Abstract 1785P
Background
Preclinical data suggest that adavosertib (AD; AZD1775), a selective WEE1 inhibitor, enhances the antitumour effect of olaparib (OL), a PARP inhibitor (Lallo 2018). This expansion study (NCT02511795; Part B) examined the safety and preliminary efficacy of the recommended phase II dose (Part A; Hamilton 2019) of AD plus OL in patients (pts) with small-cell lung cancer (SCLC).
Methods
Pts with extensive-stage or relapsed SCLC, who previously received one platinum-based therapy regimen for advanced disease and had confirmed response without disease progression on treatment, were enrolled. Pts received AD 200 mg once daily (3 days on, 4 days off treatment) for 2 of 3 weeks, plus OL 200 mg twice daily. Safety, treatment response (RECIST v1.1) and its correlation with biomarkers, and pharmacokinetics (PK) were assessed.
Results
Nine pts were treated (F:M 5:4; median age 59.0 years, range 34–74; ECOG PS 0–1). The table shows safety and efficacy data. All pts experienced AEs; 3 had serious AEs (OL related n=1, febrile neutropenia; AD related n=0). Seven pts had grade ≥3 AEs, most commonly thrombocytopenia/low platelet count and anaemia (each n=4). There was one death from pneumonia. Eight pts had AEs related to AD or OL, of whom 6 had grade ≥3 AEs. AEs led to dose reductions (AD n=1) and interruptions (AD n=3; OL n=5); no pts discontinued treatment because of AEs. Peripheral blood mononuclear cell (PBMC) analysis showed a decrease from baseline in circulating monocytes, natural killer cells and proliferating CD4+ T cells on day 15 in most pts. PK analyses will be presented Table: 1785P
Safety and efficacy
| Cohort | AEs | Objective responserate,n (%) | Disease controlrate,n (%) | CR | PR | SD | PD | NE‡ | Median progression-free survival, months (95% CI) | Median overall survival | |||
| Any | TR† | Grade ≥3 | TR† grade ≥3 | ||||||||||
| AD + OL (N=9)* | 9 | 8 | 7 | 6 | 1 (11.1) | 2 (22.2) | 0 | 1 | 1 | 6 | 1 | 1.5 (1.3–4.2) | Not calculable |
Data are number of patients, unless otherwise indicated. *Patients received AD 200 mg once daily (3 days on, 4 days off) for 2 of 3 weeks, plus OL 200 mg twice daily; †Related to either AD or OL; ‡As a result of incomplete post-baseline assessments. CI, confidence interval; CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease (≥5 weeks); TR, treatment related.
.Conclusions
The nature of AEs observed was generally consistent with known AD and OL profiles. Data suggest preliminary antitumour activity of the treatment combination with one confirmed partial response and a disease control rate of 22.2% in pts with platinum-sensitive extensive-stage or relapsed SCLC. The decrease in PBMCs is concordant with known pharmacodynamic effects of PARP/WEE1 inhibition.
Clinical trial identification
NCT02511795 (protocol release date: 5 March 2019).
Editorial acknowledgement
Medical writing assistance was provided by Laura Atkins-Schmidt, MRes, MPhil, from Comradis, funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
B.T. Li: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Daiichi Sankyo; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Eli Lilly; Advisory/Consultancy, Research grant/Funding (institution): Roche Genentech; Advisory/Consultancy, Research grant/Funding (institution): Hengrui Therapeutics; Research grant/Funding (institution): BioMedValley; Research grant/Funding (institution): GRAIL; Research grant/Funding (institution): Illumina; Advisory/Consultancy, Research grant/Funding (institution): Guardant Health; Advisory/Consultancy: Mersana Therapeutics; Advisory/Consultancy: ThermoFisher Scientific. E.P. Hamilton: Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Lilly; Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy, Research grant/Funding (institution): Mersana Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Silverback Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Black Diamond; Advisory/Consultancy: NanoString; Research grant/Funding (institution): Seattle Genetics, Cytomx, InventisBio; Research grant/Funding (institution): Hutchinson MediPharma, Clovis; Research grant/Funding (institution): OncoMed, Syros, Deciphera; Research grant/Funding (institution): MedImmune, ArQule, Unum Therapeutics; Research grant/Funding (institution): StemCentrx, EMD Serono, Sermonix Pharmaceuticals; Research grant/Funding (institution): Curis, Taiho Pharmaceutical; Research grant/Funding (institution): Verastem, Leap Therapeutics; Research grant/Funding (institution): Zymeworks, Regeneron, Sutro; Research grant/Funding (institution): Syndax, Nucana, Aravive; Research grant/Funding (institution): Lycera, Merus, Zenith Epigenetics; Research grant/Funding (institution): Rgenix. Effector, Arvinas, Karyopharm Therapeutics; Research grant/Funding (institution): Millenium, FujiFilm, Torque; Research grant/Funding (institution): TapImmune, Immunomedics; Research grant/Funding (institution): BerGenBio, AbbVie, Harpoon; Research grant/Funding (institution): Medivation, Macrogenics, Fochon; Research grant/Funding (institution): Tesaro, Takeda, Orinove, G1 Therapeutics; Research grant/Funding (institution): Eisai, Radius Health, Molecular Templates; Research grant/Funding (institution): H3 Biomedicine, Acerta, Compugen. J.S. Wang: Speaker Bureau/Expert testimony, Research grant/Funding (institution): AstraZeneca. G.S. Falchook: Licensing/Royalties: Wolters Kluwer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Fujifilm; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: EMD Serono; Travel/Accommodation/Expenses: Bristol-Myers Squibb; Research grant/Funding (institution), Travel/Accommodation/Expenses: Millennium; Research grant/Funding (institution): 3-V Biosciences, Genmab; Speaker Bureau/Expert testimony: Total Health Conferencing; Research grant/Funding (institution): Abbisko, GlaxoSmithKline; Research grant/Funding (institution): AbbVie, Hutchison MediPharma; Research grant/Funding (institution): ADC Therapeutics, Ignyta; Research grant/Funding (institution): Aileron, Incyte, University of Texas MD Anderson Cancer Center; Research grant/Funding (institution): American Society of Clinical Oncology; Research grant/Funding (institution): Amgen, Jacobio, Vegenics; Research grant/Funding (institution): ARMO, Jounce, Xencor; Research grant/Funding (institution): AstraZeneca, Kolltan; Research grant/Funding (institution): BeiGene, Loxo; Research grant/Funding (institution): Bioatla, MedImmune; Research grant/Funding (institution): Biothera, Merck; Research grant/Funding (institution): Celldex, miRNA Therapeutics; Research grant/Funding (institution): Celgene, National Institutes of Health; Research grant/Funding (institution): Ciclomed, Rgenix; Research grant/Funding (institution): Curegenix, Ribon; Research grant/Funding (institution): Curis, Strategia; Research grant/Funding (institution): Cyteir, Syndax; Research grant/Funding (institution): Daiichi, Taiho; Research grant/Funding (institution): DelMar, Takeda; Research grant/Funding (institution): eFFECTOR, Tarveda; Research grant/Funding (institution): Eli Lilly, Tesaro; Research grant/Funding (institution): Epizyme, Tocagen; Research grant/Funding (institution): Exelixis, Turning Point Therapeutics. E. Rodrigo Imedio: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. S. Kumar: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. G.M. Mugundu: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. E. De Bruin: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. D.R. Spigel: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Celgene; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): AbbVie; Advisory/Consultancy, Research grant/Funding (institution): Foundation Medicine; Advisory/Consultancy, Research grant/Funding (institution): GlaxoSmithKline; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: Moderna Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Nektar; Advisory/Consultancy, Research grant/Funding (institution): Takeda, Amgen; Travel/Accommodation/Expenses: Sysmex; Advisory/Consultancy: TRM Oncology, Precision Oncology; Travel/Accommodation/Expenses: Purdue Pharma, Spectrum Pharmaceuticals; Advisory/Consultancy: Evelo Therapeutics; Advisory/Consultancy: Illumina, PharmaMar; Travel/Accommodation/Expenses: Genzyme, Intuitive Surgical; Research grant/Funding (institution): University of Texas Southwestern Medical Center - Simmons Cancer Center; Research grant/Funding (institution): G1 Therapeutics, ARMO BioSciences; Research grant/Funding (institution): Neon Therapeutics, Ipsen; Research grant/Funding (institution): Celldex, Aeglea Biotherapeutics; Research grant/Funding (institution): Clovis Oncology, Tesaro; Research grant/Funding (institution): Daiichi Sankyo, Transgene; Research grant/Funding (institution), Travel/Accommodation/Expenses: EMD Serono; Research grant/Funding (institution): Acerta Pharma, GRAIL, Millennium; Research grant/Funding (institution): Oncogenex, Astellas Pharma. All other authors have declared no conflicts of interest.