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Mario Ouwens
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Proffered Paper session I (ID 57)
- Event: ELCC 2019
- Type: Proffered Paper session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 4/10/2019, 16:30 - 18:15, Room C
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83O - Impact of subsequent post-discontinuation immunotherapy on overall survival in patients with unresectable, stage III NSCLC from PACIFIC (ID 303)
16:30 - 18:15 | Author(s): Mario Ouwens
- Abstract
- Presentation
Background
In cancer trials, pts often receive subsequent lines of anticancer Tx following progression, which, in standard ITT analyses, can lead to bias and underestimation of OS Tx effect. In the phase 3 PACIFIC trial of durvalumab vs. placebo in Stage III NSCLC pts without progression after CRT, both primary endpoints PFS and OS were met, significantly improved with durvalumab. However, after discontinuation, many pts received further anticancer Tx (41% and 54% in the durvalumab and placebo groups), including immunotherapies (IMTs), which may have influenced OS. Using the Rank Preserving Structural Failure Time (RPSFT) model, we quantified the specific impact of subsequent IMT on OS in PACIFIC.
a9ded1e5ce5d75814730bb4caaf49419 Methods
RPSFT modeling is commonly used for analysis of trials with crossover. By assuming a similar effect for Tx in different sequences, RPSFT is capable to pinpoint the most likely effect size based on observed data. Here, we adapted RPSFT to isolate the likely effect of subsequent IMT by assuming similar mortality risk reduction for nivolumab, pembrolizumab, and durvalumab. RPSFT analyses were applied to quantify health outcomes for two hypothetical scenarios: (1) no subsequent IMT was received by pts in either arm, and (2) among placebo pts who received subsequent Tx (54%), all received IMT as first subsequent Tx, and durvalumab pts received no subsequent IMT, to test if delaying IMT was detrimental.
20c51b5f4e9aeb5334c90ff072e6f928 Results
Among pts randomized to durvalumab and placebo, 8% (38/476) and 22% (53/237), respectively, received subsequent IMT. Within the ITT population, the HR for OS with durvalumab vs. placebo was 0.68 (95% CI, 0.53–0.87), with respective median OS not reached (NR) and 28.7 months. For scenario 1, there was minimal change in OS, with an estimated HR of 0.67 (95% CI, 0.52–0.86) and identical median OS estimates. For scenario 2, the estimated HR was 0.79 (95% CI: 0.62–1.00), with median OS NR and 32.2 months, respectively.
fd69c5cf902969e6fb71d043085ddee6 Conclusions
After removing the effects of subsequent IMT, the OS benefit with durvalumab was still evident compared with the ITT analysis. In addition, early Tx with durvalumab after CRT appeared to be associated with improved OS compared with starting IMT after progression.
b651e8a99c4375feb982b7c2cad376e9 Clinical trial identification
NCT02125461.
7a6a3ffa2dadc03a6151ee2c4d6fa383 Editorial acknowledgement
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Hashem Dbouk, PhD, of Cirrus Communications, an Ashfield company, and was funded by AstraZeneca.
934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study
AstraZeneca.
213f68309caaa4ccc14d5f99789640ad Funding
AstraZeneca.
682889d0a1d3b50267a69346a750433d Disclosure
M. Ouwens, Y. Zhang, P. Mukhopadhyay: Employment, stock options: AstraZeneca, outside the conduct of the study. A. Darilay, J. Ryan: Employment, stock: AstraZeneca, outside the conduct of the study. H. Mann: Employment: AstraZeneca, outside conduct of the study. P.A. Dennis: Employment, stocks: AstraZeneca, outside the submitted work.
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LBA4 - 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 III MYSTIC study (ID 379)
16:30 - 18:15 | Author(s): Mario Ouwens
- Abstract
- Presentation
Background
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.
a9ded1e5ce5d75814730bb4caaf49419 Methods
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.
20c51b5f4e9aeb5334c90ff072e6f928 Results
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]).
fd69c5cf902969e6fb71d043085ddee6 ConclusionsDurvalumab (n=163) Chemotherapy (n=162) Pts who received study treatment, n (%) 161 (98.8) 153 (94.4) →Pts who discontinued study treatment 136 (83.4) 152 (93.8) →Pts remaining on study treatment 25 (15.3) 1 (0.6) Pts who received any subsequent treatment, n (%) 73 (44.8) 95 (58.6) →Immunotherapy 10 (6.1) 64 (39.5) →→Nivolumab 3 (1.8) 50 (30.9) →→Pembrolizumab 4 (2.5) 11 (6.8) →→Atezolizumab 2 (1.2) 3 (1.9) →→Durvalumab 0 2 (1.2) →→Tremelimumab 0 1 (0.6) →→Other immunotherapy 1 (0.6) 2 (1.2) →Cytotoxic chemotherapy 70 (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.
b651e8a99c4375feb982b7c2cad376e9 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.
934ce5ff971f1ab29e840a35e3ca96e9 Legal entity responsible for the study
AstraZeneca PLC.
213f68309caaa4ccc14d5f99789640ad Funding
AstraZeneca.
682889d0a1d3b50267a69346a750433d Disclosure
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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