 (14.3)	2 (33.3)	4 (50.0)	8 (33.3)
Immunotherapy	0	0	0	0	0
Other	1 (33.3)	1 (14.3)	0	0	2 (8.3)

† Left inguinal.

‡ Connective, subcutaneous and other soft tissues of the lower limb and hip.

ECOG PS: Eastern Cooperative Oncology Group performance status; NOS: Not otherwise specified; Q2W: Every 2 weeks; QW: Every week.

Table 2. Patient disposition.

	Avelumab dose
	3 mg/kg Q2W (n = 3)	10 mg/kg Q2W (n = 7)	20 mg/kg Q2W (n = 6)	10 mg/kg QW→Q2W (n = 8)	Total (n = 24)
Reason for treatment discontinuation, n (%)
AE	1 (33.3)	0	0	2 (25.0)	3 (12.5)
Death	0	1 (14.3)	0	0	1 (4.2)
PD	1 (33.3)	5 (71.4)	5 (83.3)	4 (50.0)	15 (62.5)
Other	0	0	0	1 (12.5)	1 (4.2)
Median duration of avelumab therapy (range), weeks	30.14 (18.0–64.0)	30.00 (5.9–56.1)	26.57 (4.0–36.0)	QW period: 8.00 (1.0–12.0) Q2W period: 14.00 (8.0–20.0)	NA
Re-initiated treatment, n (%)	0	1 (14.3)	1 (16.7)	0	2 (8.3)
Treatment ongoing, n (%)	1 (33.3)	1 (14.3)	1 (16.7)	1 (12.5)	4 (16.7)

AE: Adverse event; NA: Not available; PD: Progressive disease; Q2W: Every 2 weeks; QW: Every week.

Table 3. Safety.

	Avelumab dose, n (%)
	3 mg/kg Q2W (n = 3)	10 mg/kg Q2W (n = 7)	20 mg/kg Q2W (n = 6)	10 mg/kg QW→Q2W (n = 8)	Total (n = 24)
Any TEAE	3 (100.0)	7 (100.0)	6 (100.0)	8 (100.0)	24 (100.0)
Grade ≥3	1 (33.3)	3 (42.9)	3 (50.0)	3 (37.5)	10 (41.7)
Grade ≥4	0	2 (28.6)	1 (16.7)	1 (12.5)	4 (16.7)
Avelumab-related TEAE	3 (100.0)	5 (71.4)	6 (100.0)	6 (75.0)	20 (83.3)
Grade ≥3	0	0	0	1 (12.5)	1 (4.2)
Grade ≥4	0	0	0	0	0
Treatment-emergent irAE	0	0	0	1 (12.5)	1 (4.2)
Treatment-related irAE	0	0	0	1 (12.5)	1 (4.2)
Treatment-emergent IRR	1 (33.3)	2 (28.6)	0	2 (25.0)	5 (20.8)
Treatment-related IRR	1 (33.3)	2 (28.6)	0	2 (25.0)	5 (20.8)
Serious TEAE	1 (33.3)	3 (42.9)	2 (33.3)	2 (25.0)	8 (33.3)
Avelumab-related serious TEAE	0	0	0	0	0
TEAE leading to treatment discontinuation	1 (33.3)	1 (14.3)	0	2 (25.0)	4 (16.7)
Avelumab-related TEAE leading to treatment discontinuation	1 (33.3)	0	0	1 (12.5)	2 (8.3)
TEAE leading to death	0	1 (14.3)	1 (16.7)	0	2 (8.3)
Avelumab-related TEAE leading to death	0	0	0	0	0

irAE: Immune-related adverse event; IRR: Infusion-related reaction; Q2W: Every 2 weeks; QW: Every week; TEAE: Treatment-emergent adverse event.

Table 4. Avelumab serum pharmacokinetics on day 1 (pharmacokinetics population).

Parameter, geometric mean (geometric coefficient of variation, %)	Q2W cohorts
	3 mg/kg (n = 3)	10 mg/kg (n = 7)	20 mg/kg (n = 6)
AUC0-tau, μg•h/ml	7000 (2.9)	20,800 (27.8)	35,800 (22.3)
AUC0-tau/dose, μg•h/ml/mg/kg	2330 (2.9)	2080 (27.8)	1790 (22.3)
AUC0-t, μg•h/ml	7000 (3.0)	20,400 (31.3)	35,600 (20.6)
AUC0-t/dose, μg•h/ml/mg/kg	2330 (3.0)	2040 (31.3)	1780 (20.6)
AUC0–∞, μg•h/ml	7710 (6.2)	22,600 (29.7)	38,300 (23.4)
Cmax, μg/ml	77.6 (13.9)	294 (44.7)	450 (36.5)
Cmax/dose, μg/ml/mg/kg	25.9 (13.9)	29.4 (44.7)	22.5 (36.5)
Tmax, h^†	1.55 (1.53–1.62)	1.52 (1.00–6.90)	1.97 (1.05–5.00)
Clast, μg/ml	4.94 (33.7)	16.3 (51.2)	21.4 (50.3)
Ctrough, μg/ml	4.94 (33.7)	14.8 (47.2)^‡	21.4 (50.3)
t1/2, h	96.5 (18.6)	90.3 (21.1)	85.5 (9.1)
Parameter, mean ± SD	10-mg/kg QW cohort (n = 8)
Peak, μg/ml	344 ± 253.0	–	–
Trough, μg/ml	61.4 ± 44.59^§	–	–

† Median (range).

‡ n = 6.

§ n = 7.

AUC_0–∞: Area under the serum concentration-time curve from zero extrapolated to infinity; AUC_0-t: Area under the concentration-time curve from zero to the last sampling time; AUC_0-tau: Area under the serum concentration-time curve from zero to tau; C_max: Maximum serum concentration; C_last: Last quantifiable serum concentration; C_trough: Serum concentration observed immediately before the next dose; Q2W: Every 2 weeks; QW: Every week; SD: Standard deviation; t_1/2: Terminal elimination half-life; T_max: Time to reach maximum serum concentration.

Figure 1. Pharmacokinetics analysis set.

(A) Dose levels (Q2W cohorts), linear (± standard deviation) scale. (B) Dose levels (Q2W cohorts), semi-logarithmic scale. (C) Mean (± standard deviation) trough avelumab serum concentration-time profiles by study day for all dose levels (Q2W cohorts) on the linear scale. (D) Mean (± standard deviation) trough avelumab serum concentration-time profiles by study day for the 10-mg/kg QW→Q2W cohort on the linear scale.

Q2W: Every 2 weeks; QW: Every week.