FDA Updates Durvalumab NSCLC Label to Include OS Data

The FDA has updated the label for durvalumab for patients with unresectable, stage III non–small cell lung cancer whose disease has not progressed following concurrent platinum-based chemoradiation to include overall survival data from the phase III PACIFIC trial.

The FDA has updated the label for durvalumab (Imfinzi) for patients with unresectable, stage III non—small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemoradiation to include overall survival (OS) data from the phase III PACIFIC trial.1

In results of the primary OS analysis, the PD-1 inhibitor demonstrated a 32% reduction in the risk of death compared with placebo, which was a significant and clinically proven survival benefit in this patient population (HR, 0.68; 95% CI, 0.53-0.87; P = .0025).2

Three-year follow-up results of a posthoc OS analysis from PACIFIC were presented at the 2019 ASCO Annual Meeting. The data were consistent with the initial 2-year findings (HR, 0.69; 95% CI, 0.55-0.86).3 Moreover, 57% of patients on durvalumab were alive (95% CI, 52.3%-61.4%) compared with 44% of those who received placebo (95% CI, 37.0%-49.9%) at the 3-year mark, stated AstraZeneca, the developer of the PD-L1 inhibitor, in a press release.

“This label update coupled with the recent 3-year overall survival data continue to reinforce the PACIFIC regimen as the standard of care in this curative-intent setting,” Olivier Nataf, head of US Oncology, AstraZeneca, stated in the press release. “For patients and providers, this announcement provides further evidence and confidence in the survival benefit of Imfinzi.”

The FDA approved durvalumab in this setting in February 2018, based on the initial data of the PACIFIC study. Moreover, National Comprehensive Cancer Network clinical practice guidelines in oncology recommend durvalumab as a Category 1 post-CRT consolidation immunotherapy for patients with unresectable, stage III NSCLC.

In PACIFIC, patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy were randomized to durvalumab (n = 473) or placebo (n = 236). The co-primary endpoints were PFS and OS.

The median age of patients in the study was 64 years, and most were current or former smokers (91%). The majority of patients were male (70.1%), and most had squamous histology (45.7%). Chemotherapy use was similar between groups, as 25.8% and 28.7% received 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 inhibitor and placebo groups, respectively.

In earlier findings of PACIFC, durvalumab demonstrated a median PFS of 16.8 months compared with 5.6 months for patients who received placebo (HR, 0.52; 95% CI, 0.42-0.65; P <.0001).4 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 durvalumab.

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 prior therapy. The PFS benefit held irrespective of PD-L1 expression before chemoradiotherapy, such as patients with a PD-L1 expression level of <25% (HR, 0.59; 95% CI, 0.43-0.82), and patients with a PD-L1 expression level of ≥25% (HR, 0.41; 95% CI, 0.26-0.65).

Additionally, the ORR, as assessed by blinded independent central review, was also significantly higher with durvalumab (28.4% vs 16.0%; P <.001). Of those 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 those on placebo (P <.001).

Regarding safety, all-grade adverse events (AEs) were experienced in both groups at 96.8% for durvalumab and 94.9% for placebo. Grade 3/4 AEs were slightly more common with durvalumab (29.9% vs 26.1%). Pneumonia was the most common grade 3/4 AE, and was observed in 4.4% of patients on durvalumab 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. Approximately 29% of patients in the durvalumab group experienced serious AEs versus 22.6% of the placebo arm.

The most frequent AEs that led to discontinuation were pneumonitis or radiation pneumonitis and pneumonia in both groups. One-third of patients on durvalumab experienced any-grade pneumonitis or radiation pneumonitis versus 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.

In the preliminary 2-year OS findings, there were also updated analyses for PFS. The median PFS was 17.2 months with durvalumab and 5.6 months in the placebo group (stratified HR, 0.51; 95% CI, 0.41-0.63). The median time to death or distant metastasis was 28.3 month and 16.2 months for durvalumab and placebo, respectively (stratified HR, 0.53; 95% CI, 0.41-0.68). Regarding safety, 30.5% of the patients on durvalumab and 26.1% of those who received placebo had grade 3/4 all-cause AEs. The discontinuation rate due to AEs occurred in 15.4% and 9.8% of the durvalumab- and placebo-treated patients, respectively.

In the updated data that were presented at the 2019 ASCO Annual Meeting, the last patient had completed the protocol-defined 12 months of study treatment in May 2017. As of the data cutoff date, which was January 31, 2019, 48.75% of patients had died (43.5% and 54.0% in the durvalumab and placebo arms, respectively).

At a median follow-up of 33.3 months (range, 0.2-51.3), the median OS was not reached (95% CI, 38.4 months—not reached) with durvalumab compared with 29.1 months (95% CI, 22.1-35.1) with placebo. The 1-, 2- and 3-year OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively.

After discontinuing therapy, 43.3% and 57.8% in the durvalumab and placebo arms, respectively, received subsequent anticancer therapy, and 9.7% and 26.6% subsequently received immunotherapy.

References

  1. IMFINZI (durvalumab) US Label Updated With Overall Survival Data in Unresectable, Stage III Non-small Cell Lung Cancer. AstraZeneca. Published July 22, 2019. https://bwnews.pr/2y44LQw. Accessed July 22, 2019.
  2. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.
  3. Gray JH, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(suppl; abstr 8526). doi: 10.1200/JCO.2019.37.15_suppl.8526.
  4. 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(20):1919-1929 doi: 10.1056/NEJMoa1709937.