Durvalumab Granted FDA's Priority Review for Locally Advanced Unresectable NSCLC

lung cancer

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

Filed by AstraZeneca and MedImmune, the developers of durvalumab, the sBLA 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).¹OS 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 &ge;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&mdash;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&reg; (pembrolizumab) in Patients with Multiple Myeloma. https://www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed August 31, 2017.