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

J Randolph Hecht, Al B Benson 3rd, Dmitry Vyushkov, Yingsi Yang, Johanna Bendell, Udit Verma, J Randolph Hecht, Al B Benson 3rd, Dmitry Vyushkov, Yingsi Yang, Johanna Bendell, Udit Verma

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. The Oncologist 2017;22:243-e8.

Trial registration: ClinicalTrials.gov NCT01479465.

© AlphaMed Press; the data published online to support this summary is the property of the authors.

Figures

Figure 1.
Figure 1.
Stratified Kaplan–Meier plot of progression‐free survival by investigator assessment (FAS population). Abbreviations: CI, confidence interval; FAS, full analysis set (all patients randomized and treated with ≥1 dose of study drug); HR, hazard ratio (numbers in brackets are 95% CIs); PFS, progression‐free survival; SIM, simtuzumab.
Figure 2.
Figure 2.
Stratified Kaplan–Meier plot of overall survival (FAS population). Abbreviations: CI, confidence interval; FAS, full analysis set (all patients randomized and treated with ≥1 dose of study drug); HR, hazard ratio (numbers in brackets are 95% CIs); OS, overall survival; SIM, simtuzumab.

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