Effect of post-study immunotherapy (IO) on overall survival (OS) outcome in patients with metastatic (m) NSCLC treated with first-line durvalumab (D) vs chemotherapy (CT) in the Phase 3 MYSTIC study


10 Apr 2019


Proffered Paper session I


Niels Reinmuth


Annals of Oncology (2019) 30 (suppl_2): ii77-ii80. 10.1093/annonc/mdz094


N. Reinmuth1, B.C. Cho2, K.H. Lee3, A. Luft4, M. Ahn5, J. Schneider6, F.A. Shepherd7, S.L. Geater8, Z. Pápai-Székely9, T. Van Ngoc10, M.C. Garassino11, F. Liu12, D. Clemett13, P. Thiyagarajah14, M. Ouwens15, U. Scheuring13, S. Peters16, N. Rizvi17

Author affiliations

  • 1 Department Of Thoracic Oncology, Asklepios Lung Clinic, 82131 - Munich-Gauting/DE
  • 2 Yonsei Cancer Center, Yonsei University College of Medicine, 120-752 - Seoul/KR
  • 3 Chungbuk National University Hospital, 361-711 - Cheongju/KR
  • 4 Oncology Department, Leningrad Regional Clinical Hospital, 194291 - Lunacharskogo prospect/RU
  • 5 Samsung Medical Center, 135-710 - Seoul/KR
  • 6 NYU Winthrop Hospital, Mineola/US
  • 7 Cancer Clinical Research Unit, Princess Margaret Cancer Centre, Toronto/CA
  • 8 Prince of Songkla University, Songkla/TH
  • 9 St George Hospital of Fejer County, Székesfehérvár/HU
  • 10 Cho Ray Hospital, Ho Chi Minh/VN
  • 11 Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 - Milan/IT
  • 12 AstraZeneca, Gaithersburg/US
  • 13 AstraZeneca, Cambridge/GB
  • 14 AstraZeneca, GB216GP - Cambridge/GB
  • 15 AstraZeneca, 431 50 - Gothenburg/SE
  • 16 Centre Hospitalier Universitaire Vaudois, Lausanne University, 1011 - Lausanne/CH
  • 17 Columbia University Medical Center, 10032 - New York/US



In MYSTIC (NCT02453282), an open-label, Phase 3 study of first-line D (anti-PD-L1) ± tremelimumab vs platinum-based CT in mNSCLC, while not statistically significant, a clinically meaningful improvement in OS was seen with D vs CT in pts with tumour cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p=0.036). Here we describe subsequent treatment patterns and explore the effect of subsequent IO on the OS outcome with D vs CT.


IO/CT-naïve mNSCLC pts were randomised to D (20 mg/kg i.v. q4w until disease progression) or CT (up to 6 cycles; pemetrexed maintenance permitted). In-study crossover from CT to D was not allowed. For D vs CT, the primary endpoint was OS in pts with PD-L1 TC ≥25%. Three statistical models were employed in exploratory analyses to evaluate the effect of subsequent (post-study) IO on the OS data: the rank preserving structural failure time (RPSFT) method, the inverse probability of censoring weighting (IPCW) method, and a 2-stage method.


163 and 162 pts with PD-L1 TC ≥25% were randomised to D and CT, respectively. At data cut-off (04 Oct 2018), 44.8% of pts in the D arm and 58.6% of pts in the CT arm had received subsequent treatment (Table). Most pts started subsequent treatment within 2 mos of discontinuing study treatment. Among pts who received subsequent treatment, IO was administered to 10/73 (13.7%) pts in the D arm and 64/95 (67.4%) pts in the CT arm; most commonly nivolumab. Using the 2-stage method, which was the most appropriate for evaluating the effect of subsequent IO, OS was improved with D vs CT (HR 0.66 [95% CI 0.51, 0.86]).Table: LBA4

Durvalumab (n=163)Chemotherapy (n=162)
Pts who received study treatment, n (%)161 (98.8)153 (94.4)
→Pts who discontinued study treatment136 (83.4)152 (93.8)
→Pts remaining on study treatment25 (15.3)1 (0.6)
Pts who received any subsequent treatment, n (%)73 (44.8)95 (58.6)
→Immunotherapy10 (6.1)64 (39.5)
→→Nivolumab3 (1.8)50 (30.9)
→→Pembrolizumab4 (2.5)11 (6.8)
→→Atezolizumab2 (1.2)3 (1.9)
→→Durvalumab02 (1.2)
→→Tremelimumab01 (0.6)
→→Other immunotherapy1 (0.6)2 (1.2)
→Cytotoxic chemotherapy70 (42.9)58 (35.8)
→Other systemic therapies*18 (11.0)18 (11.1)

Denominators for percentages are the number of pts randomised.


Excluding immunotherapy and cytotoxic chemotherapy.


In the MYSTIC study, a markedly higher proportion of pts in the CT arm than in the D arm received subsequent IO, which may have confounded the primary OS outcome. An exploratory analysis showed increased OS benefit with first-line D vs CT after adjusting for the effect of subsequent IO.

Editorial acknowledgement

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

AstraZeneca PLC.




N. Reinmuth: Personal fees: BMS, Roche, AstraZeneca, Takeda, Novartis, Boehringer Ingelheim, MSD, Lilly, outside the conduct of 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. J. Schneider: Stock/other ownership: AstraZeneca, Bristol-Myers Squibb, Pfizer, Celgene, Loxo; Consulting/advisory role: Takeda Oncology; Research funding: AstraZeneca, Bristol-Myers Squibb. F.A. Shepherd: Consultancy/advisory role: Lilly, AstraZeneca, Boehringer Ingelheim, Merck Serono; Stock ownership: Lilly, AstraZeneca; Honoraria: Lilly, AstraZeneca, BMS, Roche/Genentech, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim; Research funding: Lilly, Pfizer, BMS, AstraZeneca, Roche Canada, Merrimack. 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. S.L. Geater: Research grants/funding: AstraZeneca, Roche, Novartis. T. Van Ngoc: Research funding: AstraZeneca, GSK, Novartis. M.C. Garassino: Personal fees: Eli Lilly, Boehringer Ingelheim, Otsuka Pharma, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Inivata, Takeda, Tiziana Science, Clovis, Merck Serono, Bayer, MSD, GSK. F. Liu, D. Clemett, P. Thiyagarajah, M. Ouwens, U. Scheuring: Full-time employment: AstraZeneca. N. 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.

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