Niraparib is a highly selective PARP-1/2 inhibitor approved by FDA for the maintenance therapy of ovarian cancer. It also showed promising activity as maintenance treatment in platinum sensitive SCLC PDX models. ZL-2306-005 is a randomized, double-blind, multicenter phase Ⅲ study to evaluate the efficacy and safety of niraparib (nira) versus placebo (pla) as first line (1L) maintenance therapy in extensive-stage SCLC (ES-SCLC) patients.
Patients (pts) with ES-SCLC, ECOG PS 0 or 1, CR/PR after 4 cycles of 1L etoposide/cisplatin or etoposide/carboplatin were enrolled. Prophylactic cranial irradiation (PCI) was optional. Pts were randomized 2:1 to receive nira or pla once daily as maintenance therapy until progression or unacceptable toxicity. Nira started with 300mg QD for pts with baseline body weight ≥77 kg and platelet count ≥150,000/μL, otherwise 200 mg QD. Stratified factors were gender, LDH level and PCI history. The primary endpoints were PFS by blinded independent central review (BICR) and OS; the secondary endpoints were PFS by investigator, CFI, QoL, safety and tolerability.
From Jul 2017 to Feb 2020, 272 pts were screened in 34 sites, of whom 185 were randomized and dosed according to protocol, 125 in nira arm and 60 in pla arm. The study was early terminated due to landscape changed by immunotherapy in ES-SCLC. At the data cutoff: 20 Mar 2020, there were 167 pts discontinued from the treatment and 70 pts died. Median PFS (BICR) was 1.54 m (1.41, 2.69) in nira arm and 1.36 m (1.31, 1.48) in pla arm (HR 0.66; 95% CI [0.46, 0.95]; p= 0.0242). Median OS was 9.92 m (9.33, 13.54) in nira arm and 11.43 m (9.53, NE) in pla arm (HR 1.03; 95% CI [0.42, 1.73]; p = 0.9052). Grade≥3 treatment-related AEs (TEAEs) was 34.4% in nira arm vs. 25% in pla arm. No patient had a TEAE leading to death.
Niraparib has modest improvement in PFS compared to placebo in 1L ES-SCLC maintenance with manageable and tolerated safety profile. OS benefit was not observed based on immature data. The value of adding niraparib to immunotherapy needs further investigation.
Clinical trial identification
Legal entity responsible for the study
Zai Lab. Shanghai Science and Technology Commission (18DZ1910700).
B. Zhang, D. Zhang: Full/Part-time employment: Zai Lab. All other authors have declared no conflicts of interest.