mTOR inhibitor‐induced interstitial lung disease in cancer patients: Comprehensive review and a practical management algorithm

Abstract

Mammalian target of rapamycin inhibitors (mTORi) have clinically significant activity against various malignancies, such as renal cell carcinoma and breast cancer, but their use can be complicated by several toxicities. Interstitial lung disease (ILD) is an adverse event of particular importance. Mostly, mTORi-induced ILD remains asymptomatic or mildly symptomatic, but it can also lead to severe morbidity and even mortality. Therefore, careful diagnosis and management of ILD is warranted. The reported incidence of mTORi-induced ILD varies widely because of a lack of uniform diagnostic criteria and active surveillance. Because of the nonspecific clinical features, a broad differential diagnosis that includes (opportunistic) infections should be considered in case of suspicion of mTORi-induced ILD. The exact mechanism or interplay of mechanisms leading to the development of ILD remains to be defined. Suggested mechanisms are either a direct toxic effect or immune-mediated mechanisms, considering mTOR inhibitors have several effects on the immune system. The clinical course of ILD varies widely and is difficult to predict. Consequently, the discrimination between when mTOR inhibitors can be continued safely and when discontinuation is indicated is challenging. In this review, we give a comprehensive review of the incidence, clinical presentation and pathophysiology of mTORi-induced ILD in cancer patients. We present newly developed diagnostic criteria for ILD, which include clinical symptoms as well as basic pulmonary function tests and radiological abnormalities. In conjunction with these diagnostic criteria, we provide a detailed and easily applicable clinical management algorithm. Mechanism of action of mTOR inhibitorsThe phosphatidylinositol 3-kinase (PI3K), Akt, mammalian target of rapamycin (mTOR) pathway plays a central role in the control of the growth of cells, tissues and organisms. This pathway physiologically is activated by a variety of upstream signals, such as nutrients, hypoxia, stress and growth factors. Pathologically, several genetic events can lead to constitutional activation of this pathway and in many malignancies it is overactive. mTOR is a key kinase in this pathway, which forms two distinct protein complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). When activated, mTORC1 induces mRNA transcription and the translation of numerous proteins stimulating cell cycle progression and subsequently driving cell growth, division and metabolism and inhibiting apoptosis. In addition, angiogenesis is stimulated by production of hypoxia-inducible factor 1 (HIF-1) and HIF-2 alpha and subsequently vascular endothelial growth factor (VEGF). As a result, the activation of mTORC1 leads to cell division, angiogenesis, cell survival and as such promotes cancer development. 1-3 mTORC2 not only controls the actin cytoskeleton but also phosphorylates and activates Akt, an important regulator of cell survival.Rapamycin (also known as sirolimus) and its analogs (temsirolimus and everolimus) specifically...

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors

“…The rate of severe pneumonitis (grade ≥3) with apitolisib was 8%, which is higher than reported for PI3K and dual mTOR inhibitors (18-21, 37). This is presumably related to mTOR inhibition, correlates with the frequency seen with rapalogs (38), and suggests increased mTOR pathway blockade compared to published dual PI3K/mTOR inhibitors. Given these toxicities and one grade 5 colitis on the 50 mg 28/28 schedule, the RP2D was 40 mg continuous QD oral dosing on a 28/28 schedule.…”

Targeting the Mammalian Target of Rapamycin in Lung Cancer

“…123,124 Additionally, more than 10% of patients taking mTOR inhibitors experience some grade of pulmonary toxicity. 125,126 Some of the pulmonary complications include pneumonitis, interstitial lung disease and opportunistic respiratory infections, but the mechanisms are not completely understood. Rapa-mycin can cause pulmonary fibrosis when used with lung transplantation, which might be related to rapamycin’s ability to induce epithelial-mesenchymal transition in bronchial or pulmonary cells.…”

Use of Everolimus in Liver Transplantation

“…The issue of EVR-related interstitial pneumonia, which was reported in 2% to 5% of patients on EVR in the H2304 and PROTECT trials, 13,14,17,18,30 was not addressed because its incidence is lower than what was reported in other solid organ transplant populations (ie, kidney) or in cancer patients. 62,63 …”