Ahead of NSCLC Approval Decision, FDA Now Weighing Durvalumab Data in NEJM

lung cancer

After granting a priority review to durvalumab (Imfinzi) in October for the treatment of patients with stage III, unresectable non—small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation, the FDA is now reviewing results from the phase III PACIFIC trial, which have now been published in the print edition of the New England Journal Medicine.¹

In the study, durvalumab improved progression-free survival (PFS) by 11.2 months versus placebo. Based on the same data, the FDA also granted the anti—PD-L1 agent a breakthrough therapy designation in this setting in July.

In PACIFIC, which was conducted at 235 centers in 26 countries, randomization included 709 patients with stage III NSCLC who did not have disease progression after 2 or more cycles of platinum-based chemoradiotherapy. Patients were randomized to durvalumab (n = 473) or placebo (n = 236). PFS was the primary endpoint, along with overall survival (OS). OS data are still immature and were not included in this analysis.

The median PFS from randomization was 16.8 months in the experimental arm versus 5.6 months for patients assigned to placebo (hazard ratio [HR], 0.52; 95% CI, 0.42-0.65;P<.001). The 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%, again favoring the durvalumab arm.

Investigators found the PFS benefit associated with durvalumab was consistent across all prespecified subgroups, as defined according to patient demographic characteristics, baseline clinicopathologic features, and response to previous treatment. The PFS benefit held irrespective of PD-L1 expression before chemoradiotherapy. The HR was 0.59 (95% CI, 0.43-0.82) for patients with a PD-L1 expression level of <25%, and the HR was 0.41 (95% CI, 0.26-0.65) for patients with a PD-L1 expression level of &ge;25%.

Objective response rate, as assessed by blinded independent central review, was also significantly higher with durvalumab (28.4% vs 16.0%;P<.001). Of the patients who had a response to durvalumab, 72.8% had an ongoing response at both 12 and 18 months as compared with 56.1% and 46.8%, respectively, in the placebo arm.

In the durvalumab group, 16.5% of patients experienced disease progression compared with 27.7% of the placebo group (P<.001).

Nearly all patients in both groups—96.8% for durvalumab and 94.9% for placebo&mdash;experienced adverse events (AEs) of any cause and grade. Grade 3/4 AEs were slightly more common with durvalumab (29.9% vs 26.1%). Pneumonia was most common grade 3/4 AE, and was observed in 4.4% of patients in the durvalumab group and 3.8% of patients in the placebo group.

AEs caused discontinuations in 15.4% of patients in the durvalumab group and 9.8% of patients in the placebo group. About 28% of patients in the durvalumab group experienced serious AEs compared with 22.6% of the placebo arm.

The most frequent AEs leading to discontinuation were pneumonitis or radiation pneumonitis and pneumonia in both groups. One-third of patients assigned to durvalumab experienced any-grade pneumonitis or radiation pneumonitis compared with 24.8% in the placebo group. Grade 3/4 pneumonitis or radiation pneumonitis occurred in 3.4% of the durvalumab group and 2.6% of the placebo group.

Deaths due to AEs occurred in 4.4% of patients in the durvalumab group and 5.6% of patients in the placebo group.

Writing in an accompanying editorial, Naiyer A. Rizvi, MD, with Columbia University Medical Center, and Solange Peters, MD, PhD, with Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said OS is the typical standard for treatment outcomes in locally advanced NSCLC. The &ldquo;unprecedented&rdquo; duration of PFS in this patient population is compelling.²

&ldquo;Although the overall survival data in this study have yet to mature, the clinically meaningful difference in progression-free survival merits consideration of durvalumab as a new standard of care in this patient population,&rdquo; they wrote.

References:

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer.N Engl J Med.2017;377:1919-1929.
2. Rizvi NA, Peters S. Immunotherapy for unresectable stage III non—small-cell lung cancer.N Engl J Med.2017; 377:1986-1988.