Durvalumab a “revolution” for unresectable stage III NSCLC in PACIFIC
Treatment with the PD-L1* inhibitor durvalumab after chemoradiotherapy significantly prolongs progression-free survival (PFS) by 11 months in patients with locally advanced, unresectable stage III non–small-cell lung cancer (NSCLC), with similar benefits in an Asian subset, according to the PACIFIC** study presented at ESMO Asia 2017 in Singapore.
“PACIFIC is a revolution because it addresses the question of early disease NSCLC [in contrast to other studies on immunotherapies which address advanced disease],” said invited discussant Professor Solange Peters of University of Lausanne and the Ludwig Institute in Lausanne, Switzerland. “More importantly, PACIFIC is investigating a mechanism ─ the vaccination process underlying the immunogenic cell death.”
In the planned interim analysis (median follow-up 14.5 months), the coprimary endpoint of PFS was 11 months longer in the durvalumab vs the placebo arms (median, 16.8 vs 5.6 months, hazard ratio [HR], 0.52; p<0.001). Similar improvement in PFS with durvalumab vs placebo was also seen in a subset analysis of Japanese patients (n=72 vs n=40, median PFS, not reached vs 7.2 months, HR, 0.49; p=0.02). [N Engl J Med 2017;377:1919-1929; ESMO Asia 2017, session 403O]
The PFS benefit in favour of durvalumab was observed across all prespecified subgroups, and notably, regardless of the PD-L1 expression levels of tumour cells in the overall population. The HRs for death or disease progression were 0.41 and 0.59 for patient subgroups with PD-L1 expression levels of ≥25 percent and <25 percent, respectively.
“The study remains blinded to overall survival [OS]. Final analysis of OS [will be] planned after target number of deaths has been reached,” according to study co-investigator Dr Shuji Murakami of Kanagawa Cancer Center, Yokohama, Japan, who presented the study.
“Although OS data have yet to mature, the clinically meaningful difference in PFS merits consideration of durvalumab as a new standard of care in this patient population,” commented Peters.
Response rate in the durvalumab arm was higher (28.4 percent vs 16.0 percent; p<0.001) and more durable than the placebo arm (ongoing response at 18 months, 72.8 percent vs 46.8 percent).
Also, durvalumab delayed the time to death or distant metastasis (23.2 vs 14.6 months; p<0.001), with lower incidence of new lesions, including new brain metastasis (5.5 percent vs 11.0 percent) compared with placebo.
In the overall population, no new safety signals were seen with durvalumab ─ grade 3/4 adverse events (AEs) occurred in 29.9 percent vs 26.1 percent of patients receiving durvalumab vs placebo. This was also consistent in the Japanese subset, which documented such AEs at 23.6 percent vs 12.5 percent.
Pneumonitis of any grade was more frequent with durvalumab than placebo in the overall population (33.9 percent vs 24.8 percent), although this was considered “not meaningfully different” between the groups. In the Japanese subset, pneumonitis of any grade (73.6 percent vs 60.0 percent) and of grade3/4 were also higher with durvalumab (5.6 percent vs 2.5 percent).
“[There is no reason to think] that the ethnicity would change anything in the mechanisms the [drug works],” said Peters. “[Nonetheless,] in Asian patients [there was] a slightly higher toxicity of immunotherapy, and even more so when combined with radiotherapy in terms of pneumonitis. We need more data.”
The double-blind phase III study involved 709 patients with stage III NSCLC without disease progression after ≥2 platinum-based chemoradiotherapy. They were randomized 2:1 to receive intravenous durvalumab (10 mg/kg body weight) or placebo at every 2 weeks for a maximum of 12 months, within 1–42 days after chemoradiotherapy.
“The data from the PACIFIC study may end the debate about the role of surgery in patients with stage III NSCLC, with durvalumab after chemoradiotherapy redefining best practice for all patients with stage III NSCLC,” said Peters.
Nonetheless, some questions remained, including the optimal sequence and timing of the intervention. Based on the supplemental data in NEJM, a longer interval between chemoradiotherapy and the administration of durvalumab appeared to reduce its clinical benefits, Peters pointed out.
“[This] suggests that durvalumab should be given as early as possible … maybe the earliest is concurrently with radiotherapy,” she said.