Phase 2 study of RO4929097, a gamma‐secretase inhibitor, in metastatic melanoma: SWOG 0933

Abstract

Background Aberrant Notch activation confers a proliferative advantage onto many human tumors, including melanoma. This phase II trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, on the progression-free and overall survival of patients with advanced melanoma. Methods Chemotherapy-naïve patients with metastatic melanoma of cutaneous or unknown origin were treated with RO4929097 at a dose of 20 mg orally daily, 3 consecutive days per week. A two-step accrual design was used, with an interim analysis on the first 32 patients, and continuation of enrollment if ≥4/32 patients responded. Results Thirty-six patients from 23 institutions were enrolled; 32 patients were evaluable. RO4929097 was well-tolerated, and most toxicities were grade 1 or 2. The most common toxicities were nausea (53%), fatigue (41%), and anemia (22%). There was 1 confirmed partial response lasting 7 months, and 8 patients with stable disease lasting at least through week 12, with one of these continuing for 31 months. The 6-month PFS was 9% (95% CI: 2–22%), and 1-year OS was 50% (95% CI: 32–66%). Peripheral blood T cell assays showed no significant inhibition of IL-2 production, a surrogate pharmacodynamic marker of Notch inhibition, suggesting that the drug levels were insufficient to achieve Notch target inhibition. Conclusions RO4929097 showed minimal clinical activity against metastatic melanoma in this phase II trial, possibly due to inadequate exposure to therapeutic drug levels. While Notch inhibition remains a compelling target in melanoma, our results do not support further investigation of RO4929097 at this dose and schedule.

Inhibition of γ-secretase activity synergistically enhances tumour necrosis factor-related apoptosis-inducing ligand induced apoptosis in T-cell acute lymphoblastic leukemia cells via upregulation of death receptor 5

“…Initial clinical outcomes of GSI monotherapy with R04929097 fell short of clinical expectations (20,21). Combination studies incorporating GSIs with established anti-cancer treatments, including radiation; Temsirolimus, an inhibitor of mammalian target of rapamycin (20); capecitabine, a fluorouracil pro-drug (22); bicalutamide, an androgen antagonist; letrozole, a nonsteroidal aromatase inhibitor; temozolomide, an alkylating agent; vismodegib, an inhibitor of the hedgehog pathway and ABC transporters; tamoxifen, an antiestrogen; erlotinib hydrochloride, an inhibitor of epidermal growth factor receptor tyrosine kinase; gemcitabine hydrochloride, an antimetabolite (23); vinblastine and docetaxel, microtubule targeting agents; Cisplatin, a DNA targeting agent; and cediranib maleate, a vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (24) (details of not referenced drugs are available from clinicaltrials.gov), have been evaluated or are currently undergoing evaluation for therapeutic efficacy.…”

Notch1 pathway in adrenocortical carcinomas: correlations with clinical outcome

“…This discrepancy with the JAG1 findings may reflect the profound dysregulation of the Notch pathway in ACCs and the role of additional influences downstream of Notch. The demonstration of Notch activation and the overexpression of its target genes in patients with advanced ACCs may become therapeutically relevant, considering the potential use of Notch-inhibiting drugs that act downstream of JAG1, such as g-secretase inhibitors, which are currently under investigation alone and in combination in clinical trials for Notch-dependent solid tumors (Richter et al 2014, Lee et al 2015, LoConte et al 2015, Messersmith et al 2015, or more innovative compounds, such as receptor-blocking monoclonal antibodies (Supplementary Figure S1, see section on supplementary data given at the end of this article) (Hernandez Tejada et al 2014).…”

“…Several clinical trials with these compounds alone or in combination are currently ongoing or have been recently completed (ClinicalTrials. gov) (Richter et al 2014, Lee et al 2015, LoConte et al 2015, Messersmith et al 2015. Moreover, inhibiting Notch signaling (i.e., by pretreatment) has been shown to sensitize tumors to platinum compounds or other cytotoxic drugs, such as gemcitabine (Meng et al 2009, Wang et al 2010, McAuliffe et al 2012.…”

Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

“…When treated with MK-0752 in phase I studies, clinical benefits such as complete response (CR) and prolonged stable disease (SD) were observed (75)(76)(77)(78). However, patients present no objective responses to monotherapy of RO-4929097 in phase II clinical trials of solid tumors (79)(80)(81)(82). Clinical indication of GSIs is still controversial, as a portion of cancer patients experienced SD during RO-4929097 or MK-0752 therapy, 1 advanced thyroid cancer patient achieved CR, and 71.4% (5/7) desmoid tumor patients had a partial response (PR) when they received another GSI, PF-0308414 (83).…”