NOS inhibitor shows potential for TNBC treatment
medwireNews: The pan-nitric oxide signaling (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) in combination with taxane merits further investigation in the locally advanced or metastatic triple-negative breast cancer (TNBC) setting, say researchers.
Writing in Science Translational Medicine, they explain that L-NMMA “decreased tumor cell proliferation, migration, and mammosphere formation in vitro and reduced tumor growth, lung metastases, tumor initiation, and self-renewal in TNBC patient-derived xenograft mouse models.”
The team therefore initiated a phase 1/2 trial that recruited 35 women with chemorefractory, locally advanced or metastatic TNBC; 15 were included in the dose-finding phase 1b part of the trial and 24 (including four from phase 1) in the phase 2 efficacy part. Eighty-seven percent of the phase 1b participants had metastatic disease, as did 54% of those in phase 2. The median number of previous chemotherapy regimens were four and five, respectively.
The dose-finding part – in which patients were given intravenous L-NMMA at a dose of 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, or 20.0 mg/kg on days 1–5 of each 21-day cycle alongside docetaxel 75 or 100 mg/m2 on day 1 – established L-NMMA 20.0 mg/kg plus docetaxel 100 mg/m2 as the recommended phase 2 dose.
Treatment at this dose achieved an overall response rate of 45.8% in the phase 2 population, with rates of 81.8% in locally advanced patients (n=11) and 15.4% in metastatic patients (n=13). The corresponding complete response rates were 16.7%, 36.4%, and 0.0%, and the clinical benefit rates – which additionally included patients with stable disease – were 62.7%, 90.9%, and 38.5%.
The investigators say that the observed overall response and clinical benefit rates in the metastatic patients “are noteworthy” given that this group was heavily pretreated.
With regard to the safety profile of the combination, even though 83.3% of phase 2 patients experienced adverse events (AEs) of any grade, only 20.8% had AEs of grade 3 or worse, notes the team, with infectious AEs the most common AEs of at least grade 3.
Jenny Chang (Houston Methodist Cancer Center, Texas, USA) and co-researchers also highlight that “[t]oxicity was mostly attributed to taxane chemotherapy,” and “[n]one of the grade ≥3 toxicity was attributed to L-NMMA.”
They write in conclusion that “[a] larger phase 3 trial is currently being planned that will follow up on these phase 2 results.”
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