Non-Infectious Pneumonitis (NIP) in Breast Cancer (BC) Patients (Pts) Treated with Everolimus (Afinitor™) Containing Therapy: Analysis of Five Studies.
Authors: Jerusalem G. , Ellard S. , Fasolo A. , Awada A. , Manlius C. , Vittori L. , Massacesi C. , Sahmoud T. , Moldovan C. , Baselga J. 
Published: December 2010

Abstract
Background: Everolimus (E), an oral mTOR inhibitor, has been and is currently being evaluated in combination with antitumor therapies for the treatment of BC. NIP is an infrequent but serious adverse event (AE) observed with mTOR inhibitors; NIP pathogenesis has not been clearly established. This analysis provides a descriptive summary of this AE in the BC trials reported with E to date. Materials and Methods: Overall 269 pts were treated with E-containing therapy in 5 BC studies (Table). In most pts, NIP was diagnosed and monitored by CT imaging and pulmonary function tests (spirometry, DLCO, room air O2 saturation at rest). Management guidelines based on worst grade (G) were implemented since phase 1 protocols and include: G1 no specific therapy required and continue treatment at full dose; G2/G3 short course of corticosteroids and hold and/or reduce E until improvement to ≤G1; G4 discontinuation of the treatment. Results: Few cases of NIP (2.9%) were reported in a phase 2 study of neoadjuvant E combined with letrozole for 4-months, in which chest assessments were not routinely requested (Baselga, J Clin Oncol, 2009). All 3 cases of NIP that were reported as severe AEs were resolved within 15 days of E discontinuation. In metastatic BC pretreated pts, E has been investigated in a NCI-C CTG phase 2 study (Ellard, J Clin Oncol, in press). In this study an overall NIP rate of 41% was reported, and was the reason for therapy discontinuation in 5 pts (10%). Most cases (35%) were G1 or G2, with subtle radiological changes (patchy ground-glass changes over the lung parenchyma) in the absence of clinical symptoms, or with a rapid resolution of symptoms and findings after dose reduction/treatment suspension, or corticosteroid use. In all cases, resolution of NIP occurred. In HER2+ heavily pretreated metastatic BC pts, the combination of E, trastuzumab, and paclitaxel or vinorelbine, has been investigated in 2 phase 1 studies (n=64) (O'Regan, SABCS 2008; Fasolo, SABCS 2008). Per protocols, these patients were regularly assessed with chest CT scans or X-rays every 8-9 weeks and received corticosteroids, anti-histamines, and H-2 antagonists as premedication. NIP at the time of the analysis was observed in 1 case: the pt developed a G3 event after 6 cycles and permanently discontinued treatment. After prednisolone treatment, the pt recovered within 13 days. Conclusion: NIP is an infrequent and manageable event in pts with BC treated with E alone or in combination regimens. Routine radiological screening of the chest can ensure early detection and appropriate management of this AE. Non-infectious pneumonitis n (%)AuthorStudy PhaseBC SettingN*RegimenG1/G2G3Baselga, 2009Ph 2, randomizedEstrogen receptor+neoadjuvant138E 10mg/d + L for 16 wks1 (0.7%)3 (2.2%)Ellard, 2009Ph 2, randomizedMetastatic49E 10mg/d or 70mg/wk17 (35%)3 (6%)Awada, 2008Ph 1bMetastatic18E 5-10mg/d + L00O'Regan, SABCS 2008Ph 1bHER2+ metastatic27E 5-10 mg/d or 30mg/wk + H + P01 (3.7%)Fasolo, SABCS 2008Ph 1bHER2+ metastatic37E 5mg/d or 20-30mg/wk + H + V00H, trastuzumab 2 mg/kg weekly; L, letrozole 2.5mg daily; P, paclitaxel 80 mg/m² Day 1, 8, 15 q4w; V, vinorelbine 25 mg/m² Day 1, 8 q3w. *N = patients treated with E-containing therapy.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1115.