Exploratory analyses assessing the impact of early tumour shrinkage and depth of response on survival outcomes in patients with RAS wild-type metastatic colorectal cancer receiving treatment in three randomised panitumumab trials

Abstract

PurposeTo report exploratory analyses of early tumour shrinkage (ETS) and depth of response (DpR) in patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), receiving the first-line treatment in three randomised panitumumab trials. MethodsData from the PRIME (NCT00364013), PEAK (NCT00819780) and PLANET (NCT00885885) studies were included. Median DpR, the proportion of patients achieving ETS ≥ 20% or ≥ 30% at week 8, and the impact of ETS and DpR (including by category) on outcome were analysed. Factors associated with ETS and DpR and the optimal ETS/DpR cut-off values for predicting improved overall survival (OS) were assessed.ResultsOverall, 505, 170 and 53 patients had RAS WT mCRC in PRIME, PEAK and PLANET, respectively. Patients receiving panitumumab had higher ETS rates (≥ 30%: PRIME 59% vs. 38%; PEAK 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those receiving treatment without panitumumab. In multiple regression analyses, panitumumab treatment, liver-only metastases and WT BRAF status were consistently associated with improved ETS and DpR outcomes. Irrespective of treatment, ETS and DpR were associated with improved progression-free survival, overall survival and resection rates; most resections occurred in patients in the two highest DpR categories. In PRIME and PEAK, respectively, the optimal cut-offs for predicting improved OS were 32 and 34% for ETS, and 59 and 70% for DpR.ConclusionsThese exploratory analyses suggest that panitumumab is associated ETS and DpR benefits in patients with RAS WT mCRC and that achieving these endpoints during first-line treatment is linked with favourable outcomes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00432-017-2534-z) contains supplementary material, which is available to authorized users.

Relationship Between Tumor Response and Tumor-Related Symptoms in RAS Wild-Type Metastatic Colorectal Cancer: Retrospective Analyses From 3 Panitumumab Trials

“…Of note, it has been reported that both ETS and DpR are associated with improved progression-free survival, OS, and resection rates. 14,15 We also found that changes in ECOG PS were related to whether a treatment response was observed by ETS or DpR, in line with the expectation that all symptoms could affect ECOG PS.…”

“…30% rates (PRIME: 59% vs. 38%; PEAK: 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those who received treatment without panitumumab. 14 An association between both ETS and DpR and survival outcomes has also been observed in retrospective and prospective trials of cetuximab. 13,[17][18][19] In the CRYSTAL and OPUS trials, which evaluated cetuximab with and without FOLFIRI and FOLFOX4, respectively, ETS was significantly associated with progression-free survival in both the cetuximab plus chemotherapy and chemotherapy-alone treatment arms.…”

“…All Subjects systemic anti-EGFRetargeted therapy is associated with ETS and DpR, patients both with and without symptoms at baseline may benefit from intensive systemic therapy to facilitate higher cytoreduction, in line with current recommendations from the European Society for Medical Oncology. 2,14 These recommendations highlight the fact that intensive systemic therapy is clinically relevant when conversion to resectable disease is the goal and for those patients who require a rapid reduction in tumor burden due to severe symptoms. 2 Indeed, severe symptoms may be indicative of impending clinical threat and the need for clinically relevant tumor shrinkage.…”

“…11,12 Recent retrospective analyses of clinical trial data in mCRC have included investigation of newer measures of tumor response, including early tumor shrinkage (ETS) and depth of response (DpR). 11,[13][14][15] For example, in the phase 3 PRIME trial, which compared first-line panitumumab plus FOLFOX4 with FOL-FOX4 alone in patients with previously untreated mCRC, patients in both treatment arms who experienced ETS ! 30% by 8 weeks showed longer overall survival (OS) than those who did not (panitumumab plus FOLFOX4 arm: 34.5 vs. 18.2 months; P < .0001; FOLFOX4 alone arm: 30.7 vs. 16.0 months; P < .0001), indicating the prognostic utility of ETS regardless of treatment received.…”

“…16 Both ETS and DpR have been associated with improved progression-free survival, OS, and resection rates, irrespective of treatment received, in a retrospective analysis of 3 first-line panitumumab mCRC studies. 14 In the same study, patients who received panitumumab in PRIME and PEAK (which compared panitumumab plus modified FOLFOX [mFOLFOX6] with bevacizumab plus mFOLFOX6) had higher ETS ! 30% rates (PRIME: 59% vs. 38%; PEAK: 64% vs. 45%) and greater DpR (PRIME: 54% vs. 46%; PEAK: 65% vs. 46%) than those who received treatment without panitumumab.…”