4480 - Efficacy of durvalumab in patients with Stage III NSCLC who experience pneumonitis (PACIFIC)

Background

In the Phase III PACIFIC trial of patients with unresectable, Stage III non-small cell lung cancer (NSCLC) without progression after chemoradiotherapy (CRT), durvalumab significantly improved the primary endpoints progression-free survival (PFS) and overall survival (OS) versus placebo and was well-tolerated. Any-grade pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in 161 (33.9%) and 58 (24.8%) patients treated with durvalumab and placebo, respectively, with similar grade 3/4 rates (3.6% and 3.0%). Exploratory analyses were performed to investigate the efficacy of durvalumab in patients who developed pneumonitis.

Methods

Patients with WHO PS 0/1 (irrespective of tumor PD-L1 status) with ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to durvalumab 10 mg/kg intravenously every 2 weeks or placebo for up to 12 months, stratified by age, sex, and smoking history. PFS and time to death or distant metastasis (TTDM) were assessed by blinded independent central review using RECIST v1.1. The impact of pneumonitis on efficacy was assessed via Cox proportional hazards models. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented.

Results

As of 22 March 2018, 713 patients were randomized of whom 709 received treatment. Using a step-wise approach, pneumonitis was assessed via univariate analyses and, when adjusted for the occurrence of (time-dependent) pneumonitis in the models, OS, PFS, and TTDM were consistent with results for the ITT population (Table). The pneumonitis time-dependent covariate was not significant (P > 0.1) in all models.Table:

1459PD OS, PFS, and TTDM, adjusted for the time-dependent occurrence of pneumonitis* and for the ITT population

Data cutoff: 22 March 2018.

Pneumonitis occurred on Tx and within 90 days of last dose or prior to subsequent anticancer therapy (whichever occurred earlier).

A Cox proportional hazards model adjusted for the time-dependent occurrence of pneumonitis using two sets of covariate models was used (with the Breslow method to control for ties): (1) accounting for stratification factors at randomization: age at randomization (<65 vs ≥ 65), sex (male vs female) and smoking history (smoker vs non-smoker), as used for the ITT population (base model); and (2) the base model plus additional baseline prognostic factors: stage of disease at study entry (IIIA vs IIIB), histology (squamous vs all other), best response to prior anticancer therapy (CR vs PR vs SD), WHO performance status (normal vs restricted activity), region (Asia vs Europe vs North America and South America ) and race (White vs Black/African-American vs Asian vs Other).

The analysis was performed using a stratified Log rank test, adjusted for age at randomization (<65 vs ≥ 65), sex (male vs female) and smoking history (smoker vs non-smoker) with ties handled using the Breslow approach. CR, complete response; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease; TTDM, time to death or distant metastasis.

Conclusions

Treatment benefit with durvalumab versus placebo was maintained regardless of the occurrence of pneumonitis, which predominantly occurred with low-grade severity as previously reported. These findings suggest that low-grade pneumonitis should not deter use of durvalumab.

Clinical trial identification

NCT02125461 (release date: 29 April 2014).

Editorial acknowledgement

Andrew Gannon, MS, MA, of Cirrus Communications (New York, NY), an Ashfield company, in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.F. Vansteenkiste: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: BMS. J. Naidoo: Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche/Genentech. C. Faivre-Finn: Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Elekta; Travel / Accommodation / Expenses: Pfizer. M. Özgüroğlu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Jannsen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. A. Villegas: Speaker Bureau / Expert testimony: AstraZeneca. D. Daniel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Janssen Research and Development; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis Pharmaceuticals Corporation; Research grant / Funding (institution): Abb Vie, Inc.; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merus NV; Research grant / Funding (institution): Daiichi Sankyo. S. Murakami: Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. R. Hui: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. K.H. Lee: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca. B.C. Cho: Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): MOGAM Institute; Research grant / Funding (self): Dong-A ST; Research grant / Funding (self): Champions Oncology; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Yuhan; Advisory / Consultancy, Research grant / Funding (self): Ono; Research grant / Funding (self): Dizal Pharma; Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy: MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K. Kubota: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Novaltis; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Kyowa Hakko KIRIN. M. Taboada: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Wadsworth: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P.A. Dennis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.J. Antonia: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self): CBMG; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Memgen; Advisory / Consultancy, Travel / Accommodation / Expenses: FLX Bio; Shareholder / Stockholder / Stock options: Cellular Biomedicine Group.