Aranda, Enrique

3520 Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and anti-EGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values <0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p<.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p<.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p<.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p<.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p<0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p<.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

675 Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p < 0.001), have lung metastases (mets) (56% vs. 37%, p < 0.001), and have 2 or more metastatic sites (64% vs. 60%, p < 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p < 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.

658 Background: In patients (pts) with mCRC with an asymptomatic primary tumor, there is limited evidence regarding the indication for primary tumor resection. The primary objective was to evaluate the prognostic value of primary tumor resection in synchronous mCRC pts. Methods: In this IPD analysis, a total of 3,423 pts from 8 first-line randomized trials (RCTs) with systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Five RCTs included targeted (anti-VEGF and/or anti-EGFR) agents. Synchronous mCRC was defined as distant metastases occurring ≤ 6 months of the initial CRC diagnosis. Overall survival (OS) and progression-free survival (PFS) were compared by stratified multivariate Cox models. Results: There were 710 (21%), 1,705 (50%) and 1,008 (29%) pts with non-resected and resected synchronous mCRC and metachronous mCRC, respectively. Compared to the non-resection group, pts in the synchronous resection group were associated with female gender, colon tumor, isolated liver/lung involvement, single metastatic site, and lower LDH (all p<.001). Adjusted for age, gender, performance status and prior chemotherapy, the non-resection group had a significantly worse median OS (16.4m) compared to the resection (22.2m; HR 1.60, 95% CI 1.43-1.78) and metachronous (22.4m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, PFS was significantly worse for the non-resection group (7.9m) compared to the resection (9.7m; HR 1.31, 95% CI 1.19-1.44) and metachronous group (8.9m; HR 1.47, 95% CI 1.30-1.66). Similar trends were observed in pts treated with non-targeted vs targeted agents, and anti-VEGF vs anti-EGFR therapy. In a subset analysis (n= 526), the observed associations remained after additional adjustment for primary tumor location, liver/lung involvement, number of metastatic sites, BMI and LDH. Conclusions: In this largest IPD analysis of mCRC trials to date, primary tumor resection is associated with better OS and PFS in synchronous mCRC pts. These results may be subject to bias since reasons for (non)resection were not available. Prospective RCTs on this topic are ongoing.