In MYSTIC (NCT02453282), an open-label, Phase 3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs CT in mNSCLC, while not statistically significant, a clinically meaningful improvement in overall survival (OS) was seen with D vs CT in pts with tumour cell PD-L1 expression ≥25% (TC ≥25% [primary analysis population]; D vs CT, HR 0.76 [97.54% CI 0.56–1.02], p=0.036; D+T vs CT, HR 0.85 [98.77% CI 0.61–1.17], p=0.202). Here we report OS in clinically relevant pt subgroups and safety results from MYSTIC.
Immunotherapy/CT-naïve pts with mNSCLC were randomised (1:1:1) to D (20 mg/kg q4w); D (20 mg/kg q4w) + T (1 mg/kg q4w for 4 cycles); or CT. OS was analysed in pt subgroups based on baseline clinical characteristics in the PD-L1 TC ≥25% population (prespecified: age, gender, race, histology, smoking history and immune cell [IC] PD-L1 expression ≥25% vs <25%; post hoc: ECOG performance status). Safety (CTCAE v4.03) and tolerability were evaluated in all treated pts.
The subgroup analysis included 488 pts (D, 163; D+T, 163; CT, 162). Baseline characteristics were balanced between treatment groups. Treatment with D±T resulted in numerical improvement in OS vs CT in most clinical subgroups. OS in pts aged ≥65 y, PD-L1 IC ≥25%, and performance status 0 showed a HR (95% CI) of 0.66 (0.45, 0.95), 0.63 (0.38, 1.04), and 0.54 (0.34, 0.84), respectively, with D vs CT and a HR (95% CI) of 0.72 (0.50, 1.02), 0.64 (0.39, 1.05), and 0.76 (0.50, 1.14) with D+T vs CT. Rates of TRAEs leading to discontinuation and imAEs were highest with D+T and rates of Grade ≥3 TRAEs were highest with CT (Table).Table: LBA3
|D (n=369)||D+T (n=371)||CT (n=352)|
|Any TRAE leading to discontinuation (PT), n (%)||20 (5.4)||49 (13.2)||33 (9.4)|
|→Pneumonitis||3 (0.8)||7 (1.9)||1 (0.3)|
|→Interstitial lung disease||2 (0.5)||5 (1.3)||1 (0.3)|
|→Blood creatinine increased||0||1 (0.3)||4 (1.1)|
|→Diarrhoea||0||4 (1.1)||1 (0.3)|
|Any Grade ≥3 TRAE (PT), n (%)||55 (14.9)||85 (22.9)||119 (33.8)|
|→Neutropenia||1 (0.3)||0||35 (9.9)|
|→Fatigue||6 (1.6)||8 (2.2)||7 (2.0)|
|→Lipase increased||3 (0.8)||13 (3.5)||1 (0.3)|
|Any imAE (grouped term), n (%)||50 (13.6)||105 (28.3)||12 (3.4)|
|→Hypothyroidism||21 (5.7)||28 (7.5)||2 (0.6)|
|→Pneumonitis||8 (2.2)||25 (6.7)||5 (1.4)|
|→Diarrhoea||7 (1.9)||17 (4.6)||1 (0.3)|
|→Rash||5 (1.4)||16 (4.3)||2 (0.6)|
|→Colitis||2 (0.5)||12 (3.2)||0|
5 most common events in each category listed in descending order of frequency across the 3 treatment arms. PT, preferred term; TRAE, treatment-related AE; imAE, immune-mediated AE.
In MYSTIC, results of OS analyses across most pt subgroups showed favourable HRs for D±T vs CT, consistent with the overall primary analysis. The safety profile of D±T was manageable and consistent with previous studies with lower rates of Grade ≥3 TRAEs reported compared to CT.
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Samantha Holmes, PhD, of Cirrus Communications (Macclesfield, UK), an Ashfield company, and was funded by AstraZeneca.
Legal entity responsible for the study
B.C. Cho: Grants/research support: Novartis, AstraZeneca, Yuhan, ONO/BMS, MSD, Bayer; Advisor/honoraria fees: AstraZeneca, Roche, Boehringer Ingelheim, Yuhan, BMS, MSD, Novartis; Speaker’s bureau fees: AZ, BMS, MSD, Novartis. N. Reinmuth: Personal fees: BMS, Roche, AstraZeneca, Takeda, Novartis, Boehringer Ingelheim, MSD, Lilly, outside the conduct of the study. A. Smolin: Grants: AstraZeneca; Grants, personal fees: AstraZeneca, Roche, MSD, BMS; Personal fees: BIOCAD, Boehringer Ingelheim. S.J. Antonia: Advisory boards/contracted research: Novartis; Advisory boards: BMS, Merck, CBMG, Boehringer Ingelheim, AstraZeneca, Memgen, FLX Bio, Nektar, Venn. G. Robinet: Grants, personal fees: AstraZeneca, MSD; Personal fees: Boehringer Ingelheim. R. Natale: Spouse employed (Medical Science Liaison): AstraZeneca - However, her salary and compensation is completely unrelated to the contracted research work performed at my institution for which I am a co-investigator. E.B. Garon: Research funding: Merck, Genentech, AstraZeneca, Novartis, Lilly, BMS, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics. 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. 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. F. Liu, P. Thiyagarajah: Full-time employment: 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 (patent filed by MSKCC). All other authors have declared no conflicts of interest.