Citations

659 Background: Regular physical activity (PA) is associated with reduced risk of recurrence and mortality in non-metastatic colorectal cancer. Its influence on patients with metastatic colorectal cancer (mCRC) is largely unexplored. Methods: 1231 patients participating in CALGB 80405 (first-line phase III chemotherapy trial for mCRC) completed questionnaires that included self-report on PA at time of chemotherapy initiation and total metabolic equivalent task (MET)-hours/week were determined based on responses. The primary endpoint of the clinical trial and this companion study was overall survival (OS), with progression-free survival (PFS) as a secondary endpoint. To minimize confounding by poor and rapidly declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and adjusted for known prognostic factors, comorbid illness, and weight loss over the previous six months. Results: Compared with patients engaged in less than three MET-hours/week of PA, patients engaged in 18 or more MET-hours/week experienced an adjusted hazard ratio for OS of 0.81 (95% CI 0.67 to 0.98, P for trend 0.03) and for PFS of 0.84 (95% CI 0.71 to 1.00, P for trend 0.03). Greater nonvigorous PA and walking duration were both associated with improved OS ( P for trend 0.01 and 0.04, respectively). Conclusions: In mCRC patients from CALGB 80405, greater total PA was associated with improved PFS and OS, while greater walking duration and non-vigorous PA were associated with reduced risk of all-cause mortality. Support: U10CA180821, U10CA180882. ClinicalTrials.gov ID: NCT00265850 [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]

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]

LBA3 Background: Irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6), combined with bevacizumab (BV) or cetuximab (CET), are first-line treatments for metastatic adenocarcinoma of the colon or rectum (MCRC). The optimal antibody combination is unknown. Methods: Patients (pts) with KRAS wild-type (wt)(codons 12 and 13) MCRC and performance status 0-1 received FOLFIRI or mFOLFOX6 (MD/pt choice at enrollment) and randomized to either CET 400 mg/m2 X 1, then 250 mg/m2 qw or BV 5 mg/kg q2w. The original study included unselected MCRC pts receiving FOLFIRI or mFOLFOX6 and randomized to CET, BV, or both. After 1,420 pts accrued the study amended as follows: only pts with KRAS wt tumors (codon 12 and 13) were included and the combination CET + BV arm was deleted. Rx continued until progression, death, unacceptable toxicity, curative surgery; treatment holidays of 4 wks permitted. Subsequent Rx not mandated. Accrual goal was 1,142 pts. One° endpoint was overall survival (OS). Results: Between November 2005 and March 2012, 3,058 unselected pts enrolled, 2,334 KRAS wt pts randomized; final N =1137 (333 pre-amend eligible retrospective KRAS test, 804 post-amend), median f/u = 24 mos; Median age – 59 y; 61% male. Chemo/BV – 559; chemo/CET – 578. FOLFIRI = 26.6%, mFOLFOX6 = 73.4%. OS analysis planned at 849 events; efficacy futility boundary crossed at 10th interim analysis on 1/29/14. OS - chemo/BV v. chemo/CET = 29.04 (25.66 - 31.21) v. 29.93 (27.56 - 31.21) mos; HR = 0.92 (0.78, 1.09) (p value = 0.34). PFS (by investigator): chemo/BV v. chemo/CET: 10.84 (9.86 - 11.4) v. 10.45 (9.66 - 11.33) mos. There were 94 pts free of disease following surgery, median f/u 40 mos (range 8.0 - 86.0). Outcomes similar by gender. On-study toxicity and deaths as expected. Analyses underway: Expanded RAS, FOLFOX v. FOLFIRI, subsequent therapies, long-term survivors, correlates. Conclusions: Chemo/CET and chemo/BV equivalent in OS in pts KRAS wt (codons 12 + 13) MCRC; either is appropriate in first line. Overall OS of 29 + mos and 8% long-term survivors confirms progress in MCRC. The preference for FOLFOX limits chemotherapy comparison. Expanded RAS and other molecular and clinical analyses may identify subsets of pts who get more or less benefit from specific regimens. Clinical trial information: NCT00265850.

LBA385 Background: Regorafenib (BAY 73-4506) is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal kinases. The phase III CORRECT trial was conducted to evaluate efficacy and safety of regorafenib in 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 regorafenib (160 mg od po, 3 weeks on/1 week off) plus BSC, or placebo (PL) plus BSC. Pts continued on treatment until progression, death, or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), safety, and quality of life. Results: From May 2010 to March 2011, 760 pts were randomized (regorafenib: 505; PL: 255). Baseline characteristics were balanced between two arms. Preliminary results are available from a pre-planned formal interim analysis. The estimated hazard ratio (HR) for OS was 0.773 (95% CI: 0.635, 0.941; 1-sided p=0.0051). Median OS was 6.4 mos (95% CI: 5.9, 7.3) for regorafenib and 5.0 mos (95% CI: 4.4, 5.8) for PL. The estimated HR for PFS was 0.493 (95% CI: 0.418, 0.581; 1-sided p < 0.000001). Median PFS was 1.9 mos (95% CI: 1.88, 2.17) for regorafenib and 1.7 mos (95% CI: 1.68, 1.74) for PL. ORR was 1.6% for regorafenib and 0.4% for PL. DCR was 44% for regorafenib and 15% for PL (p < 0.000001). Since the prespecified OS efficacy boundary was crossed (nominal α: 0.0093), the Data Monitoring Committee recommended to unblind the study and pts on PL were allowed to cross over to regorafenib. The most frequent grade 3+ AEs in the regorafenib arm were hand-foot skin reaction (17%), fatigue (15%), diarrhea (8%), hyperbilirubinemia (8%), and hypertension (7%). Updated results will be presented. Conclusions: Statistically significant benefit in OS and PFS was observed for regorafenib over PL in pts with mCRC who have failed all approved standard therapies. No new or unexpected safety signal was found.

260 Background: Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib in PNET noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co-primary endpoints were RR and 6-month PFS. Planned enrollment is 50 patients, with interim analysis after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: Confirmed PR was documented in 11 of the first 25 (44%) evaluable patients. 20 of 25 (80%) patients were progression-free at 6 months. Both endpoints exceeded pre-defined criteria to continue enrollment. For 35 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were leukopenia (12%), hypertension (12%), hyperglycemia (12%), mucositis (9%), and fatigue (9%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 44%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing. Supported by NCI N01 Contracts: 662205, 62203, 62208, 62209, 62206, 62204, 62207, 62201.