Phase IB/II Study of Second-Line Therapy with Panitumumab, Irinotecan, and Everolimus (PIE) in KRAS Wild-Type Metastatic Colorectal Cancer

Abstract

Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab, and everolimus. Patients with exon 2 wild-type (WT) mCRC following failure of fluoropyrimidine-based therapy received i.v. irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14-day cycle. The primary endpoint of the phase II study was response rate (RR). Secondary survival outcomes were calculated using the Kaplan-Meier method, and results were analyzed as intention to treat. A preplanned exploratory biomarker analysis was performed. Forty-nine patients were enrolled. Dose level 1 (irinotecan 200 mg/m, panitumumab 6 mg/kg, and everolimus 5 mg alternate day) was declared the MTD with no dose-limiting toxicities in six patients. Forty patients were treated at dose level 1: median age, 60 years (37-76); 65% male; 45% and 52.5%, respectively, with Eastern Cooperative Oncology Group values of 0/1. Median dose intensity was 85%. Grade 3 toxicities were diarrhea (23%), mucositis (18%), rash (13%), fatigue (8%), dehydration (5%), neutropenia (20%), febrile neutropenia (8%), hypomagnesemia (20%), and hypokalemia (8%). Grade 4 toxicities were hypomagnesemia (5%) and neutropenia (3%). RR was 48%, and stable disease was 43%. Median progression-free survival (PFS) was 5.6 months, and median overall survival (OS) was 10.8 months. Twenty-five patients were WT and had an RR of 60%, median PFS of 6.4 months, and OS of 11.8 months. The toxicity of the panitumumab, irinotecan, and everolimus regimen is as expected and manageable. The RR of 60% in all WT supports further study of this combination..

A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor effect through EGFR downstream signaling pathways in colorectal cancer

“…Another phase IB/II clinical study in combination with panitumumab, irinotecan and everolimus, a second-line treatment of KRAS wild-type mCRC, showed that the median PFS was 5.6 months and the median OS was 10.8 months. Its toxicity is expected and controllable (51). The combination of dual inhibitors of mTORC1 and mTORC2 and anti-EGFR therapy has also been investigated in the treatment of CRC.…”

PI3K/Akt/mTOR Signaling Pathway as a Target for Colorectal Cancer Treatment

“…Rapalogs such as everolimus and temsirolimus have been approved for treating breast cancer, neuroendocrine tumors, and renal cell carcinoma [ 27 ]. Several phase I/II trials have also investigated the utility of rapamycin and raplogs in the treatment of mCRC [ 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Currently, no mTOR inhibitors are available for CRC treatment; however, several dual mTORC1/2 kinase inhibitors in pre-clinical studies have shown potential [ 125 , 126 , 127 , 128 ] and could effectively alleviate the feedback activation of Akt in CRC treatment.…”

<p>The impact of panitumumab treatment on survival and quality of life in patients with <em>RAS</em> wild-type metastatic colorectal cancer</p>

“…Several trials are currently investigating HER2 blockade strategies in HER2 -amplified mCRC, opening new perspectives for this subset of patients. Other novel treatment strategies combining EGFR inhibitors with different targeted agents (ie panitumumab plus the mTOR inhibitor everolimus;68 or panitumumab plus BRAF and MEK inhibition in BRAF V600E-mutant tumors69), aiming to overcome primary resistance to anti-EGFR agents, are also under investigation.…”