Characterisation of the lung toxicity of the cell cycle inhibitor temsirolimus

Abstract

The aims of this study were reviewing our experience regarding the pulmonary toxicity of the mammalian target of rapamycin (mTOR) inhibitor temsirolimus, discussing potential pathogenic mechanisms and proposing management strategies. Medical records and radiological reports of 22 patients treated with weekly doses of temsirolimus 25 mg were reviewed. Eight (36%) out of 22 patients developed pulmonary abnormalities compatible with drug-induced pneumonitis. Half were asymptomatic and in those with symptoms, dyspnea and dry cough were the most common. Radiologically two different patterns, ground glass opacities and lung parenchymal consolidation, were described. The management of this toxicity was variable, ranging from no intervention to discontinuation of the drug. In our experience temsirolimus may cause drug-induced pneumonitis at a higher incidence than that previously reported. The presentation and its severity are variable. The risk of developing this toxicity may be increased among subjects with abnormal pre-treatment pulmonary functions or history of lung disease.

Introduction

The mammalian target of rapamycin (mTOR) is a serine–threonine kinase that participates in the regulation of cell growth, proliferation and apoptosis through modulation of cell cycle progression.1, 2 mTOR modulates translation of key mRNAs of proteins required for cell cycle progression from G₁ to S phase, such as 4E-binding protein (4E-BP1) and p70^S6 kinase.³ Rapamycin (sirolimus) and its derivatives are immunosuppressive macrolides that block mTOR and yield potential antiproliferative activity in a variety of malignancies.

Sirolimus, produced by Streptomyces hygroscopicus, binds intracellularly to the immunophilin FKBP-12 (FK 506-binding protein-12) creating a complex that inhibits the protein kinase activity of mTOR. Inhibition of mTOR prevents phosphorylation of p70^S6 kinase, 4E-BP1 and, indirectly, other proteins involved in transcription and cell cycle control, leading to G₁ growth arrest of lymphocytes. In addition to its immunosuppressive properties, sirolimus has been shown to exert potential anticancer effects through different mechanisms. These include interference with the proliferation of endothelial and vascular smooth muscle cells required for tumour angiogenesis, and induction of apoptosis, thereby sensitising cancer cells to DNA-damaging agents such as cisplatin. Furthermore, sirolimus inhibits the oncogenic transformation of human cells induced by either PI3K or PKB/Akt, and causes tumour growth inhibition in xenograft models.4, 5 Sirolimus has been increasingly used either alone or in combination with low doses of calcineurin inhibitors in patients following renal transplantation for prevention of allograft rejection. The main toxicity observed with sirolimus has been dose-dependent and consist primarily of hypercholesterolemia, hypertriglyceridemia and thrombocytopenia. Case series in the literature have reported on the rare occurrences of sirolimus-associated pulmonary toxicity in the form of diffuse interstitial pneumonitis.6, 7, 8, 9 In spite of its antiproliferative activity, the unfavourable pharmaceutical properties of sirolimus, such as poor aqueous solubility and instability, preclude its clinical development as an anticancer agent. Other sirolimus analogs with improved pharmacological profiles have thus been developed.

Clinical trials using three sirolimus derivatives have been performed, these include temsirolimus¹⁰[CCI-779; Wyeth], everolimus¹¹ [RAD001; Novartis] and AP23573¹² [Ariad Pharmaceuticals]. The pharmacological action of these compounds, like sirolimus, is mediated through intracellular binding to FKBP-12 and subsequent inhibition of mTOR.¹³

Temsirolimus (sirolimus 42-ester 2,2-bis hydroxymethyl propionic-acid) is a more water-soluble ester derivative of sirolimus, selected for development as an anticancer agent based on its favourable pharmaceutical characteristics and superior therapeutic index in preclinical studies. At several non-toxic doses temsirolimus demonstrated antitumour activity alone or in combination with cytotoxic agents in a variety of human cancer models such as gliomas, rhabdomyosarcomas, head and neck, prostate, pancreatic and breast cancers.10, 14, 15, 16, 17 Temsirolimus has already been tested in phase I and II trials with promising activity and good safety profile.18, 19, 20 Different doses ranging from 0.75 to 250 mg/m² in either a daily or a weekly schedule have been used and pharmacokinetic (PK) studies have shown that temsirolimus C_max and AUC values increase in a less-than-proportional manner with increasing doses. However no difference in activity has been observed in higher versus lower doses with increased toxicity in the former. In phase I studies of temsirolimus rash and mucositis were dose-limiting, and other adverse events observed include eczematous reactions, dry skin, herpes-type lesions, nail disorders, mild myelosupression, hypercholesterolemia, hypertriglyceridemia, reversible decreases in serum testosterone and rare episodes of euphoria. Pulmonary toxicity has been previously described in the clinical literature of temsirolimus.²⁰

RAD001 or everolimus, is an oral sirolimus derivative compound with similar in vivo activity and a better pharmacokinetic profile than its parent compound. Its antineoplastic activity has been evaluated in different human cancer cell lines and in xenograft models with median inhibitory (IC₅₀) values in the range of 5–1800 nM. The main toxicities reported include hypercholesterolemia, hypertriglyceridemia, mild leukocytopenia and thrombocytopenia.¹ A recently reported phase I trial concluded 10 mg on a daily schedule and 50 mg on a weekly schedule as the recommended phase II doses, with stomatitis, neutropenia and hyperglycaemia being dose limiting.1, 11, 21 Other toxicities included rash, fatigue, headache, anorexia and hypercholesterolemia.

AP23573 is a phosphorus-containing analog of sirolimus. Preclinical and clinical data have shown activity of this compound administered either as a single agent or in combination with cytotoxic or targeted agents.22, 23 Grade 3 mucositis has been dose-limiting in a phase I trial where AP23573 was given intravenously daily for 5 days every 2 weeks. Other side effects were mild to moderate and consistent with those seen with this class of drugs, such as fatigue, nausea, rash, anaemia, neutropenia, diarrhoea, hyperlipidemia and thrombocytopenia.¹²

Sirolimus and its derivatives constitute a family of antineoplastic drugs that possess acceptable toxicity profiles, with skin rashes and mucositis being dose-limiting. Pulmonary toxicity has been described with sirolimus and temsirolimus, but only scant information is published about the latter. Consistent clinical or radiological patterns have not been defined, and no pathogenic mechanisms have been proposed as potential causes of this visceral toxicity with temsirolimus. Furthermore, guidelines on the clinical management of this toxicity are needed. In this report, we present our experience with the pulmonary toxicity encountered in a subgroup of patients receiving weekly doses of temsirolimus on two clinical trials, along with a review of the literature on this topic, and a discussion about potential pathogenic mechanisms and management strategies.