A Multicenter Phase II Study of AMG 337 in Patients with MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other MET-Amplified Solid Tumors.

PURPOSE: MET gene amplification is associated with poor prognosis in gastric/gastroesophageal junction/esophageal (G/GEJ/E) cancers. We determined antitumor activity, safety, and pharmacokinetics of the small-molecule MET inhibitor AMG 337 in MET-amplified G/GEJ/E adenocarcinoma or other solid tumors.Patients and Methods: In this phase II, single-arm study, adults with MET-amplified G/GEJ/E adenocarcinoma (cohort 1) or other MET-amplified solid tumors (cohort 2) received AMG 337 300 mg/day orally in 28-day cycles. The primary endpoint was objective response rate (ORR; cohort 1). Secondary endpoints included ORR (cohort 2), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 2101 patients screened for MET amplification, 132 were MET-amplified and 60 were enrolled: 45 in cohort 1, and 15 in cohort 2. Fifty-six patients (97%) had metastatic disease; 57 had prior lines of therapy (1 prior line, 29%; ≥2 prior lines, 69%). A protocol-permitted review showed efficacy that was lower-than-expected based on preliminary data from a first-in-human study, and enrollment was stopped. Fifty-eight patients received ≥1 AMG 337 dose. ORR in cohort 1 was 18% (8 partial responses). No responses were observed in cohort 2. Of 54 evaluable patients, median (95% CI) PFS and OS were 3.4 (2.2-5.0) and 7.9 (4.8-10.9) months, respectively. The most frequent adverse events (AEs) were headache (60%), nausea (38%), vomiting (38%), and abdominal pain, decreased appetite, and peripheral edema (33% each); 71% had grade ≥3 AEs and 59% had serious AEs. CONCLUSIONS: AMG 337 showed antitumor activity in MET-amplified G/GEJ/E adenocarcinoma but not in MET-amplified non-small-cell lung cancer.See related commentary by Ma, p. 2375.

The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines.

Cancer stem cells (CSC) are rare drug-resistant cancer cell subsets proposed to be responsible for the maintenance and recurrence of cancer and metastasis. Telomerase is constitutively active in both bulk tumor cell and CSC populations but has only limited expression in normal tissues. Thus, inhibition of telomerase has been shown to be a viable approach in controlling cancer growth in nonclinical studies and is currently in phase II clinical trials. In this study, we investigated the effects of imetelstat (GRN163L), a potent telomerase inhibitor, on both the bulk cancer cells and putative CSCs. When breast and pancreatic cancer cell lines were treated with imetelstat in vitro, telomerase activity in the bulk tumor cells and CSC subpopulations were inhibited. Additionally, imetelstat treatment reduced the CSC fractions present in the breast and pancreatic cell lines. In vitro treatment with imetelstat, but not control oligonucleotides, also reduced the proliferation and self-renewal potential of MCF7 mammospheres and resulted in cell death after <4 weeks of treatment. In vitro treatment of PANC1 cells showed reduced tumor engraftment in nude mice, concomitant with a reduction in the CSC levels. Differences between telomerase activity expression levels or telomere length of CSCs and bulk tumor cells in these cell lines did not correlate with the increased sensitivity of CSCs to imetelstat, suggesting a mechanism of action independent of telomere shortening for the effects of imetelstat on the CSC subpopulations. Our results suggest that imetelstat-mediated depletion of CSCs may offer an alternative mechanism by which telomerase inhibition may be exploited for cancer therapy.