Citations

479 Background: Recent long-term clinical trial follow-up suggests that adding Ox to a fluoropyrimidine (FP) may provide less benefit in adjuvant CC than originally believed (Tournigand JCO 2012). In addition, emerging data on tissue biomarkers such as microsatellite mismatch repair (MMR) and the 12-gene Recurrence Score (RS) suggest these assays may be helpful in better defining treatment benefit, and a new report provides evidence that RS may specifically predict the value of Ox. (O’Connell ASCO 2012) In view of these developments we sought to document current use of adjuvant chemotherapy and physician perceptions about these decisions. Methods: US-based oncologists were recruited to complete a survey and contribute treatment data for their last 3 patients (pts) with stage II disease and last pt with a stage III tumor. Results: 25 gastrointestinal cancer clinical investigators and 77 practicing oncologists participated, providing data from a total of 408 cases (92% treated since 2011). Findings from the 2 groups are similar and are presented in aggregate. A median of 9 and 15 pts annually were evaluated with stage II and III tumors, respectively. Clinicians stated that they require a median of a 5% absolute reduction in relapse rate to use a FP alone and an additional 5% reduction to add Ox. Ox/FP was administered to 95 of 102 pts with stage III tumors (93%) and 85 of 306 pts with stage II disease (28%), particularly to those under age 70 or with T4 tumors (Table). MMR was evaluated in 127 pts (42%) with stage II and 20 pts (20%) with stage III disease. RS was obtained for 46 pts (15%) with stage II tumors, but only 2 pts (2%) with stage III. Conclusions: Adjuvant Ox is employed extensively in spite of the fact that it may provide less benefit than many oncologists report requiring to initiate its use. However, several recent research developments may be laying the groundwork for a change in this treatment practice. [Table: see text]

467 Background: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Methods: Regorafenib (REG) is an oral multikinase inhibitor that has recently demonstrated significant overall survival benefit vs placebo in the randomized phase III CORRECT study. We examined the time course of adverse events (AEs) in the CORRECT study. Results: The safety population comprised 753 patients (pts): REG n=500; placebo n=253. The mean treatment duration was 12.1 ± 9.7 weeks in the REG group and 7.8 ± 5.2 weeks in the placebo group. Treatment-emergent AEs occurred at any grade in 99.6% of REG pts and 96.8% of placebo pts, at grade 1/2 in 21.6% and 47.8%, respectively, at grade 3 in 56.0% and 26.5%, respectively, and at grade 4/5 in 22.0% and 22.5%, respectively. AEs occurring in ≥10% more REG than placebo pts were fatigue, hand–foot skin reaction (HFSR), anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, low platelet count. The most frequent AEs deemed to be regorafenib related were HFSR, fatigue, diarrhea, hypertension, and rash/desquamation. The frequency of these AEs over time is shown in the Table. The incidence of HFSR, fatigue, hypertension, and rash/desquamation peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles. The incidence of diarrhea remained relatively constant throughout treatment. AEs led to dose modification in 66.6% of pts in the REG group and 22.5% in the placebo group. Data on dose intensity across treatment cycles will be presented. Conclusions: In the CORRECT trial, the incidences of the most common AEs in the REG group peaked early during treatment. There appeared to be no evidence for cumulative toxicity of REG. Clinical trial information: NCT01103323. [Table: see text]

381 Background: In the CORRECT Ph3 trial, regorafenib demonstrated significant improvement in OS and PFS vs. placebo in subjects with metastatic colorectal cancer (mCRC) who had progressed on standard therapies. An exploratory biomarker substudy was conducted on samples collected from subjects enrolled in CORRECT. Methods: DNA was isolated from archival tumor tissue and fresh baseline plasma samples that were available from 239 (31%) and 503 (66%) subjects enrolled in CORRECT, respectively. Mutations in KRAS, PIK3CA and BRAF were evaluated via BEAMing technology. Results: Mutations were readily detected in DNA isolated from both tumor and plasma samples: KRAS: 59/69%; PIK3CA: 12/17% and BRAF: 1.5/3.4%. The frequency of KRAS mutation detected in tumor samples via BEAMing (59%) was identical to the frequency determined from pre-existing “historical” KRAS mutation data that was available from 96% of the subjects enrolled in the study. Concordance among the mutations detected via BEAMing in tumor vs. plasma was 76% (KRAS), 88% (PIK3CA), and 97% (BRAF). A subset of CRC which was found to be KRAS-wildtype in DNA from archival tumor, but KRAS-mutant in DNA from fresh plasma was identified and may represent subjects whose KRAS mutational status had changed during prior therapy. Correlative subgroup analyses demonstrated that regorafenib mediated a trend for clinical benefit vs. placebo in both KRAS wildtype and mutant subgroups identified by plasma BEAMing (OS: KRAS WT, HR: 0.67, 95% CI: 0.41–1.08; KRAS mutant, HR: 0.81, 95% CI: 0.61–1.09; interaction p=0.561). Similar results were noted for PIK3CA WT/mutant subgroups (OS: WT, HR: 0.75, 95% CI: 0.57–0.99; mutant, HR: 0.84, 95% CI: 0.47–1.50; interaction p=0.723). BRAF was not analysed due to the small number of BRAF-mutant samples. Conclusions: The mutational analysis of DNA isolated from fresh plasma is feasible and robust using the BEAMing platform and may better represent the mutational status of the tumor(s) that a mCRC patient harbors at the time of enrollment than does the mutational analysis of archival primary tumor tissue. Regorafenib was associated with clinical benefit (vs. placebo) in all mutational subgroups evaluated. Clinical trial information: NCT01103323.

767 Background: The CORRECT trial (NCT01103323) showed that REG improves overall survival (OS) vs placebo (PBO) in patients with mCRC who failed approved therapies (OS HR 0.77; 1-sided p=0.0052; Grothey 2013). A total of 760 patients were randomized to REG (n=505) or PBO (n=255) in more than 100 centers across North America, Europe, Asia, and Australia. We conducted a post-hoc exploratory subgroup analysis of the 83 (11%) patients from 18 US centers. Methods: Eligible patients had an ECOG PS ≤1 and had received approved therapies, including a fluoropyrimidine, oxaliplatin, irinotecan, and bevacizumab, and if KRAS wild-type cetuximab and/or panitumumab. Data from the overall cohort, including US patients, are provided for perspective. Descriptive statistics are shown. Results: Of the 83 US patients, 36 (43%) were randomized to PBO and 47 (57%) to REG. Baseline characteristics of the US group were consistent with the overall cohort: median age in the US was 58 yr (range, 34 – 85) vs 61 (22 – 85) overall, 49% of US patients were ECOG PS1 (vs 46%), and 46% received ≤ 3 treatments for mCRC (vs 52%). KRAS status mutant/wild-type was 57%/34% in the US vs 57%/39% overall. All patients in the trial had prior bevacizumab and 57% of US patients also had prior cetuximab and/or panitumumab (vs 51% overall). However, higher proportion of patients in the US were Black (11% vs 2%), KRAS status unknown (10% vs 4%), and had colon as the primary disease site (82% vs 65%). Mean percentages of planned REG dose were similar (76% US vs 79% overall) and mean REG treatment duration was 3.1 mos in US vs 2.8 mos overall. Rates of dose modifications REG/PBO were 87%/47% in the US vs 76%/38% overall and grade ≥3 adverse events REG/PBO were 74%/64% vs 78%/49%, respectively. Based on 44 total death events, the HR for OS in the US subgroup was 0.46 (95%CI 0.25 – 0.84) favoring REG; median OS was 4.7 mos for PBO, but could not be estimated for REG due to censored data. However, this analysis was based on a relatively small sample size and event count. Conclusions: Patients treated in the CORRECT study in the US appear similar to the overall cohort and results are generally consistent with the overall findings of the trial. Clinical trial information: NCT01103323.

710 Background: In the CORRECT phase III trial (NCT01103323), the multikinase inhibitor REG significantly improved overall survival (OS) and PFS vs placebo in patients with mCRC who had disease progression after other standard therapies (HR for OS: 0.77; 1-sided p =0.0052; Grothey 2013). A post-hoc exploratory subgroup analysis was conducted to evaluate patients in the REG treatment group who had a PFS longer than 4 months (long-PFS) defined as patients who progressed, died, or discontinued treatment for other reasons after 4 months. Methods: Of the505 patients randomized to REG in CORRECT, 98 (19.4%) were classified as having a long-PFS benefit. Baseline characteristics, safety, and dosing parameters were analyzed descriptively. Results: The long-PFS subpopulation was representative of the overall study population (Table). Long-PFS patients received a median of 6 cycles of REG (1-12), 92% received ≥5 cycles, and 20% had > 8 cycles. Overall 34% of patients had dose reductions and 87% had dose interruptions. The actual mean daily dose was 139 mg and the mean percent of the planned dose was 81%. Adverse events (AE) of any grade were experienced by all long-PFS patients, and the most common grade ≥3 AEs were hand-foot skin reaction (20%), hypertension (17%), diarrhea (17%), and fatigue (16%). Conclusions: A subset of 98 (19.4%) patients treated with REG in the CORRECT study had a PFS > 4 months, confirming the clinical benefit and tolerability of REG as a treatment option for patients with mCRC. Prospective validation of these findings in conjunction with biomarker analysis from real-life clinical experience is needed. Clinical trial information: NCT01103323. [Table: see text]

702 Background: Median overall survival (OS) in mCRC has significantly improved over the past 20 yrs, but the observed range of OS in pts remains wide; a large percentage of pts have OS <1 yr or >4 yrs. ARIES was a prospective OCS conducted from 2006–2012 that evaluated outcomes in pts receiving BV + chemotherapy (CT) for mCRC in general clinical practice. The objective of this analysis is to examine clinical characteristics of pts with long vs short OS. Methods: This analysis included 1,417/1,550 first-line (1L) BV-treated mCRC pts who died or had complete follow-up on study. Long OS was defined as OS within the upper quartile of the analysis population (range 42–67 mos); short OS was defined as OS within the lower quartile (range 0.3–12 mos). Progression-free survival (PFS) was estimated using Kaplan-Meier methods. Pt and disease characteristics and treatment patterns were described using summary statistics. Results: Pt and disease characteristics are shown in the Table. Median PFS was 22.3 mos (95% CI, 19.9–23.3) vs. 4.9 mos (95% CI, 4.6–5.4), in the long-OS vs. short-OS groups. More pts with long OS received any second-line (2L) therapy (71% vs. 46%), and were exposed to 5-fluorouracil, oxaliplatin, and irinotecan throughout the course of their disease (53% vs. 32%) compared with pts with short OS. KRAS/BRAF mutation status was not collected. Conclusions: Pts with long OS had better baseline performance status, primary tumors more likely to have been resected, and were more likely to have received 2L CT. Additional analyses of detailed treatment patterns and safety are ongoing. Clinical trial information: NCT00388206. [Table: see text]

678 Background: Improvements in outcome of medical therapy for mCRC are closely linked to availability of active agents. Based on phase III clinical data, regorafenib, a multikinase inhibitor, received FDA approval September 2012 for patients with mCRC previously treated with all approved therapies. Post regorafenib therapy (PRTx) has not been established. Based on clinical observations, we established a multi-institution collaboration to assess chemotherapy response in mCRC after regorafenib therapy. Methods: After IRB approval, patient records at Mayo Clinic (MC), MD Anderson (MDA) and the University of Southern California (USC) from April 2010 to February 2014 were reviewed for regorafenib use and outcomes for mCRC. Therapies, patient and tumor characteristics were reviewed. Response and progression were determined by investigator review. Kaplan-Meier method was used to calculate survival. Results: Regorafenib was given to 173 patients with mCRC (MC:59 MDA:95 and USC:19). Of these, 11 (6%) continued on regorafenib at time of analysis and 98 (57%) received no additional therapy. PRTx was given to 64 (37%) patients, 31 of which went on a clinic trial. 33 patients were treated with standard approved therapy of which 11 (33%) progressed, 20 (61%) showed response or SD, and 2 (6%) were not evaluable. Out of the 33 treated with standard agents, 8 (24%) had stable disease or response to a treatment previously discontinued without definitive PD, whereas 4 (12%) responded to rechallenge with chemotherapy previously discontinued due to PD. Response was noted in 8 (24%) patients that received an agent not given prior to regorafenib. After discontinuation of regorafenib, mOS was 6.5 mo (CI 4.9 – 9.4), and the probability of survival at 6 and 12 months was 52% and 27% respectively. Conclusions: With the caveat of a small sample size and a potential selection bias, our multi-institution study shows that re-utilizing standard treatment options after regorafenib may be beneficial in select patients with mCRC including in patients with progression on identical therapy before regorafenib. Further retrospective and prospective studies could be warranted to define the role of regorafenib as a chemotherapy re-sensitizing agent.

735 Background: In the phase III CORRECT study, regorafenib significantly improved overall survival and progression-free survival (PFS) vs placebo in patients with treatment-refractory mCRC. CONSIGN (NCT01538680) was a large phase IIIb study that included 2872 patients from 25 countries; it was designed to provide continued access to regorafenib for patients with mCRC who failed standard therapy and to further characterize the safety of regorafenib. In CONSIGN, adverse events (AEs) and PFS were consistent with those reported in phase III studies. We present a retrospective subgroup analysis of patients enrolled in CONSIGN in the USA. Methods: Patients with mCRC who progressed on standard therapies and had an ECOG PS 0─1 received regorafenib 160 mg QD for the first 3 weeks of each 4-week cycle. Treatment was continued until disease progression, death, or unacceptable toxicity. The primary endpoint was safety. PFS (per investigator) was the only efficacy variable assessed. Results: A total of 364 patients in the USA were assigned to treatment (all evaluable for safety). The median age was 60 years; 38% and 62% had ECOG PS 0 and 1, respectively. KRAS mutation was present in 59%, KRAS wt in 38%; 74% had ≥ 3 prior regimens for metastatic disease. Median duration of treatment was 2.3 months (range: 0–30). Median PFS (95% CI) was 2.3 (2.0–2.6) months (2.1 months KRAS wt; 2.3 months KRAS mutant). NCI-CTCAE v4.0 grade ≥ 3 AEs occurred in 81% of patients and were considered drug-related in 53% (Table). Grade ≥ 3 hepatobiliary disorders occurred in 2%. Grade ≥ 3 treatment-emergent laboratory toxicities included bilirubin (9%), AST (6%), and ALT (3%). Conclusions: In patients from the USA enrolled in CONSIGN, the safety profile of regorafenib was consistent with that of the overall population and the known safety profile of regorafenib in mCRC. Median PFS was in the range of that reported in phase III trials. Clinical trial information: NCT01538680. [Table: see text]

710 Background: Leptomeningeal metastasis (LM) has been described as a rare form of metastatic disease progression in colorectal cancer (CRC). There remains a paucity of literature with regards to the course and management of LM in CRC. The aim of this study was to estimate the incidence of LM in CRC patients seen at our institution over a 15-year period, and to describe the clinical course and outcome of these cases. Methods: LM in CRC primary cases between 2000 and 2014 were identified in the Mayo Clinic databases. The charts were retrospectively reviewed. Results: Of 17,095 CRC primaries, we identified 10 patients with LM (0.058%) in this 15-year period. Nine cases were included in the analysis. Four had metastatic disease at the time of their initial CRC diagnosis. One patient also had a lung adenocarcinoma diagnosed during initial staging for the CRC primary. Median overall survival after CRC diagnosis was 25.7 months (range 4.7-74.8). Median time to diagnosis of LM after CRC diagnosis was 25.3 months (range 1-68.1). All patients had MRI findings consistent with LM: 3 patients with spinal LM, 5 patients with intracranial LM, 1 with both. One of three CSF analyses at the time of LM workup was positive for malignant cells; all had elevated protein. Neurologic symptoms correlated with site of the lesions, with headache, cranial nerve palsy, lower extremity weakness, and gait disturbance among the most frequently reported. However, not all patients had neurologic findings, with LM lesions found incidentally in two cases. Seven patients (78%) had palliative radiotherapy (RT) for LM. Three patients continued to receive systemic chemotherapy after diagnosis of LM. No patients underwent intrathecal chemotherapy. Median survival after LM diagnosis was 7 weeks (range 2-39). Conclusions: The diagnosis of LM is an exceedingly rare development in the natural course of CRC. It continues to confer an extremely poor prognosis with limited treatment options. At our institution, most patients had their disease addressed by palliative means, with many receiving RT to control their neurologic symptoms. Based on our series, supportive care remains a sensible approach to the management of LM in CRC.

656 Background: Patients (pts) with peritoneal metastases from CRC (pmCRC) have reduced OS compared to mCRC pts without peritoneal involvement. Here we further investigated the impact of number and location of metastases among pts receiving first-line systemic chemotherapy. Methods: Individual patient data were available on 9,265 pts (median age 64; 63% male; 93% ECOG PS 0-1; 68% colon primary tumor; brain metastases excluded) enrolled onto 12 first-line randomized trials (4 tested targeted regimens). Stratified multivariable Cox models were used to assess the associations with overall survival (OS); adjusted hazard ratios (HRadj) and 95% confidence intervals are reported (CI). Results: There were 7,963 (86%) pts with non-pmCRC (3,904 with one disease site; 4,059 with ≥2 disease sites), 191 (2%) pts with isolated pmCRC, and 1,111 (12%) non-isolated pmCRC. These groups were similar in age, race, and use of targeted chemotherapy. Compared to non-pmCRC, pts with pmCRC were more likely to be female (41% vs. 36%, p<.001), have colon primary tumors (85% vs. 67%, p<.0001), and have PS2 (10% vs. 6%, p<.0001). Compared to isolated pmCRC, pts with solitary non-peritoneal sites (both M1a) had significantly better OS (HRadj=0.78; CI, 0.64-0.94, p=.009) while pts with ≥2 non-peritoneal sites had similar OS (HRadj=1.06; CI 0.88-1.28, p=.535). OS of pts with pmCRC with a single other disease site (n=446) was similar to isolated pmCRC (HRadj=1.13; CI 0.91-1.40, p=.28), but those with pmCRC + ≥2 additional disease sites (n=665) had shortest survival (HRadj=1.44; CI 1.17-1.77, p<.001). A combination of peritoneal and liver metastases (n=821; HRadj=1.37, CI 1.12-1.67, p=.002) was associated with poorer survival compared with isolated pmCRC; but combination with extrahepatic sites (n=290; HRadj=1.15, CI 0.91-1.45, p=.25) was not. Conclusions: pmCRC pts have significantly worse survival than those with other solitary site mCRC. Among those with multiple disease sites, poorer survival is a function of increased number of metastatic sites and peritoneal involvement, which indicates prognostic heterogeneities among M1b pts.