A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

I Duran, J Kortmansky, D Singh, H Hirte, W Kocha, G Goss, L Le, A Oza, T Nicklee, J Ho, D Birle, G R Pond, D Arboine, J Dancey, S Aviel-Ronen, M-S Tsao, D Hedley, L L Siu, I Duran, J Kortmansky, D Singh, H Hirte, W Kocha, G Goss, L Le, A Oza, T Nicklee, J Ho, D Birle, G R Pond, D Arboine, J Dancey, S Aviel-Ronen, M-S Tsao, D Hedley, L L Siu

Abstract

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

Figures

Figure 1
Figure 1
Maximal percentages of tumour reduction for target lesion(s) by RECIST criteria (Note: some patients with PD progressed owing to new or increasing non-target lesions, or by symptomatic progression).
Figure 2
Figure 2
Time to progression for entire study cohort.
Figure 3
Figure 3
Overall survival for entire study cohort.
Figure 4
Figure 4
Pre- and post-treatment liver biopsies. Tissue sections were first immunofluorescence-labelled for S235/236-S6 ribosomal protein, imaged, and then restained with H&E. The grey scale images of pS6 are unenhanced, at original resolution.
Figure 5
Figure 5
PI3K/AKT/mTOR pathway showing the mTOR protein complexes, mTOR/RAPTOR and mTOR/RICTOR, and the feedback loop involving IGF-IR. Arrows indicate activation; bars indicate inhibition.

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