A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma

Abstract

Lessons Learned. The safety profile in the patient groups who received FOLFIRI and simtuzumab did not differ from that in the FOLFIRI and placebo group.The addition of simtuzumab to chemotherapy with FOLFIRI does not improve clinical outcomes in patients with metastatic KRAS mutant colorectal carcinoma.Background.Simtuzumab, a humanized IgG4 monoclonal antibody to lysyl oxidase‐like 2 (LOXL2), blocks desmoplastic reaction in colorectal carcinoma (CRC) cells in vitro.Methods.Patients with metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant CRC were randomized to receive second‐line 5‐fluorouracil, leucovorin, and irinotecan (FOLFIRI) with either 200 or 700 mg simtuzumab or placebo every 2 weeks in cycles of 28 days. Progression‐free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were assessed.Results.In total, 249 patients were randomized and treated with FOLFIRI/simtuzumab 700 mg (n = 84), FOLFIRI/simtuzumab 200 mg (n = 85), and FOLFIRI/placebo (n = 80). After a median follow‐up of 5.1, 3.8, and 5.5 months, respectively, median PFS for each of the respective treatment groups was 5.5 months (adjusted HR [95% CI], p value versus placebo; 1.32 [0.92, 1.89]; p = .10), 5.4 months (1.45 [1.01, 2.06]; p = .04), and 5.8 months. Median OS was 11.4 months (1.23 [0.80, 1.91]; p = .25), 10.5 months (1.50 [0.98, 2.30]; p = .06), and 16.3 months, respectively. ORR was 11.9%, 5.9%, and 10%, respectively. Simtuzumab was tolerable in metastatic KRAS mutant CRC patients.Conclusion.The addition of simtuzumab to FOLFIRI did not improve clinical outcomes in patients with metastatic KRAS mutant CRC.

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

“…Simtuzumab exhibited a good safety profile compared to the placebo group . However, despite greater supporting evidence in prior cellular studies in both the phase I & IIa clinical trials, Simtuzumab failed to show improved clinical outcomes when compared with the control arm .…”

“…Simtuzumab exhibited a good safety profile compared to the placebo group . However, despite greater supporting evidence in prior cellular studies in both the phase I & IIa clinical trials, Simtuzumab failed to show improved clinical outcomes when compared with the control arm . Cellular and human tissue studies conducted by Park showed a strong association between LOXL2 and metastatic potential, therefore it was surprising that the clinical trial showed no effect in this patient group.…”

“…KRAS mutations are prevalent in 30–40% of colorectal cancer cases and is associated with poorer survival rates than wild‐type KRAS . The trial (Table , Entry 2) was conducted in a similar manner as the phase II clinical trials with metastatic PaCa patients; a double‐blind randomized control trial with three arms . In this trial, 249 patients were enrolled, and all received FOLFIRI (Folinic acid, Fluorouracil, and Irinotecan) with either placebo, 200 or 700 mg of simtuzumab in a 1:1:1 ratio on days 1 and 15 of each 28‐day cycle …”

Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy

“…Latest clinical data might underline the necessity to conduct further studies. Recently, phase II trials combining treatment with a LOXL2-directed antibody (simtuzumab) with chemotherapygemcitabine in PDAC and FOLFIRI regiment in CRC-ended with unsatisfactory results Hecht et al, 2017). Drug scheduling in these trials were not designed to synergistically profit from improved drug delivery after ECM modification, but on the assumption of an additive effect of the cytotoxic drugs with the antitumoral effect that has been demonstrated preclinically for LOXL2 blockade by itself (Barry-Hamilton et al, 2010;Rodriguez et al, 2010).…”

Charting the unexplored extracellular matrix in cancer

“…), or in a phase II trial in metastatic KRAS mutant colorectal adenocarcinoma (Hecht et al . ). However, it should be pointed out here that in these trials, the late‐stage terminal nature of disease in these patients was unlikely to yield significant results, and as such, earlier treatment will likely lead to more promising results in line with preclinical studies using lysyl oxidase inhibitors in breast (Erler et al .…”