Results of TRIO-14, a phase II, multicenter, randomized, placebo-controlled trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-ganitumab in newly diagnosed epithelial ovarian cancer

Gottfried E Konecny ,H Chen,Lynda D Roman ,Jalid Sehouli ,Achim Rody ,Sven Mahner ,Beth Y Karlan ,Boris Winterhoff ,Pa Fasching ,Isabelle Ray‐Coquard ,Andrea E Wahner Hendrickson ,Paul Cottu ,Adela Yachnin ,T Davidson ,Paul Haluska ,Gabriele Feisel-Schwickardi ,Diane Provencher ,Ml Poelcher ,Sally A Mullany ,Sisi Ma ,John A Glaspy ,Dennis J Slamon

doi:10.1016/j.ygyno.2021.09.025

Abstract

PurposeInsulin-like growth factor (IGF) signaling is implicated in pathogenesis and chemotherapy resistance of epithelial ovarian cancer (EOC). We explored efficacy and safety of adding ganitumab, a monoclonal antibody targeting IGF-1R, to carboplatin/paclitaxel (CP) chemotherapy in patients with primary EOC. DesignPatients were randomly assigned to receive CP/ganitumab (18 mg/kg q3w) or CP/placebo for 6 cycles followed by 6 cycles of single agent ganitumab/placebo maintenance therapy as front-line therapy. Primary endpoint was progression free survival. Secondary endpoints were time to progression and overall survival. Pretreatment samples were prospectively collected for retrospective biomarker analyses. Results170 patients enrolled. 165 patients assessable for toxicity. Median PFS was 15.7 months with CP/ganitumab and 16.7 months with CP/placebo (HR 1.23; 95% CI 0.82–1.83, P = 0.313). All grade neutropenia (84.1% vs 71.4%), thrombocytopenia (75.3% vs 57.1%) and hyperglycemia (15.9% vs 2.6%) were more common in the ganitumab group compared to the placebo group. Ganitumab/placebo related serious adverse events were reported in 26.1% of the patients with ganitumab and in 6.5% with placebo. Non-progression related fatal events were more common with ganitumab (5 versus 2 patients). The ganitumab group experienced more dose delays which resulted in lower relative dose intensity of chemotherapy in the experimental group. In an exploratory model IGFBP2 expression was predictive of ganitumab response (treatment interaction; PFS, P = 0.03; OS, P = 0.01). ConclusionAddition of ganitumab to CP chemotherapy in primary EOC did not improve PFS. Our results do not support further study of ganitumab in unselected EOC patients.

Highlights

Ovarian cancer (OC) continues to have the highest mortality rate of all gynecological cancers and 4 of 5 patients are diagnosed with advanced disease [1]
The insulin-like growth factor signaling axis is composed of 2 receptors; insulin-like growth factor 1 receptor (IGF-1R) and the insulin receptor (INSR); 3 ligands, IGF-1, IGF-2, and insulin; and 6 binding proteins that are believed to be important regulators of IGF signaling by determining bio-availability of IGF-1 and IGF-2 [5]
We sought to evaluate whether the addition of ganitumab to carboplatin and paclitaxel chemotherapy therapy would prolong progression free survival when compared to chemotherapy alone in patients with newly diagnosed ovarian cancer

Summary

Introduction

Ovarian cancer (OC) continues to have the highest mortality rate of all gynecological cancers and 4 of 5 patients are diagnosed with advanced disease [1]. IGF-1R subsequently signals the Ras/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT pathways [8] This IGF signaling axis is a critical regulator of ovarian follicular growth, proliferation and survival [9]. In patients with EOC, IGF-2 expression is associated with higher tumor grade and advanced disease stage and is considered an independent predictor of poor survival [11] These findings suggest that inhibition of the IGF/IGF-1R signaling pathway may be a promising approach for the treatment of patients with ovarian cancer. Preclinical studies indicate that IGF-2 can modulate resistance of ovarian cancer cells to chemotherapeutic agents such as cisplatin or paclitaxel [14,15] These findings provided the rationale to test ganitumab in combination with carboplatin and paclitaxel in patients with ovarian cancer. We sought to evaluate whether the addition of ganitumab to carboplatin and paclitaxel chemotherapy therapy would prolong progression free survival when compared to chemotherapy alone in patients with newly diagnosed ovarian cancer

Methods

Results

Conclusion