British Journal of Cancer (2007) 96, 177
`& 2007 Cancer Research UK All rights reserved 0007 – 0920/07 $30.00
`
`www.bjcancer.com
`
`Letter to the Editor
`Evaluating the activity of temsirolimus in neuroendocrine cancer
`
`PH O’Donnell1 and MJ Ratain*,1
`1Section of Hematology/Oncology, Department of Medicine, University of Chicago, 5841 S Maryland Ave. MC 2115, Chicago, IL 60637, USA
`
`British Journal of Cancer (2007) 96, 177. doi:10.1038/sj.bjc.6603513 www.bjcancer.com
`Published online 12 December 2006
`& 2007 Cancer Research UK
`
`

`
`Sir,
`Duran et al (10 October 2006) reported the results of a phase II
`trial of temsirolimus in 37 patients with advanced neuroendocrine
`carcinomas (NEC). The authors cite an intent-to-treat response
`rate of 5.6% (two out of 36 patients who received temsiroliums
`achieved a partial response by RECIST criteria), and conclude
`therefore that ‘temsirolimus appears to have little activity and does
`not warrant further single-agent evaluation in advanced NEC’. Yet,
`Duran et al found that tumour control (partial response plus stable
`disease), measured as the percent tumour change from baseline,
`was achieved in 23 out of the 36 patients (63.9%) on temsirolimus.
`When it is considered that all patients in this trial had to have
`documented, progressive disease within 6 months of the study
`entry, the significant percentage of patients experiencing disease
`stabilisation on temsirolimus and the 1-year progression-free rate
`of 40.1% suggest drug activity beyond the natural course of the
`disease. Temsirolimus also compares favourably with other agents
`previously studied in NEC (Oberg, 2002). As a comparison, Faiss
`et al (2003) prospectively studied the use of interferon-alpha and
`the somatostatin analogue lanreotide in treatment-naı¨ve NEC
`patients and found tumour control rates of 32% (lanreotide),
`30% (interferon-alpha), and 25% (combination) at 1 year. Another
`study of 15 patients with metastatic NEC refractory to lanreotide
`examined the use of slow-release octreotide, and a partial response
`
`was seen in 7% of patients, stable disease in 40%, and progressive
`disease in 53% (Ricci et al, 2000). Duran et al also cite other recent
`reports of the use of sunitinib and, separately, gefitinib in NEC and
`acknowledge that the response rate and median time to progres-
`sion with temsirolimus ‘compares favourably with other targeted
`therapies tested in this tumour population’.
`This trial exemplifies the difficulty of interpreting the results of
`single-arm trials using the RECIST criteria (Michaelis and Ratain,
`2006). This is especially true for noncytotoxic agents being studied
`in indolent diseases for which one would expect a high rate of
`stable disease in the absence of treatment. In fact, the response rate
`for temsirolimus in NEC compares favourably to that observed
`with sorafenib in advanced renal cell cancer, where the RECIST
`response rate is less than 5% (Ratain et al, 2006). Furthermore, if
`one compares the figures demonstrating ‘tumour size change from
`baseline’ for sorafenib in renal cell cancer to that of temsirolimus
`in NEC, the response distributions are nearly identical. However,
`the use of a randomised discontinuation design for the phase II
`trial of sorafenib demonstrated convincing evidence of activity
`and its subsequent widespread approval for the treatment of this
`disease. Rather than abandoning further evaluation of temsirolimus
`as a single-agent
`therapy for NEC, one should abandon the
`concept of single-arm studies of novel agents in neuroendocrine
`carcinomas.
`
`REFERENCES
`
`Faiss S, Pape UF, Bohmig M, Dorffel Y, Mansmann U, Golder W,
`Riecken EO, Wiedenmann B,
`International Lanreotide Interferon
`Alfa Study Group (2003) Prospective,
`randomized, multicenter
`trial on the antiproliferative effect of
`lanreotide,
`interferon alfa,
`and their combination for
`therapy of metastatic neuroendocrine
`gastroenteropancreatic
`tumors
`–
`the
`International
`Lanreotide
`J Clin Oncol 21(14): 2689 –
`and Interferon Alfa Study Group.
`2696
`Michaelis LC, Ratain MJ (2006) Measuring response in a post-RECIST
`world: from black and white to shades of grey. Nat Rev Cancer 6(5):
`409 – 414
`
`Oberg K (2002) Carcinoid tumors: molecular genetics, tumor biology, and
`update of diagnosis and treatment. Curr Opin Oncol 14(1): 38 – 45
`Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, Gore M,
`Desai AA, Patnaik A, Xiong HQ, Rowinsky E, Abbruzzese JL, Xia C,
`Simantov R, Schwartz B, O’Dwyer PJ (2006) Phase II placebo-controlled
`randomized discontinuation trial of sorafenib in patients with metastatic
`renal cell carcinoma. J Clin Oncol 24(16): 2505 – 2512
`Ricci S, Antonuzzo A, Galli L, Ferdeghini M, Bodei L, Orlandini C, Conte PF
`(2000) Octreotide acetate long-acting release in patients with metastatic
`neuroendocrine tumors pretreated with lanreotide. Ann Oncol 11:
`1127 – 1130
`
`*Correspondence: Dr MJ Ratain;
`E-mail: mratain@medicine.bsd.uchicago.edu
`Published online 12 December 2006
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`PAR-ZORT-001007
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`NOVARTIS EXHIBIT 2175
`Par v Novartis, IPR 2016-00084
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