Durvalumab "Game-Changer" for Locally Advanced Lung Cancer

The PD-L1 inhibitor durvalumab improved median progression-free survival by 11.2 months compared with placebo for patients with locally advanced, unresectable stage III lung cancer who had not progressed following chemoradiotherapy.

Luis Paz-Ares, MD

The PD-L1 inhibitor durvalumab (Imfinzi) improved median progression-free survival (PFS) by 11.2 months compared with placebo for patients with locally advanced, unresectable stage III non—small cell lung cancer (NSCLC) who had not progressed following chemoradiotherapy, according to phase III results from the PACIFIC trial presented at the 2017 ESMO Congress and published in the New England Journal of Medicine.

UPDATE 2/16/2018: FDA Approves Durvalumab for Locally Advanced NSCLC

In the study, the median PFS was 16.8 months (95% CI, 13.0-18.1) with durvalumab compared with 5.6 months (95% CI, 4.6-7.8) for placebo (HR, 0.52; 95% CI, 0.42-0.65; P <.0001). At 12 months, 55.9% of those in the durvalumab arm remained progression free compared with 35.3% with placebo. The 18-month PFS rates were 44.2% and 27.0%, for durvalumab and placebo, respectively. An analysis of overall survival had not yet been conducted and this endpoint remained blinded.

"This is a clear improvement in the outcome, with increased PFS—by about 11 months—consistent improvement in response rate, and decreases in the development of metastatic disease," said lead investigator Luis Paz-Ares, MD, chair, Medical Oncology Department, Hospital Universitario Doce de Octubre. "Overall, durvalumab is a promising option for patients with stage III non—small cell lung cancer treated with chemoradiation."

Results from the PACIFIC study represent the first major advance for patients with stage III lung cancer, and are the only phase III findings for a checkpoint inhibitor in this space. The median PFS with chemoradiotherapy alone is approximately 8 to 10 months, representing more than a doubling with durvalumab.

The double-blind PACIFIC trial randomized 713 patients with stage III locally advanced, unresectable NSCLC to durvalumab (n = 476) or placebo (n = 237). Durvalumab was administered at 10 mg/kg every 2 weeks for up to 12 months. All patients were within 1 to 42 days post chemoradiotherapy and were stratified by age, sex, and smoking history.

The median age of patients in the study was 64 years, and most were current or former smokers (91%). The majority were men (70.1%), and most had squamous histology (45.7%). Chemotherapy use was similar between groups, with 25.8% and 28.7% receiving induction chemotherapy before definitive chemoradiotherapy, in the durvalumab and placebo groups, respectively. Response to chemoradiotherapy was similar between the two arms, with objective response rates (ORR) of 50.6% and 49.8%, for the PD-L1 and placebo groups, respectively.

The median time to death or distant metastasis was significantly longer with durvalumab versus placebo (23.2 versus 14.6 months; HR, 0.52; 95% CI, 0.39-0.69; P <.001). New lesions occurred for 20.4% of those treated with durvalumab versus 32.1% of those in the placebo group. Additionally, there were fewer new brain lesions in the durvalumab group versus placebo (5.5% vs. 11.0%).

Similar PFS benefits were seen across all patient subgroups, including by PD-L1 status, noted Paz-Ares. Durvalumab reduced the risk of progression or death by 41% versus placebo in those with PD-L1 expression of <25% (HR, 0.59; 95% CI, 0.43-0.82) and by 59% in those with PD-L1 expression ≥25% (HR, 0.41; 95% CI, 0.26-0.65).

"Most of the subgroups do have the same benefits. It’s the same for stage IIIa and IIIb and squamous and nonsquamous," said Paz-Ares. "We're seeing similar benefits for PD-L1 status positive versus negative."

Adverse events (AEs) of all grades were experienced by 96.8% of those in the durvalumab group and by 94.9% of those in the placebo arm. Overall, 29.9% of those in the PD-L1 group had a grade 3/4 event versus 26.1% with placebo. Grade 5 AEs were similar between groups (4.4% versus 5.6%, for durvalumab and placebo, respectively). Treatment-related AEs occurred in 67.8% and 53.4% and serious AEs were seen for 28.6% and 22.6% of patients in the durvalumab and placebo groups, respectively.

AEs leading to discontinuation occurred in 15.4% of patients in the durvalumab group versus 9.8% of those treated with placebo. The most common AEs leading to discontinuation for durvalumab and placebo, respectively, were pneumonitis or radiation pneumonitis (6.3% vs 4.3%) and pneumonia (1.1% vs 1.3%). The most frequently observe all-grade AEs of special interest with durvalumab versus placebo, respectively, were diarrhea (18.3% vs 18.8%), pneumonitis (12.6% vs 7.7%), rash (12.2% vs 7.3%), and pruritus (12.2% vs 4.7%).

"The safety profile of durvalumab was consistent with that of other immunotherapies and with its known safety profile as monotherapy in patients with more advanced disease," said Paz-Ares. "No new safety signals were identified."

Based on findings from the PACIFIC trial, AstraZeneca, the company developing durvalumab, has already entered discussions with global health authorities for regulatory approval. In July 2017, durvalumab received a breakthrough therapy designation from the FDA as a potential treatment for patients with locally advanced, unresectable NSCLC whose disease has not progressed following chemoradiotherapy. Durvalumab is already approved for the treatment of patients with advanced urothelial carcinoma.

References

  1. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: A double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA1_PR.
  2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non—Small-Cell Lung Cancer. N Engl J Med. Published online September 8, 2017. DOI: 10.1056/NEJMoa1709937.

<<< View more from the 2017 ESMO Congress

The ORR following treatment with durvalumab was 28.4% compared with 16% in the placebo group (relative risk, 1.78; 95% CI, 1.27-2.51). The complete response rate was 1.4% with durvalumab versus 0.5% with placebo. The median duration of response was not reached with durvalumab versus 13.8 months with placebo. At the 18-month analysis, 72.8% of patients continued to respond to the PD-L1 inhibitor versus 46.8% of those in the placebo group.