Naveed Saleh, MD, MS, for MDLinx | October 08, 2018
Durvalumab (IMFINZI®) extended overall survival (OS) in patients with stage III, unresectable non-small cell lung cancer (NSCLC) who did not develop disease progression following concurrent chemoradiotherapy, according to a new study in the New England Journal of Medicine.
“Immune checkpoint inhibitors targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown activity in the treatment of numerous cancers, including advanced NSCLC,” wrote the authors, led by Scott J. Antonia, MD, PhD, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Patients with stage III, unresectable NSCLC and a good performance status have historically been administered doublet chemotherapy along with definitive-dose radiotherapy. Nevertheless, clinical outcomes for such patients have been poor, with disease progression to stage IV cancer following chemotherapy occurring in up to 90% of patients, corresponding to a median survival time of ≤ 28 months.
Durvalumab is a selective human immunoglobulin G1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, thus permitting T cells to identify and kill tumor cells. On the basis of prior preclinical evidence, researchers have hypothesized that chemoradiotherapy may up-regulate PD-L1 expression in tumor cells, and PD-L1 blockade may play a role in restoring systemic and long-term immune response after chemoradiotherapy.
PACIFIC was a phase 3, randomized, placebo-controlled trial in which the investigators assessed durvalumab treatment in 709 of 713 enrolled control participants (n=236) and patients with stage III, unresectable NSCLC without disease progression (n=473) following concurrent chemoradiotherapy over a median follow-up of 25.2 months.
In the first interim analysis of the PACIFIC trial, researchers analyzed progression-free survival (PFS) as the first primary outcome. They found that durvalumab improved PFS by 11.2 months compared with placebo (16.8 months [95% CI: 13.0-18.1] vs 5.6 months [95% CI: 4.6-7.8], respectively).
“On the basis of these results, durvalumab was approved for the treatment of unresectable, stage III NSCLC in patients whose disease had not progressed after platinum-based chemoradiotherapy,” the authors wrote.
Durvalumab was approved by the US Food and Drug Administration in February 2018, making it the first treatment option for this patient population after concurrent chemotherapy.
In this analysis of the PACIFIC trial, the investigators evaluated OS (the second primary outcome). They found that the 24-month OS rate was 66.3% (95% CI: 61.7-70.4) in durvalumab-treated patients vs 55.6% (95% CI: 48.9-61.8) in those taking placebo (two-sided P=0.005).
“The results of the analysis of OS indicate that the PFS benefit has translated to a significant prolongation in OS,” wrote Dr. Antonia and colleagues.
In both analyses, the safety and tolerability of durvalumab were similar; however, serious or potentially lethal adverse reactions were reported. The most common adverse reactions were cough, fatigue, dyspnea, and radiation pneumonitis. Other adverse reactions included hepatitis, colitis or diarrhea, endocrinopathies, nephritis, rash or dermatitis, infection, and infusion-related reactions.
In total, 30.5% of durvalumab-treated patients sustained a grade 3 or 4 adverse event (AE) vs 26.1% of those administered placebo. Furthermore, 15.4% of patients taking durvalumab discontinued treatment secondary to AEs vs 9.8% of patients in the placebo group.
Overall, however, the authors did not identify any new safety signals after additional follow-up. They asserted that despite the trial’s limitations in distinguishing causality for some AEs and identifying risk factors for occurrence, their findings help to further define the safety profile of durvalumab treatment following chemoradiotherapy in this patient population.
“In this updated analysis of the PACIFIC trial, the [second] primary endpoint of OS was significantly longer with durvalumab than with placebo among patients with unresectable, stage III NSCLC,” the authors concluded.
Dr. Antonia reflected on the implications of the study: “The significant survival benefit observed using the PACIFIC regimen provides confidence and clear rationale for a new standard of care.”
This trial was funded by AstraZeneca.