Inhibition of mTOR in addition to EGFR may overcome upstream resistance to EGFR inhibitors in CRC. This phase II study evaluated the efficacy and safety of the combination of irinotecan, panitumumab and everolimus based on dosing established in the previously reported phase Ib study (Townsend JCO 2013 (suppl;abstr 14506)).
Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan (200mg/m2), panitumumab (6mg/kg) every 2 weeks, and everolimus 5mg orally alternate days throughout a 14 day cycle. The primary endpoint was response rate (RR) and secondary endpoints were safety and tolerability, progression free survival (PFS) and overall survival (OS). Survival outcomes were calculated using Kaplan-Meier method and all results analysed as intention to treat.
40 patients were enrolled in the expansion phase. Median age 60 years (37-76), M/F 26/14, ECOG 0/1/2 18/21/1, neutrophil/lymphocyte ratio >3 at baseline in 53%. The median number of cycles of the PIE combination received was 5 (range 0-28 cycles) and mean 8.2 cycles with 4 patients still on treatment. Grade 3 toxicities were diarrhoea 23%, mucositis 18%, rash 13%, fatigue 8%, dehydration 5%, neutropenia 20%, febrile neutropenia 8%, hypomagnesemia 20% and hypokalaemia 8%. Grade 4 toxicities were hypomagnesemia 5% and neutropenia 3%. The median relative dose intensity was 85%. 4 patients ceased everolimus within 30 days due to toxicity. RR was 45%, stable disease 45%, and disease progression 10%. 2 patients underwent subsequent liver resection. The median PFS was 5.6 months and median OS 10.8 months. The 12 month OS was 48% and 18 month OS 33%.
This regimen has major toxicities of diarrhoea, mucositis and rash. The RR of 45% supports further study of this combination. Median OS was relatively short noting poor prognostic markers and analysis of extended RAS/BRAF is ongoing and will be presented.
Clinical trial identification
Legal entity responsible for the study
Central Adelaide Local Health Network
Amgen provided funding Novartis provided everolimus
A. Townsend: Research funding from Amgen. N. Tebbutt: Advisory board for Amgen Research funding from Amgen and Novartis. C. Karapetis: Advisory board member for Amgen. T.J. Price: Amgen Advisory board membership. All other authors have declared no conflicts of interest.