Monalizumab plus durvalumab plus platinum-based chemotherapy for first-line treatment of extensive stage small-cell lung cancer: Early efficacy results from MOZART trial.

Abstract

8098 Background: Extensive stage small cell lung cancer (ES-SCLC) is an area of unmet need where novel treatment strategies are urgently needed. Preclinical data in SCLC demonstrate higher expression of NKG2A, an immune checkpoint expressed on natural killer (NK) cells and CD8+ T cells, with consequent reduced NK cell mediated anti-tumor activity, substantially enhanced metastatic dissemination of tumor cells, and amelioration of metastasis with hyperactivation of NK cells. We hypothesized that NKG2A inhibitor monalizumab (M) may enhance the efficacy of first-line therapy in ES-SCLC by promoting both NK and CD8+ T cell functions. Methods: We conducted a single arm, multicenter, investigator-initiated phase II study with a safety lead-in cohort, evaluating M in combination with platinum (P), etoposide (E), and durvalumab (D) in patients (pts) with previously untreated ES-SCLC. One prior cycle of EP ± D was allowed. Pts received EP + D + M every 3 weeks for 4 cycles followed by D + M every 4 weeks until disease progression or unacceptable toxicity. Primary endpoints were 1-year (yr) progression-free survival (PFS) and safety. Secondary endpoints were objective response rate (ORR), 1-year overall survival (OS) and intracranial PFS (iPFS). We hypothesize that the combination will lead to improvement in 1-yr PFS to 33% compared to historical control of 18% (1-sided alpha:10%, power: 80%). Results: 30 pts were enrolled (median age:62.5yrs (range, 53-79)). 10pts (33.3%) were female and 6 (20%) were Black. 14pts (46.7%) received one cycle of EP ± D prior to study entry. ORR was 73.3% (complete response = 3, partial response = 19). At median follow-up of 14.2months (mo) (range, 6.4-not estimable (NE)): estimated 1-yr PFS: 20.6%, 18-mo PFS: 15.5%, median (m) PFS: 4.8mo (4.5-5.3), 1-yr OS: 67.4%, mOS: NE (10.2-NE). Most common site of progression was brain with miPFS of 5.3mo (4.8-10.8); 1-yr iPFS: 21.7%, 18-mo iPFS: 16.3%. 4pts had PFS longer than 1yr, 3 of whom had brain metastasis at baseline. No dose limiting toxicities were identified in the safety lead-in cohort. Treatment related AEs (TRAEs) at least possibly related to D and/or M occurring in ≥10% of pts were fatigue (23%), decreased lymphocyte count (13%), hypothyroidism (10%), decreased neutrophil count (10%), and increased lipase (10%). 5 pts (17%) had grade (G) 3/4 TRAEs: decreased neutrophil count (n = 3), encephalitis (n = 1), acute kidney injury (n = 1). Toxicities solely attributed to M were all G 1: increased lipase (n = 2), headache (n = 1), and increased amylase (n = 1). Conclusions: Addition of M to first-line EP + D led to no new severe AEs in patients with ES-SCLC. Estimated 1-yr PFS was not statistically superior to historical control with EP +D, yet a subset of patients including those with baseline brain metastasis derived durable benefit. Long term follow-up and biomarker analysis are ongoing. Clinical trial information: NCT05903092 .