Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer
Tae Won Kim, Anneli Elme, Joon Oh Park, Anghel Adrian Udrea, Sun Young Kim, Joong Bae Ahn, Ricardo Villalobos Valencia, Srinivasan Krishnan, Nebojsa Manojlovic, Xuesong Guan, Catherine Lofton-Day, A Scott Jung, Eduard Vrdoljak, Tae Won Kim, Anneli Elme, Joon Oh Park, Anghel Adrian Udrea, Sun Young Kim, Joong Bae Ahn, Ricardo Villalobos Valencia, Srinivasan Krishnan, Nebojsa Manojlovic, Xuesong Guan, Catherine Lofton-Day, A Scott Jung, Eduard Vrdoljak
Abstract
Introduction: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS.
Patients and methods: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline.
Results: Overall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS; hazard ratio [HR], 0.72; P = .015) and progression-free survival (PFS; HR, 0.45; P < .0001) were improved with panitumumab with BSC versus BSC. Similar improvements were seen for patients with wild type RAS, and wild type BRAF tumors (OS: HR, 0.75; P = .04; PFS: HR, 0.45; P < .0001). Median DpR was 16.9% for the evaluable panitumumab with BSC wild type RAS population. Overall, 69.5% experienced any type of tumor shrinkage at week 8; 38.2% experienced ≥ 20% shrinkage. Similar improvements in OS and PFS were seen with stratification according to ETS.
Conclusion: This analysis showed that panitumumab improved outcomes in wild type RAS mCRC and indicated that ETS and DpR could be used as additional efficacy markers.
Keywords: Anti-EGFR therapy; Biomarkers; Gastrointestinal cancer; Randomized controlled trial; Treatment outcome.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed