Phase Ib study of gevokizumab (GEVO) in combination with standard-of-care (SoC) anticancer therapies in patients (pts) with metastatic colorectal cancer (mCRC), metastatic gastroesophageal cancer (mGEC), and metastatic renal cell cancer (mRCC).

135 Background: GEVO, a humanized monoclonal antibody, binds to interleukin-1β (IL-1β) and inhibits its activity. We report results from a phase Ib study of GEVO + SoC anticancer therapies in pts with mCRC/mGEC/mRCC. Methods: This open-label study enrolled pts aged ≥18 years in cohorts A (first line mCRC, [A]), B (second line [2L] mCRC, [B]), C (2L mGEC, [C]) and D (2L/third line mRCC, [D]). The primary objectives were to determine the pharmacodynamically-active dose (PAD) of GEVO monotherapy in A/B, the safety and tolerability, and the recommended dose for expansion (RDE) of GEVO + SoC in A/B/C/D, and the efficacy of GEVO + SoC at RDE in A/B/C measured by the progression-free survival (PFS) rate. The proof of concept (PoC) criteria for PFS rates were ≥42% at 15 months (m) (lower 80% CI limit ≥29%) in A, ≥48% at ~9 m (lower 80% CI limit ≥37%) in B, ≥51% at 6 m (lower 60% CI limit ≥38%) in C. The relationship between baseline levels of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and IL-1β, and on-treatment decrease of circulating tumor DNA (ctDNA) levels with clinical response was explored. Results: As of March 1, 2023, 71 (A), 62 (B), 26 (C) and 7 pts (D) were treated. The PAD was established as 120 mg GEVO intravenous (IV) every 4 weeks (Q4W) and the RDE as 120 mg GEVO IV Q4W + SoC. There were 2 dose-limiting toxicities: grade 4 decreased neutrophil count (1 pt in C) and grade 3 hyponatremia (1 pt in D). The most frequent grade ≥3 treatment-related adverse events (≥15% of all pts) were neutropenia (A/B: 21.1%/22.6%), decreased neutrophil count (A/B/C: 18.3%/17.7%/15.4%) and hyponatremia (D: 28.6%). The PFS rates were 29.0% (80% CI: 20.4, 38.2), 39.4% (80% CI: 29.8, 48.9), 20.0% (60% CI: 13.3, 27.6) in A/B/C, respectively. In B, median PFS and overall survival (OS) were significantly longer in pts with baseline hs-CRP <10 mg/L (low [L]) than ≥10 mg/L (high [H]), IL-6 <9.58 pg/mL (L) than ≥9.58 pg/mL (H), and IL-1β <0.12 pg/mL (L) than ≥0.12 pg/mL (H). In A + B, a median on-treatment decrease of ctDNA fraction by >72% (H) was associated with significantly longer OS. Conclusions: The safety and tolerability of GEVO combinations was acceptable. The primary PFS rates did not meet the PoC criteria. Baseline levels of hs-CRP, IL-6 and IL-1β in pts with 2L mCRC, and on-treatment reduction of ctDNA in pts with 1L + 2L mCRC may have prognostic value. Clinical trial information: NCT03798626 . Variables PFS HR (95% CI) p-value OS HR (95% CI) p-value Ahs-CRP L / HIL-6 L / HIL-1β L / H 1.74 (0.81, 3.73)1.38 (0.70, 2.72)1.50 (0.74, 3.01) 0.1550.3520.259 1.99 (0.66, 5.98)1.73 (0.71, 4.20)0.98 (0.38, 2.52) 0.2210.2250.973 Bhs-CRP L / HIL-6 L / HIL-1β L / H 2.56 (1.27, 5.18)2.92 (1.33, 6.40)2.41 (1.13, 5.13) 0.0090.0070.022 3.04 (1.40, 6.60)3.25 (1.43, 7.36)3.60 (1.54, 8.44) 0.0050.0050.003 A + BctDNA decrease L / H 0.65 (0.39, 1.10) 0.108 0.45 (0.24, 0.83) 0.011

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