G and D have both shown efficacy in patients (pts) with NSCLC; G + D may improve durability of response.
This Phase 1 dose escalation (Part A) and expansion (Part B) study (NCT0208811) assessed G 250 mg once daily + D 3 mg/kg (Part A) or 10 mg/kg (Parts A + B) every 2 weeks in pts with locally advanced/metastatic NSCLC. Part A pts were all comers who had failed to respond/relapsed following standard treatment (Tx). Part B pts had sensitising EGFR mutations and were tyrosine kinase inhibitor naïve: Arms 1 + 1a received G + D; Arm 2 received G (4 weeks) before G + D. Primary objective: safety/tolerability. Secondary objectives: pharmacokinetics (PK), pharmacodynamics, immunogenicity (anti-drug antibodies [ADAs]) and efficacy. Exploratory objective: evaluation of biomarkers (e.g. tumour programmed cell death ligand-1 [PD-L1]) and relationship with efficacy.
There were no dose limiting toxicities in Part A (n = 16) and D 10 mg/kg was used in Part B. In Part B (n = 40) all pts had possible Tx related adverse events (TRAEs; Table): diarrhoea (68%) and elevated alanine aminotransferase (ALT; 58%) were the most common TRAEs; elevated ALT (20%) and aspartate aminotransferase (15%) were the most common TRAEs leading to discontinuation. PK were as expected, inhibition of soluble PD-L1 was observed in all pts and no Tx emergent ADAs were observed. In Arms 1 + 1a, most patients achieved objective response (63.3%; 95% confidence intervals [CI]: 43.9, 80.1), median duration of response was 9.2 months (95% CI: 3.7, 14.0) and median progression-free survival (mPFS) was 10.1 months (95% CI: 5.5, 15.2; Table). PD-L1 expression ≥20% was associated with numerical improvements in mPFS (Table).
G + D had a high discontinuation rate due to liver related TRAEs and there was no additional benefit vs historical data for G alone. However, tumours expressing PD-L1 had favourable PFS and could be investigated further.
NCT02088112; March 14, 2014.
Medical writing support, under the direction of the authors, was provided by Lauren McNally, MSci, of CMC CONNECT, a division of McCann Health Medical Communications Ltd, Glasgow, UK, with funding from AstraZeneca PLC, in accordance with Good Publication Practice (GPP3) guidelines.
MedImmune LLC (a wholly owned subsidiary of AstraZeneca PLC).
AstraZeneca PLC.
T. Yeh, W. Tang, M. Tang, H.K. Angell, M.P. Roudier, M. Marotti: Employee: AstraZeneca. R. Taylor: Employee, contractor: AstraZeneca. D.L. Gibbons: Advisory boards/research funding: AstraZeneca. All other authors have declared no conflicts of interest.