Adding Durvalumab to Chemoradiation Improves OS in Unresectable Stage III NSCLC

Scott J. Antonia, MD

Durvalumab (Imfinzi) induced a clinically meaningful improvement in overall survival (OS) compared with placebo in patients with stage III, unresectable non—small cell lung cancer (NSCLC) who have not progressed following chemoradiotherapy.

Patients treated with durvalumab after chemoradiotherapy demonstrated a 24-month OS rate of 66.3% (95% CI, 61.7%-70.4%) compared with 55.6% (95% CI, 48.9-61.8) in patients who received placebo (two-sided P = .005). An update from the PACIFIC trial was presented at the 19th World Conference on Lung Cancer (WCLC) in Toronto, Canada,¹ and results were simultaneously published in the New England Journal of Medicine.²

“We’ve cured 15% to 30% of patients [with stage III, unresectable NSCLC]. But of course, we’ve been stuck with those numbers for decades. We have not been able to make any inroads to improving the outcomes of these patients for quite some time,” said Scott J. Antonia, MD, PhD, department chair of the Thoracic Oncology Department at Moffitt Cancer Center and professor of oncologic sciences at the University of South Florida College of Medicine.

In the randomized, double-blinded, placebo-controlled, multicenter phase III PACIFIC trial—which comprised 713 patients in 235 study centers across 26 countries—investigators randomly assigned patients 2:1 to receive either 10 mg/kg durvalumab intravenously (n = 476) or placebo (n = 237) every 2 weeks for up to 12 months after chemoradiotherapy.

Progression-free survival (PFS) and OS served as co-primary endpoints, and secondary endpoints included time to death or distant metastasis (TTDM), time to second progression, and safety.

At the first planned interim analysis of the trial, the investigators observed an 11.2-month improvement in PFS with durvalumab versus placebo. As of March 22, 2018, median follow-up was 25.2 months (range, 0.2-43.1).

Durvalumab significantly prolonged OS compared with placebo (HR, 0.68; 99.73% CI, 0.469-0.997; P = .00251). Median OS was not reached in the durvalumab group and was 28.7 months in the placebo arm.

Updated analyses of PFS were similar to those previously reported. Median PFS by blinded independent central review was 17.2 months with durvalumab and 5.6 months in the placebo arm (HR, 0.51; 95% CI, 0.41-0.63).

The investigators evaluated PFS and OS by subgroup, from which data are still being evaluated; however, some trends still emerged. “Interestingly, patients who were nonsmokers did benefit from durvalumab, a situation where a benefit from immunotherapy has much of an impact,” Antonia noted. “It also interestingly appears, in the OS analysis, that cisplatin was the better platinum drug to use in the conventional therapy portion of treatment.”

The agent was found to improve secondary endpoints as well. TTDM was 28.3 months in the durvalumab group and 16.2 months in the placebo group (HR, 0.53; 95% CI, 0.41-0.68), and 22.5% and 33.8% of patients, respectively, developed new lesions following treatment.

Antonio noted no new safety issues with the updated data. In total, 30.5% of those in the durvalumab arm and 26.1% of those in the placebo group experienced grade 3 or 4 adverse events (AEs) of any cause. Serious AEs occurred in 29.1% and 23.1% of patients, respectively. In total, 15.4% of patients treated with durvalumab discontinued treatment compared with 9.8% of those treated with placebo.

“PACIFIC is the first study to demonstrate a survival advantage for unresectable, stage III non-small cell lung cancer, supporting the PACIFIC regimen as standard of care,” Antonia said.

In a follow-up discussion, Everett Vokes, MD, John E. Ultmann Professor of Medicine and Radiation Oncology, physician-in-chief, and chair in the Department of Medicine at the University of Chicago Medicine, noted that maintenance durvalumab is the new standard of care and that it can also serve as a control reference for future randomized trials. However, he added, questions still remain.

“An important question is, ‘Should stage III patients be tested for PD-L1 expression?’ The answer is ‘Yes’ because that is how we will have to learn how to treat them better. It is unlikely patients [with PD-L1 expression] had great benefit [from durvalumab]. We have to learn more strategies in this population,” Vokes said.

“Do these results apply to mutation-driven tumors? Likely, yes,” Vokes added. “And what is the optimal treatment duration? These are all questions that remain.”

References

1. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.01.
2. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online ahead of print September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809697.