Durvalumab (D), a human IgG1 mAb against PD-1 and CD80, has shown clinical activity in patients (pts) with non-small cell lung cancer (NSCLC). Tremelimumab (T) is a human IgG2 mAb against CTLA-4. D+T has previously also shown durable responses in metastatic NSCLC (mNSCLC). MYSTIC (NCT02453282) was an open-label, Phase 3 trial of first-line treatment with D vs platinum-based doublet chemotherapy (CT) and D+T vs CT in mNSCLC.
Eligible pts had mNSCLC; were immunotherapy/chemotherapy-naïve; and had no EGFR sensitising mutation or ALK rearrangement. Tumour cell (TC) PD-L1 expression (≥25% vs <25%) and histology were stratification factors. Patients were randomised (1:1:1) to D (20 mg/kg i.v. q4w); D+T (D: 20 mg/kg i.v. q4w; T: 1 mg/kg i.v. q4w [up to 4 doses]); or CT (intended up to 6 cycles; pemetrexed maintenance permitted in eligible pts) until disease progression. Primary endpoints were overall survival (OS) for D vs CT and OS and progression free survival (PFS; blinded independent central review [RECIST v1.1]) for D+T vs CT in pts with PD-L1 TC expression ≥25%, defined by the VENTANA PD-L1 (SP263) assay. Data cutoffs were 4 Oct 2018 (OS and safety) and 1 Jun 2017 (PFS).
1118 pts were randomised. Baseline characteristics were balanced. Efficacy findings are presented for the 488 pts with PD-L1 TC ≥25%. Median OS was 16.3 vs 12.9 months for D vs CT (HR 0.76 [97.54% CI, 0.564, 1.019]; p=0.036) and 11.9 vs 12.9 months for D+T vs CT (HR 0.85 [98.77% CI, 0.611, 1.173]; p=0.202). Median PFS was 3.9 vs 5.4 months for D+T vs CT (HR 1.05 [99.5% CI, 0.722, 1.534]; p=0.705). 39.5% pts in the CT arm received subsequent immunotherapy after treatment discontinuation vs 6.1% and 3.1% pts in the D and D+T arms. Incidence of Grade 3/4 treatment-related AEs was 14.6%, 22.1% and 33.8% with D, D+T and CT, respectively. Efficacy based on additional PD-L1 cutoffs will be presented.
In pts with mNSCLC, while statistical significance was not achieved for primary OS and PFS endpoints, first-line D demonstrated clinically meaningful improvement in OS vs CT (PD-L1 TC ≥25%). Safety data were consistent with the known safety profiles of D+/-T. Further analyses are ongoing.
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Rebecca Douglas, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.
NCT02453282 (release date: May 25, 2015).
AstraZeneca plc.
AstraZeneca.
N.A. Rizvi: Advisory boards: Abbvie, AZ, BMS, EMD Serono, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Neogenomics, Oncomed, Gritstone, Bellicum; Equity: Oncomed, Gritstone, Bellicum, ARMO; Royalties: PGDX. B. Chul Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD Consultancy: Novartis, AZ, BI, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD; Stock: TheraCanVac, Inc. N. Reinmuth: Personal fees: AstraZeneca, Roche, Boehringer-Ingelheim, Takeda, MSD, BMS, Novartis, Pfizer, Merck. A. Smolin: Grants: AstraZeneca; Grants and personal fees: AstraZeneca, Roche, MSD, BMS; Personal fees: BIOCAD, Boehringer-Ingelheim. S.J. Antonia: Advisory board/contracted research: BMS, Novartis, Merck, CBMG, Boehringer-Ingelheim, AstraZeneca/MedImmune, Memgen, FLX Bio, Nektar, Venn. G. Robinet: Grants and personal fees: AstraZeneca; Grants and personal fees: MSD; Personal fees: Boehringer-Ingelheim. R. Natale: Spouse: Employee (Medical Science Liaison) of AZ (salary/compensation completely unrelated to the contracted research work performed at my institution that is the subject of the submitted abstract). K. Nakagawa: Research funding: GlaxoSmithKline K.K., AstraZeneca K.K., Kyowa Hakko Kirin, Pfizer Japan Inc., AbbVie Inc., Novartis Pharma K.K., Nippon Boehringer-Ingelheim, Daiichi Sankyo, Eli Lilly Japan K.K., MSD K.K., Quintiles Inc., Ono Pharmaceutical, BMS, EPS International, Chugai Pharmaceutical, ICON Japan K.K., Gritstone Oncology, Inc., Linical, Yakult Honsha, Parexel International Corp., Otsuka Pharmaceutical, Astellas Pharma Inc., AC Medical Inc., Taiho Pharmaceutical, Merck Serono, EPS Associates, Quintiles Inc., Japan Clinical Research Operations, Eisai, PPD-SNBL K.K., Takeda Pharmaceutical, Covance Inc., inVentiv Health Japan, A2 Healthcare Corp., EP-CRSU; Honoraria: Astellas Pharma Inc., AstraZeneca K.K., Novartis Pharma K.K., Pfizer Japan Inc., Chugai Pharmaceutical, Ono Pharmaceutical, Nippon Boehringer-Ingelheim, BMS, Kissei Pharmaceutical, Eli Lilly Japan K.K., MSD K.K., EPS Holdings Inc., Showa Yakuhin Kako, Clinical Trial, CareNet, Inc., Nikkei Business Publications, Inc., Nichi-Iko Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ayumi Pharmaceutical Corporation, Kyowa Hakko Kirin, Sym Bio Pharmaceuticals, Medicus Shuppan Publishers, Reno Medical K.K., Yodosha, Nanzando; Consulting or advisory role: Astellas Pharma Inc., Eli Lilly Japan K.K., Ono Pharmaceutical, Takeda Pharmaceutical. L. Zhao: Full time employment: AstraZeneca. P.K. Stockman: Full-time employee, stock ownership: AstraZeneca. V. Chand: Full-time employment: AstraZeneca; stock ownership: BMS. S. Peters: Personal fees: Abbvie, Amgen, AZ, Bayer, Biocartis, BI, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda; Non-financial support: Amgen, AZ, BI, BMS, Clovis, F. Hoffmann-La Roche, Illumina, MSD, Merck Serono, Novartis, Pfizer. All other authors have declared no conflicts of interest.