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

Abstract

Background: Aberrant Notch activation confers a proliferative advantage to many human tumors, including melanoma. This phase 2 trial assessed the antitumor activity of RO4929097, a gamma-secretase inhibitor of Notch signaling, with respect to the progression-free and overall survival of patients with advanced melanoma.

Methods: Chemotherapy-naive patients with metastatic melanoma of cutaneous or unknown origin were treated orally with RO4929097 at a dose of 20 mg daily 3 consecutive days per week. A 2-step accrual design was used with an interim analysis of the first 32 patients and with continuation of enrollment if 4 or more of the 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 there were 8 patients with stable disease lasting at least through week 12, with 1 of these continuing for 31 months. The 6-month progression-free survival rate was 9% (95% confidence interval [CI], 2%-22%), and the 1-year overall survival rate was 50% (95% CI, 32%-66%). Peripheral blood T-cell assays showed no significant inhibition of the production of interleukin-2, a surrogate pharmacodynamic marker of Notch inhibition, and this suggested that the drug levels were insufficient to achieve Notch target inhibition.

Conclusions: RO4929097 showed minimal clinical activity against metastatic melanoma in this phase 2 trial, possibly because of inadequate exposure to therapeutic drug levels. Although Notch inhibition remains a compelling target in melanoma, the results do not support further investigation of RO4929097 with this dose and schedule.

Trial registration: ClinicalTrials.gov NCT01120275.

Keywords: Notch; RO4929097; gamma-secretase inhibitor; metastatic melanoma.

Figure 1

Progression Free Survival

Figure 2

Overall Survival

Figure 3. T cell functional studies

SEA-stimulated IL-2 production by peripheral blood lymphocytes (panel A), compared to control inhibition using a non-clinical gamma secretase inhibitor (panel B).

Figure 4

Pretreatment and on treatment tumor tissue from one patient showed a lack of inhibition of Notch target genes Hey1 and Hes1 by real-time RT-PCR.

Figure 5

Notch1 expression was seen by IHC in all 12 of available patient tumor samples (7 had moderate expression and 5 had strong expression). Two representative samples are shown here.

Figure 6

Notch1 activation was demonstrated by increased expression of Hes1 (Panel A) and Hey1 mRNA (Panel B) at baseline.