Mitazalimab Combo Shows Lasting Responses in Metastatic Pancreatic Cancer

Data from the phase 2 OPTIMIZE-1 trial demonstrate efficacy with mitazalimab/mFOLFIRINOX in patients with metastatic pancreatic adenocarcinoma.

Investigators found that giving second-generation CD40 agonist antibody mitazalimab in combination with modified fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) met the primary end point of objective response rate (ORR) of 30% or greater in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (PDAC), according to findings from the phase 1b/2 OPTIMIZE-1 trial (NCT04888312) published in The Lancet.

Additionally, the combination therapy exhibited a manageable safety profile and showed encouraging efficacy in treatment of the disease.

Among 57 patients evaluated for activity, the ORR was 40% (one-sided 90% CI ≥ 32) in phase 2 of the study. Additionally, 1 dose-limiting toxicity was observed in patients receiving the recommended phase 2 dose of 900 µg/kg of mitazalimab in phase 1b of the trial.

Investigators of the single-arm, phase 1b/2 OPTIMIZE trial enrolled 70 patients between September 29, 2021, and March 28, 2023, in 14 hospitals in Belgium, France, and Spain. Intravenous mitazalimab was provided via 2-hour, rate-controlled infusions in combination with intravenous mFOLFIRINOX for phase 2 dose determination. Of enrolled patients, 65 received 900 µg/kg of mitazalimab, and 5 received 450 µg/kg of mitazalimab.

Primary end points were to determine the dose-limiting toxicity–assessed recommended phase 2 dose of mitazalimab in phase 1b and ORR in phase 2. Reported secondary end points included best overall response, duration of response (DOR), time to progression, disease control rate, progression-free survival (PFS), and overall survival (OS).

At data cutoff on November 14, 2023, median follow-up was 12.7 months (95% CI, 11.1-15.7). Of 57 patients, 29, 18, and 11 remained on the study, on treatment, or in survival at follow-up, respectively. Additionally, 39 patients discontinued treatment, 32 had disease progression, and 18 received second-line systemic therapies.

Of the full analysis set (n = 57), 1 patient achieved a complete response, and 22 patients achieved partial responses for best overall response. Furthermore, 22 and 12 patients had best overall responses of stable or progressive disease, respectively. The disease control rate was 79% (n = 45).

Median DOR was 12.5 months (95% CI, 7.5-not evaluable [NE]), and median time to progression was 7.7 months (95% CI, 5.8-NE). Median PFS was 7.7 months (95% CI, 5.8-11.3), with 6- and 12-month rates of 62% (95% CI, 48.3%-73.6%) and 34% (95% CI, 20.8%-47.7%), respectively. Additionally, median OS was 14.3 months (95% CI, 10.0-21.6), with 6- and 12- months rates of 90% (95% CI, 81.9%-97.8%) and 59% (95% CI, 44.2%-71.7%), respectively.

Treatment-emergent adverse effects (TEAEs) of grades 1 or 2 were observed at rates of 100% and 97% of the 450 µg/kg mitazalimb and 900 µg/kg mitazalimb arms, respectively. Additionally, grade 3 TEAEs occurred in 60% and 80% in each arm. Grade 4 TEAEs were only observed in the 900 µg/kg mitazalimb arm at a rate of 18%.

Common grade 3 TEAEs occurring in the 900 µg/kg mitazalimb arm at a rate of 15% or greater included blood/lymphatic system disorders (40%)—which mainly consisted of neutropenia (23%)—gastrointestinal disorders (26%), metabolism or nutrition disorders (22%), nervous system disorders (17%), general disorders or administration site reactions (15%), and infections or infestations (15%).

“The long-lasting responses and biomarker associations reported in OPTIMIZE-1 are highly encouraging, implying a potential immunomodulatory contribution of mitazalimab. Data are supportive of the continued development of mitazalimab and mFOLFIRINOX in metastatic [PDAC] in a confirmatory setting. A randomized, controlled international phase 3 study is being prepared to assess the effect of mitazalimab and mFOLFIRINOX on [OS] in patients with metastatic [PDAC] compared with mFOLFIRINOX alone,” lead study author Jean-Luc Van Laethem, MD, professor at the Laboratory of Experimental Gastroenterology at the Université Libre de Bruxelles in Brussels, Belgium, and coauthors concluded.

Reference

Van Laethem JL, Borbath I, Prenen H, et al. Combining CD40 agonist mitazalimab with mFOLFIRINOX in previously untreated metastatic pancreatic ductal adenocarcinoma (OPTIMIZE-1): a single-arm, multicentre, phase 1b/2 study. Lancet Oncol. 2024;25(7):853-864. doi:10.1016/S1470-2045(24)00263-8