FDA Grants Priority Review to Durvalumab for Locally Advanced Unresectable NSCLC

The FDA has granted a priority review to a supplemental biologics license application (sBLA) for durvalumab (Imfinzi) for the treatment of patients with stage III, unresectable non—small cell lung cancer (NSCLC), based on positive progression-free survival (PFS) results from the PACIFIC trial.

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

The sBLA filed by AstraZeneca and MedImmune, the developers of durvalumab, is seeking approval for treatment of patients whose disease has not progressed following platinum-based chemoradiation therapy.

Patients in the double-blind phase III PACIFIC trial took place at 235 centers in 26 countries, and were randomly assigned to durvalumab (n = 473) or placebo (n = 236). PFS was the primary endpoint, along with overall survival (OS).¹ OS data are still immature and were not included in this analysis.

Median PFS from randomization showed an 11.2-month benefit associated with the experimental arm (16.8 months vs 5.6 months; 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 a PFS benefit associated with durvalumab was consistently across all pre-specified 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 ≥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.

Just 16.5% of patients in the durvalumab group 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, 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.

In August 2017, the FDA stopped 1 durvalumab trial and put partial holds on 5 others due to safety concerns that arose in studies evaluating the PD-1 inhibitor pembrolizumab (Keytruda) in combination with immunomodulatory agents for the treatment of patients with multiple myeloma.2

The agency placed a full hold on MEDI4736-MM-002, a phase Ib multicenter, open-label study aiming to establish an appropriate dose and regimen for the combination of durvalumab and lenalidomide (Revlimid) with and without low-dose dexamethasone in patients with newly diagnosed multiple myeloma. No new patients will be enrolled and patients in that trial will discontinue treatment.

Three studies exploring durvalumab in multiple myeloma—MEDI4736-MM-001, MEDI4736-MM-003, and MEDI4736-MM-005—were placed on partial hold. MEDI4736-NHL-001, exploring the drug as a monotherapy in patients with lymphoma or chronic lymphocytic leukemia, and MEDI4736-DLBCL-001, assessing durvalumab in combination with R-CHOP or R2 CHOP, where also given a partial hold. Patients deriving clinical benefit from treatment, as determined by the investigator, can remain on treatment in these 5 studies, but enrollment has stopped for the time being.

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. doi: 10.1056/NEJMoa1709937.
2. FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA® (pembrolizumab) in Patients with Multiple Myeloma. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed August 31, 2017.