Rilotumumab Potential for MET-Expressing Gastric Cancer

Phase Ib/II study results indicate rilotumumab may be effective for treating gastric and oesophagogastric cancer expressing MET

  • Date: 27 Jun 2014
  • Author: Lynda Williams, Senior medwireNews Reporter
  • Topic: Gastric Cancer

medwireNews: Monoclonal antibody therapy against the Hepatocyte growth factor (HGF) and its receptor MET has promise for the treatment of gastric or oesophagogastric junction adenocarcinoma, preliminary research suggests.

Trial results for rilotumumab, in combination with epirubicin, cisplatin and capecitabine (ECX), indicate improved progression-free survival (PFS) compared with ECX alone for patients with unresectable locally advanced or metastatic disease, and enhanced survival for those with tumours expressing MET.

“Our study shows initial data supporting the hypothesis that rilotumumab added to chemotherapy might benefit the almost two-thirds of patients in the study whose cancer expressed MET”, report Timothy Iveson, from University Hospital Southampton in the UK, and team.

“A phase 3 study (RILOMET-1) is testing this hypothesis in patients with MET-positive gastric and oesophagogastric junction cancer,” Iveson and colleagues write in The Lancet Oncology.

The team conducted a phase Ib/II study and report that three dose-limiting toxicities occurred in two of seven patients given at least one dose of rilotumumab 15 mg/kg in phase Ib, including palmar–plantar erythrodysesthesia, cerebral ischaemia, and deep vein thrombosis.

For the phase II section of the trial, 40 patients were randomly assigned to receive rilotumumab 15 mg/kg, 42 patients to receive rilotumumab 7.5 mg/kg and 39 patients to receive placebo. The patients were also given ECX every 3 weeks and followed-up for a median of 21.7 months.

Patients given rilotumumab 15 mg/kg achieved a median PFS of 5.1 months, rising to 6.8 months for those given a 7.5 mg/kg dose, and when the active treatment groups were combined the median PFS was 5.7 months. By comparison, placebo was associated with a median PFS of just 4.2 months, giving significant hazard ratios for PFS events for the 15 mg/kg, 7.5 mg/kg and combined rilotumumab groups of 0.69, 0.53 and 0.60, respectively.

Overall survival (OS) was also longer in the 15 mg/kg, 7.5 mg/kg and combined rilotumumab groups than controls, at a median of 9.7, 11.1, 10.6 and 8.9 months, respectively.

Tumour MET expression was successfully assessed in 91 patients, with 64% of patients having tumours with membranes that stained positively for MET.

MET-positive controls had shorter OS than MET-negative controls (5.7 vs 11.5 months).

Moreover, MET-positive patients given either rilotumumab dose had significantly longer OS than placebo-treated patients (10.6 vs 5.7 months), while OS was comparable in MET-negative patients given rilotumumab and placebo (11.1 vs 11.5 months). A similar pattern was found for PFS, the researchers add.

Adverse events were significantly more common in patients given rilotumumab than placebo, including grade 3 or 4 cases of neutropaenia (44 vs 28%) and venous thromboembolism (20 vs 10%). But anaemia was the only serious adverse event more common in rilotumumab-treated patients than controls (12 vs 0%).

In an accompanying comment, Florian Lordick, from University Clinic Leipzig in Germany, notes that rilotumumab plus ECX is “substantially more toxic” than ECX alone.

exposure of a susceptible population of patients to a demanding drug combination might cause problems, especially if the population to be treated in real life is older and frailer than the relatively young (median 60 years) and fit (42% ECOG performance status 0) study population”, he cautions.

Nevertheless, Florian Lordick writes that the HGF/MET axis is a “very interesting druggable target in gastric cancer” and rilotumumab is a “promising new drug for a disease that is aggressive and difficult to treat”.

He concludes: “The time of molecularly stratified drug development in gastric cancer has started”, adding that “[n]ew technologies might offer new chances for the precision treatment of gastric cancer.”

References

Iveson T, Donehower R, Davidenko I, et al. Rilotumumab in combination with epirubicin, cisplatin, and capecitabine as first-line treatment for gastric or oesophagogastric junction adenocarcinoma: an open-label, dose de-escalation phase 1b study and a double-blind randomised phase 2 study. Lancet Oncol 2014; Early online publication, 23 June. doi:10.1016/S1470-2045(14)70023-3

Lordick F. Targeting the HGF/MET pathway in gastric cancer. Lancet Oncol 2014; Early online publication, 23 June. doi:10.1016/S1470-2045(14)70273-6

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