Previous studies have reported that primary side of the tumor has a prognostic impact in mCRC, and may also influence efficacy of biological agents. Previous communications comparing biologicals evaluated patients with KRAS WT or RAS WT. It has been proposed that tumor sidedness is a surrogate for the different biological characteristics of the primary tumors. The aim of this analysis is to compare the association between tumor location and anticancer treatment efficacy in mCRC patients with a RAS/BRAF WT primary tumor.
Data from three Amgen-sponsored clinical trials were analyzed for treatment outcomes in relation to location of the primary tumor. All studies were randomized: a first-line phase 3 (PRIME; NCT00364013), a first-line phase 2 (PEAK; NCT00819780) and a second-line phase 3 (181; NCT00339183) study. In order to have a biomarker refined patient population, only RAS/BRAF WT cases were included. Information on tumor location (left/right colon) was obtained from the free-text surgery descriptions and from the original pathology reports. Primary tumors located in the caecum to transverse colon were coded as right-sided and tumors located from the splenic flexure to rectum were coded as left-sided.
Tumor location ascertainment rate was greater than 80%. Between 80% and 85% of cases are left sided. Results for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) for each treatment arm in the 3 studies are summarized in table 1. Patients with right-sided tumors did worse for all parameters compared to left sided. Panitumumab provided better outcomes than the comparator on the left side. On the right side, the small number of patients does not allow drawing definitive conclusions, but a lack of efficacy of panitumumab was not confirmed, contradicting previous reports on the impact of tumor sidedness.
The result of these retrospective analyses on a homogenous RAS/BRAF WT subpopulation confirms that primary CRC arising on the right side is associated with poor prognosis regardless of treatment received. Moreover, panitumumab plus chemotherapy provide a benefit over chemotherapy with or without bevacizumab in left-sided tumors. No final conclusions can be drawn on the optimal treatment in patients with right-sided primary tumors.
(CR/PR = complete/partial response; HR = hazard ratio)
|n patients (R/L)||OS(m)||PFS(m)||CR + PR(%)|
|PRIME (1st line)|
|Pmab-FOLFOX||26/156||22.5 (8.1-30.8)||32.5 (27.5-37.6)||8.9 (5.5-11.3)||12.9 (10.0-14.9)||52.0||70.3|
|FOLFOX||32/148||21.5 (10.8-26.0)||23.6 (18.2-27.7)||7.3 (4.2-11.1)||9.3 (7.7-10.8)||41.2||54.8|
|HR||0.94 (0.53-1.67)||0.67 (0.56-0.859)||0.71 (0.4-1.27)||0.69 (0.54-0.88)|
|PEAK (1st line)|
|Pmab-FOLFOX||13/52||22.5 (8.4-36.9)||43.4 (34.2-63.0)||10.3 (6.1-11.6)||14.6 (11.6-18.1)||69.2||63.5|
|Beva FOLFOX||13/53||23.3 (6.0-29.0)||32.0 (26.9-48.5)||12.6 (1.8-18.4)||11.5 (9.3-13.0)||46.2||58.5|
|HR||0.63 (0.26-1.54)||0.77 (0.46-1.28)||0.88 (0.39-2.02)||0.67 (0.44-1.02)|
|181 (2nd line)|
|Pmab-FOLFIRI||22/143||11.9 (6.4-16.0)||20.1 (16.6-21.7)||6.8 (3.7-10.3)||8.0 (7.3-9.3)||19||50.7|
|FOLFIRI||26/144||10.9 (6.7-13.0)||16.9 (15.1-22.2)||3.7 (2.0-5.9)||6.6 (5.3-7.4)||3.8||13.5|
|HR||0.84 (0.46-1.54)||0.97 (0.76-1.26)||0.62 (0.34-1.13)||0.89 (0.69-1.13)|
Clinical trial identification
Legal entity responsible for the study
A. Toler: Amgen contractor. G. Kafatos: Amgen Ltd employee and company stock owner. K. Lowe: Amgen, Inc employee and stock owner. G. Demonty: employee of Amgen. M. Peeters: Research grant, Advisor and speaker Amgen. All other authors have declared no conflicts of interest.