Pharmacokinetics and immunogenicity
For the dose-escalation cohorts, oleclumab mean serum concentration–time profiles during cycle 1 are shown in Supplementary Figure 2 and PK parameters for oleclumab as monotherapy or in combination with durvalumab by dose level are shown Supplementary Table 3. Oleclumab serum exposures increased with increasing doses and were not affected by the addition of durvalumab. Following the first dose, oleclumab appeared to exhibit nonlinear PK at the lowest dose of 5 mg/kg, as most evident in the trough concentrations, and showed linear PK at doses of 10 mg/kg and higher. The PK exposures, as determined by CBecause of the Q2W dosing and the long half-life of monoclonal antibodies, terminal elimination phase PK of oleclumab were not collected and available observed oleclumab serum concentration data were insufficient for derivation of half-life. Therefore, half-life was calculated based on PK profiles simulated by a preliminary population PK model, which indicated the terminal half-life of oleclumab was 13 days at doses ≥ 10 mg/kg Q2W. The PK profile of durvalumab in combination with oleclumab was similar to that previously reported for durvalumab monotherapy (data not shown) [No patients in the dose-escalation cohorts had ADAs to oleclumab at baseline or post-baseline. In the dose-escalation combination therapy cohorts, 2 of 18 assessed patients were ADA-positive for durvalumab at baseline, but none of 14 assessed patients were ADA-positive post-baseline.In the expansion cohorts, 3 of 124 (2.4%) patients assessed were positive for ADAs to oleclumab at baseline, and 1 of 109 (0.9%) patients assessed were ADA-positive post-baseline; this patient was among those who were ADA-positive at baseline and showed persistent ADA-positive status for ≥ 16 weeks. The presence of ADAs did not alter oleclumab PK. Four of 122 (3.3%) patients assessed had ADAs to durvalumab at baseline, and 2 of 96 (2.1%) had ADAs post-baseline.