Erasme University Hospital, Brussels, Belgium
Jean-Luc Van Laethem , Ivan Borbath , Karen Paula Geboes , Philippe Alexandre Cassier , Aurélien Lambert , Emmanuel Mitry , Hans Prenen , Lorenzo Pilla , Jean-Frédéric Blanc , Inmaculada Gallego Jiménez , Roberto A. Pazo Cid , Mercedes Rodríguez Garrote , Jaime Feliú , Karin Nordbladh , Karin Enell Smith , David Gomez Jimenez , Peter Ellmark , Yago Pico de Coaña , Sumeet Vijay Ambarkhane , Teresa Macarulla
Background: With a 5 year overall survival (OS) rate <5%, PDAC is a leading cause of cancer related mortality. Currently available systemic therapies are not curative and new therapeutic options are needed. Mitazalimab is a human CD40 agonistic IgG1antibody that reduces immune suppression, sensitizes the tumor to chemotherapy, and induces long lasting anti-tumor T cell responses. OPTIMIZE-1 (NCT04888312) is a Phase 1b/2, open label, multicenter study assessing mitazalimab's safety and efficacy combined with mFOLFIRINOX (mFFX) in chemotherapy naïve mPDAC patients (pts). Methods: In the first 21 day cycle, mitazalimab was administered on day 1 and 10 and mFFX infusion started on day 8. In subsequent cycles, treatment followed a 14 day cycle with mitazalimab given 2 days after mFFX. The primary endpoint is objective response rate (ORR) compared to 30% ORR for FFX (Conroy, 2011) (80% power; α (1-sided) =0.10). Secondary and exploratory endpoints include Duration of Response (DoR), progression free survival (PFS), OS, safety, PK and PD biomarker assessments. Results: Seventy pts with mPDAC were treated with mFFX + mitazalimab (safety set: 5 at 450 µg/kg and 65 at 900 µg/kg). 57 patients at 900 µg/kg received ≥2 treatment cycles and were efficacy evaluable. The most common grade ≥3 AEs were neutropenia (25.7%), anemia (11.4%), hypokalemia (15.7%) and thrombocytopenia (11.4%), consistent with FFX safety profile. Two pts discontinued treatment due to AEs. Confirmed ORs were observed in 23 pts (40.4%), including 1 complete responder (CR). Median OS, PFS and duration of Response (DoR) were 14.3 months (mo), 7.4 mo and 12.5 mo respectively, with a median follow up of 12.7 mo. 29 pts (51%) remain in the study (32% on treatment, 19% in survival follow up). Efficacy results including correlation with detected KRAS G12 mutations are summarized (Table). Conclusions: Mitazalimab in combination with mFFX is a feasible regimen with a manageable safety profile. The primary endpoint was met; KRAS G12 V and R mutations were associated with better efficacy. Given the promising DoR linked with survival benefit in previously untreated mPDAC, these results merit continued development of mitazalimab in a confirmatory phase 3 study. Clinical trial information: NCT04888312.
n(%[95%CI]) | KRASa G12D (n=20) | KRAS G12V (n=21) | KRAS G12R (n=5) | Efficacy Evaluable (n=57) |
---|---|---|---|---|
ORR (confirmed) | 5 (25 [10.4 - 45.6]) | 13 (61.9 [41.7 - 79.4]) | 3*(60 [18.9 – 92.4]) | 23* (40.4 [29.4 - 52.1]) |
Median DoR, mo | NE | 12.5 [7.5-NE] | NE | 12.5 [7.5-NE] |
Median PFS, mo | 5.7 [1.9 - 8.2] | 10.8 [6.2; NE] | 7.8 [5.7; NE] | 7.7 [5.8 - 11.3] |
6 mo PFS, % | 45 [23.1 - 64.7] | 76.2 [51.9 - 89.3] | 80 [20.4 - 96.9] | 62.4 [48.3 - 73.6] |
Median OS, mo | 9.2 [6.4; NE] | 14.4 [11.8; NE] | 15 [6.1; NE] | 14.3 [10 - 21.6] |
12 mo OS, % | 39 [16.9 - 60.8] | 69.3 [43.2 - 85.2] | 60 [12.6 - 88.2] | 59.3 [44.2 - 71.7] |
*1 CR; aKRAS mutations not detected in 11pts; NE=Not Estimable.
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