Hurwitz, Herbert I.

PurposeProgression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination.MethodsIndividual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models.ResultsForty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy.ConclusionIn modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents.

ABSTRACTPurposeThis analysis from Avastin® Registries: Investigation of Effectiveness and Safety (ARIES) examined the association between exposure to bevacizumab after disease progression (PD) and postprogression survival (PPS) in bevacizumab‐exposed metastatic colorectal cancer (mCRC) through the application of time‐dependent and time‐fixed analytical methods.MethodsPatients with mCRC who were treated with first‐line bevacizumab and who survived first PD (PD1) were included. A time‐dependent Cox regression model was fitted to assess the effect of cumulative bevacizumab exposure on PPS, while controlling for potential confounders. In addition to support findings from previous studies, a modified intent‐to‐treat (mITT) analysis compared PPS in patients who received bevacizumab beyond disease progression (BBP) with those who did not (No‐BBP).ResultsOf 1550 patients, 1199 survived PD1 and had a median PPS of 13.4 months. Cumulative bevacizumab exposure was associated with improved PPS (p = 0.0040). After adjusting for confounders, the hazard ratios (HRs) for PPS decreased, on average, by 1.2% (range, 1.1–1.3%) with each additional dose of bevacizumab. In the mITT analysis, the median PPS for BBP (n = 438) was 14.4 months vs 10.6 months with for No‐BBP (n = 667). BBP was found to be independently associated with longer PPS in a multivariable Cox regression analysis (HR, 0.84; 95% confidence interval, 0.73–0.97). Protocol‐specified adverse events suspected to be associated with bevacizumab occurred in 13.0% of patients with BBP.ConclusionThis analysis supports the observation that bevacizumab exposure after PD1 is associated with longer PPS in mCRC. Copyright © 2014 John Wiley & Sons, Ltd.

Abstract Background. The Avastin® Registry: Investigation of Effectiveness and Safety (ARIES) study is a prospective, community-based observational cohort study that evaluated the effectiveness and safety of first-line treatment patterns, assessing the impact of chemotherapy choice and treatment duration. Methods. The ARIES study enrolled patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy with bevacizumab and followed them longitudinally. The protocol did not specify treatment regimens or assessments. Analyses included all patients who initiated bevacizumab in combination with either first-line oxaliplatin with infusional 5-fluorouracil and leucovorin (FOLFOX) or irinotecan with infusional 5-fluorouracil and leucovorin (FOLFIRI). Progression-free survival (PFS) and overall survival (OS) times were estimated using Kaplan–Meier methods. Hazard ratios (HRs) were estimated with multivariate Cox regression analysis, adjusting for potential confounding factors. Results. In total, 1,550 patients with first-line mCRC were enrolled (median follow-up, 21 months) and most received FOLFOX–bevacizumab (n = 968) or FOLFIRI–bevacizumab (n = 243) as first-line therapy. The baseline characteristics and median treatment duration were generally similar between subgroups. There were no significant differences in the median PFS (10.3 months vs. 10.2 months) or OS (23.7 months vs. 25.5 months) time between the FOLFOX–bevacizumab and FOLFIRI–bevacizumab subgroups, respectively, by unadjusted analyses. Multivariate analyses showed FOLFIRI–bevacizumab resulted in a similar PFS (HR, 1.03; 95% confidence interval [CI], 0.88–1.21) and OS (HR, 0.95; 95% CI, 0.78–1.16) outcome as with FOLFOX–bevacizumab. The incidence proportions of bevacizumab-associated adverse events were similar for FOLFOX- and FOLFIRI-based therapies. Conclusions. In first-line mCRC patients, the FOLFOX–bevacizumab and FOLFIRI–bevacizumab regimens were associated with similar treatment patterns and clinical outcomes.

Abstract Background and Aims: Cancer and Leukemia Group B 80303 was a randomized, phase III study in patients with advanced pancreatic cancer treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. Experimental Design: DNA from 351 patients was genotyped for more than 550,000 single-nucleotide polymorphisms (SNP). Associations between OS and SNPs were investigated using the log-linear 2-way multiplicative Cox proportional hazards model. The subset of 294 genetically European patients was used for the primary analysis. Results: A nonsynonymous SNP in interleukin (IL)17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (P ≤ 10−7). Median OS was significantly shorter (P = 2.61 × 10−8) for the rs763780 heterozygotes [3.1 months; 95% confidence interval (CI), 2.3–4.3] than for the patients without this variant (6.8 months; 95% CI, 5.8–7.3). After adjustment by stratification factors, the P value for the association was 9.51 × 10−7. Conclusions: The variant 161R form of IL-17F is a natural antagonist of the antiangiogenic effects of wild-type 161H IL-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenetic potential of pancreatic cancers in patients with variant IL-17F is higher than that of tumors in patients with wild-type IL-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer. Clin Cancer Res; 18(2); 577–84. ©2011 AACR.

Purpose In the phase III study AVF2107g, bevacizumab (BV) demonstrated a survival benefit when added to irinotecan, fluorouracil, and leucovorin (IFL) in first-line metastatic colorectal cancer (mCRC). In a parallel phase III study, Intergroup N9741, oxaliplatin plus fluorouracil and leucovorin (FOLFOX) also demonstrated a survival benefit compared with IFL. As these two superior therapies have differing mechanisms of action, we explored whether the improved survival associated with the superior therapy was dependent on tumor response. Patients and Methods For these retrospective, exploratory analyses, patients were defined as responders or nonresponders by whether complete or partial response was achieved with first-line therapy. Results Compared with IFL alone, BV plus IFL and FOLFOX each demonstrated statistically significant improvements in progression-free survival (PFS) and overall survival (OS) regardless of objective tumor response. BV-treated nonresponders had a hazard ratio (HR) of 0.63 (P = .0001) for PFS and 0.76 (P = .0188) for OS compared with IFL-treated nonresponders. FOLFOX-treated nonresponders had an HR of 0.75 (P = .0029) for PFS and 0.74 (P = .0030) for OS compared with IFL-treated nonresponders. Conclusion In both AVF2107g and N9741, objective response did not predict the magnitude of PFS or OS benefit from the superior therapy; nonresponders, despite a poorer prognosis than responders, achieved extended PFS and OS from BV plus IFL or FOLFOX compared with IFL. On the basis of these data, tumor response in metastatic colorectal cancer is not a necessary factor for a therapy to provide benefit to an individual patient.