A randomized phase II trial of nab‐paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer

Abstract

Purpose Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. Patients and Methods Aphase 2, randomized, placebo‐controlled, multicenter trial evaluated the activity of tarextumab in combination with nab‐paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19‐9 level and randomized 1:1 to nab‐paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti‐tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression‐free survival (PFS), 12‐month OS, overall response rate (ORR), and safety and biomarker investigation. Results Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab‐treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. Conclusions The addition of tarextumab to nab‐paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first‐line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab‐treated patients. Clinical trial registry no NCT01647828.

Pharmacological disruption of the Notch transcription factor complex

“…The activity of RIN1 has yet to be assessed, in regard to therapeutic efficacy and intestinal toxicity (31), and comparative evaluation with CB-103 warrants future consideration. One of the major dose-limiting toxicities and hurdles to the therapeutic application of the pan-Notch inhibitor has been intestinal toxicity (22,23). Genetic studies in mice show that Notch acts as a stem and progenitor cell gate keeper and is important for secretory versus absorptive cell fate differentiation.…”

“…However, GSIs also block the processing of more than 90 other substrates, which may complicate the interpretation of results produced by GSIs (16). Although both MAbs and GSIs have shown beneficial effects in preclinical Notch-driven tumor models and clinical studies (12,(17)(18)(19)(20)(21), none of these Notch inhibitors have been clinically approved, largely due to on-target dose-limiting toxicities of the intestinal epithelium (22,23). Treatment of patients with GSIs is frequently associated with diarrhea, vomiting, and nausea, which may be severe (24,25).…”

Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives

“…In the Phase Ib ALPINE trial, which enrolled 35 patients, tarextumab was generally well-tolerated in patients and demonstrated an encouraging correlation between antitumour activity and Notch 3 activity [ 197 ]. The Phase II portion of this trial, which recruited 177 patients, failed to reach the study endpoint of OS or the secondary endpoints of PFS, ORR and Notch biomarker activity; in fact, tarextumab treated patients had significantly worse outcomes than those on the placebo treatment arm [ 198 ]. Encouraging reports of the Phase Ib PINNACLE trial indicated a dose-efficacy association with a survival benefit in a subgroup of patients (15 of 27 patients enroled) treated with a higher dose of tarextumab, in addition to a manageable safety profile [ 199 ].…”

Targeting Oncoimmune Drivers of Cancer Metastasis

“…Ipafricept is a recombinant fusion protein with the extracellular domain of FZD8 and has been evaluated in combination with chemotherapy in a phase I study for advanced solid tumors [ 140 ]. Tarextumab (OMP-59R5) is an anti-NOTCH2/3 mAb and has been evaluated in phase I/II studies for solid tumors, including pancreatic cancer [ 141 , 142 ] γ-secretase is essential for NOTCH activation, and thus many inhibitors, including MK0752 [ 143 ], BMS-906024 [ 144 ], LY3039478 [ 145 ], RO4929097 [ 146 ], and LY900009 [ 147 ], have been evaluated in combination with/without chemotherapy in phase I studies for advanced or metastatic cancer.…”