PACIFIC
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Clinical Question
In patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum-based anti-programmed death ligand 1 antibody, does durvalumab as a consolidation therapy improve progression-free survival or overall survival?
Bottom Line
Interim analysis at median follow-up of 14.5 months showed progression-free survival to be significantly longer with durvalumab than with placebo.
Major Points
Several small and large randomized trials in diabetics had previously suggested a sizable benefit of tight glycemic control in reducing cardiovascular risk. The ACCORD trial was the largest study of its kind and demonstrated that not only does euglycemia (ie, HbA1c <6%) not reduce cardiovascular risk, it also is associated with a trend towards increased mortality.
The standard treatment for patients with unresectable Stage III NSCLC with a good performance status remains concurrent chemoradiation therapy with doublet platinum-based chemotherapy and definitive radiation therapy (54 to 66 Gy). Median progression-free survival for these patients remains poor at 8 months [1]. Darvuluman is an immune checkpoint inhibitor that is a human IgG1 antibody that blocks PDL1 binding to PDL1 and CD80 receptors found on T-cells. Radiation therapy and plantinumb-based chemotherapy has been shown to upregulate PDL-1 expression in tumor cells in biological studies and the PACIFIC trial hypothesized that darvulumab following standard platinum-based concurrent chemoradiation therapy may be beneficial [2].
Guidelines
No guidelines have been published that reflect the results of this trial.
Design
- Multicenter, randomized to treatment in a 2:1 ratio, controlled trial.
- N=709
- Darvulumab (n=(473)
- Placebo (n=256)
- Setting: International multicenter
- Enrollment: May 2014 and April 2016
- Mean follow-up: 14.5 months
- Analysis: Intention-to-treat
- Primary outcome: Progression-free survival
Population
Inclusion Criteria
- Histologically or cytologically documented stage III, locally advanced, unresectable NSCLC according to the Staging Manual in Thoracic Oncology [3]
- Received two or more cycles (defined according to local practice) of platinum-based chemotherapy (containing etoposide, vinblastine, vinorelbine, a taxane [paclitaxel or docetaxel], or pemetrexed)
- Concurrent definitive radiation therapy (54 to 66 Gy). in
- Mean dose to the lung was less than 20 Gy AND/OR
- V20 was less than 35%.
- No disease progression following concurrent chemoradiotherapy
- WHO Performance status 0 or 1
- Age ≥18 years
Exclusion Criteria
- Previous exposure to anti–PD-1 or PD-L1 antibodies
- Any receipt of immunotherapy or an investigational drug within 4 weeks before the first dose (6 weeks for monoclonal antibodies)
- Active or previous autoimmune disease (within the past 2 years)
- History of primary immunodeficiency or evidence of uncontrolled, concurrent illness or ongoing or active infections
- Unresolved toxic effects of grade 2 or higher (according to the Common Terminology Criteria for Adverse Events [CTCAE]); and grade 2 or higher pneumonitis from previous chemoradiotherapy.
Baseline Characteristics
- Mean age: 64 years
- Male: 70.1%
- Stage
- IIIA: 52.9%
- IIIB: 44.7%
- Other: 2.4%
- Histology
- Squamous: 45.7%
- Non-squamous: 54.3%
- Smoking Status
- Current: 16.4%
- Former: 74.6%
- Never: 9.0%
Interventions
- Patients were randomized to durvalumab (10 mg per kilogram of body weight IV) or matching placebo 1 to 42 days following chemoradiotherapy.
- Patients received durvalumab or placebo every 2 weeks for up to 12 months.
Outcomes
Durvalumab vs. placebo. HR stands for hazard ratio and CI stands for confidence interval. Statistics only given when provided by authors.
Primary Outcomes
- Mean progression-free survival
- 16.8 months (95% CI, 13.0 to 18.1) versus 5.6 months (95% CI, 4.6 to 7.8). HR: 0.52 (95% CI, 0.42 to 0.65; two-sided P<0.001).
Secondary Outcomes
- Time to death or distant metastasis
- 23.2 months (95% CI, 23.2 to not reached) versus 14.6 months (95% CI, 10.6 to 18.6). Hazard ratio: 0.52 (95% CI, 0.39 to 0.69; two-sided P<0.001).
- Percentage of patients alive without disease progression at 12 months
- 55.9% (95% CI, 51.0 to 60.4) versus 35.3% (95% CI, 29.0 to 41.7).
- Percentage of patients alive without disease progression at 12 months
- 44.2% (95% CI, 37.7 to 50.5) versus (95% CI, 19.9 to 34.5).
- Time to death or distant metastasis
- 23.2 months (95% CI, 23.2 to not reached) versus 14.6 months (95% CI, 10.6 to 18.6). Hazard ratio: 0.52 (95% CI, 0.39 to 0.69; two-sided P<0.001).
- Objective response rate
- 28.4% versus 16.0% (P<0.001).
Subgroup Analysis
Subgroup analysis of PD-L1 expression status before chemoradiotherapy was conducted. For patients with a PD-L1 expression level of <25%, progression-free survival benefit was maintained (HR: 0.59, 95% CI: 0.43 to 0.82). For a PD-L1 expression level of >25% progression-free survival benefit was also observed (HR: 0.41, 95% CI: 0.26 to 0.65).
Adverse Events
"Darvulumab versus Placebo."
- Adverse events of any cause and grade
- 96.8% versus 94.9%
- Grade 3 or 4 adverse events
- 29.9% versus 26.1%
- Discontinuation due to adverse events occurred
- 15.4% versus 9.8%
- Serious adverse events
- 28.6% and 22.6%
- Death due to adverse events
- 4.4% versus 5.6%
Criticisms
Funding
Funding provdied by the sponsor, AstraZeneca. The study was designed by representatives of the sponsor and academic advisors. Medical writing support was funded by the sponsor. All authors participated in the writing of the manuscript.