Citations

3502 Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Results: 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm: hazard ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p=0.0052), median OS 6.4 vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p<0.000001), median PFS 1.9 vs 1.7 mos. Comparable OS and PFS benefits were observed in exploratory subgroup analyses by region, age, time from diagnosis of mCRC to randomization, prior lines of treatment, and KRAS status (shown in table). The most common grade 3+ AEs related to REG were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea (7.2%) and rash/desquamation (5.8%). QoL data will be presented. Conclusions: REG demonstrated statistically significant improvement in OS and PFS over PL, as well as comparable efficacy benefits across pt subgroups analyzed. [Table: see text]

6 Background: Rates and survival outcomes for second-line therapy for mCRC for OA vs. YA are poorly understood. Methods: Pts with available subsequent treatment data after progression from 10 1st line trials were included. Associations between key clinical/disease characteristics, time to initial progression (TTiP) and rate of receipt of second-line therapy were evaluated. Time to progression (TTP) and overall survival (OS) were compared between OA and YA who were enrolled on second-line trials by Cox regression, adjusting for age, sex, ECOG PS, number of metastatic sites, presence of metastasis in lung/liver/peritoneum. Results: OA comprised 16.4% of first-line trials. OA and ECOG PS >0 were less likely to receive second-line therapy than YA. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariate analysis (p=0.0117). OA enrolled in second-line trials experience similar mTTP and mOS as YA (5.1 vs. 5.2mos; 11.6 vs 12.4mos, respectively). Conclusions: OA are less likely to receive 2nd line therapy for mCRC. We did not observe a statistical difference in survival outcomes for OA vs. YA following second-line therapy. Further study is needed to examine unmeasured factors, including comorbidity and functional status given observed inferior outcomes among adults with ECOG PS >0, and consideration given to inclusion of geriatric assessment to select OA likely to benefit from 2nd line therapy for mCRC. [Table: see text]

3501 Background: 6m of oxaliplatin-based treatment is an option as adj chemotherapy for patients with high risk stage II CC (T4, inadequate nodal harvest, poorly differentiated, obstruction, perforation or vascular/perineural invasion). The IDEA collaboration showed shorter treatment duration to be appropriate for most pts with stage III colon cancer. The results of the 4 IDEA studies with stage II pts are presented here. Methods: A prospective, pre-planned pooled analysis of high-risk stage II patients from 4 concurrently conducted randomized phase III trials (SCOT, TOSCA, ACHIEVE-2, HORG) was performed to evaluate non-inferiority (NI) of 3m compared with 6m (ref) of adj FOLFOX/CAPOX (regimen preselected, not randomized). The primary endpoint was disease-free survival (DFS), NI was to be declared if the 2-sided 80% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.2. 542 DFS events were required to provide 80% power to declare NI. NI was also examined within regimen, T4 (Yes v No) and inadequate nodal harvest (Yes v No) as pre-planned subgroups. Results: The primary analysis included 3273 randomised pts of which 1254 had FOLFOX and 2019 had CAPOX. There were 552 events and the median follow-up was 60.2 m. There was significantly less grade 3-5 toxicity with 3m treatment (p < .0001). The 5-year DFS rate was 80.7% and 84.0% for 3m and 6m treatment with an estimated DFS HR of 1.18 (80% CI:1.05-1.31, p for NI = 0.404). For CAPOX the estimated HR was 1.02 (80% CI: 0.88-1.17, p for NI = 0.087) and for FOLFOX the estimated HR was 1.42 (80% CI: 1.19-1.70, p for NI = 0.894). The test for interaction between duration and regimen was not statistically significant (p = .174 adjusted for multiple testing) but was stronger than that for the other subgroups examined. Conclusions: In the overall population non-inferiority for 3m adj treatment in pts with high-risk stage II CC was not shown. As with the stage III population the choice of adj regimen appears important (although this did not reach statistical significance) with a small difference in DFS between 3 and 6 m treatment if CAPOX is used. Clinical trial information: ISRCTN59757862.

3554 Background: There is considerable variability in the outcomes between second line (SL) trials in mCRC. The aim of this analysis is to compare the outcomes of patients (pts) with mCRC treated either on SAFL, with protocol defined SL treatment, or DSLT. Methods: Individual pt data was available on pts with mCRC enrolled in 1 of 10 trials (7 DSLT, 3 SAFL) in the ARCAD database. Regimens included FOLFIRI, FOLFOX, and irinotecan (IRI), since pts did not receive biologic agents in SL on SAFL. For pts on a SAFL, PFS and OS were defined as time from initiation of SL treatment to second progression (SP)/death and death, respectively. Descriptive statistics and multivariable Cox models were used to assess differences in PFS and OS. Results: 5,076 pts were included; 63% were male; median age was 62. See Table for treatment details. Pts treated on SAFL had shorter OS (0.7-1.5 months (mos>) shorter) and PFS (0.6-2.6 mos shorter), compared to those treated on DSLT. These findings were statistically significant and differences in OS did not attenuate after adjustment for age, gender, and prior treatment. PFS differences in FOLFOX became insignificant after multivariable adjustment. Conclusions: There are modest differences in both PFS and OS between pts with mCRC treated on SAFL and those on DSLT, suggesting differences in these pt populations. Caution is needed when applying these data to pts, as we were unable to control for potential confounders (ECOG PS, number and sites of metastases) at initiation of SL in SAFL, which may impact outcomes. [Table: see text]

LBA1 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Abstract Background In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. Methods This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. Results In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in &lt;1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6–2.7). Conclusion In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. Implications for Practice Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.