Phase 3 Study of Durvalumab Combined with Oleclumab or Monalizumab in Patients with Unresectable Stage III NSCLC (PACIFIC-9)

Introduction Based on the findings of the PACIFIC trial, durvalumab as consolidation therapy is the standard-of-care for patients with unresectable Stage III NSCLC and no disease progression following chemoradiotherapy (CRT; the PACIFIC regimen). However, further improvements in outcomes are needed for this population and, to build upon the backbone of PD-L1 inhibition with durvalumab, immunotherapy combinations including anti-TIGIT, anti-CD73, and anti-NKG2a mAbs are now being explored. Two potential candidates, oleclumab and monalizumab, have demonstrated encouraging clinical activity in a phase 2 study when combined with durvalumab in this setting. Oleclumab (MEDI9447) is a human IgG1-lambda mAb that inhibits the function of CD73, to reduce extracellular adenosine production and thus promote antitumour immunity. Monalizumab (IPH2201) is a first-in-class, humanised, IgG4 mAb that prevents NKG2A from binding to HLA-E, which reduces inhibition of NK and CD8+T cells. The combination of each of these molecules with durvalumab consolidation therapy was evaluated in the phase 2 COAST study (NCT03822351). In COAST (n=189), patients receiving combination therapy reported numerically higher ORR (durvalumab+oleclumab: 30.0%; durvalumab+monalizumab: 35.5%; durvalumab monotherapy: 17.9%) and prolonged PFS vs durvalumab alone, with no new/significant safety signals. Thus, the combination of oleclumab or monalizumab with consolidative durvalumab warrants further evaluation in a phase 3 trial.

Methods PACIFIC-9 (NCT05221840) is a phase 3, double-blind, placebo-controlled, randomised, international study. Eligible patients (age≥18 years) must have EGFR/ALK wild-type unresectable Stage III NSCLC, ECOG-PS 0/1, documented PD-L1 status, and must not have progressed following≥2 cycles of definitive, platinum-based concurrent CRT. Patients (N≈999) will be randomised (1:1:1) to receive up to 12 months of treatment (in 28-day cycles) with durvalumab plus either oleclumab (Arm A); monalizumab (Arm B); or placebo (Arm C). The primary endpoint is PFS (RECIST v1.1) by BICR. OS is a key secondary endpoint. Other secondary endpoints include ORR and DOR (RECIST v1.1; BICR), PROs, PD-L1 expression on tumor cells relative to efficacy outcomes, and safety/tolerability. Enrolment in PACIFIC-9 is ongoing.

Publikationsverlauf

Artikel online veröffentlicht:
09. März 2023