Yoshino, Takayuki

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.

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]

512 Background: Angiogenesis is an important therapeutic target in CRC; VEGF plays a key role in angiogenesis. RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The RAISE study evaluated the efficacy and safety of adding RAM to standard second-line treatment FOLFIRI. Methods: Eligible pts with mCRC who progressed on or after first-line combination therapy with bev, ox, and fp, had an ECOG PS of 0 or 1, and adequate organ function were randomized 1:1 (stratified by region, KRAS mutation status, and time to progressive disease [PD] after beginning first-line treatment) to receive RAM (8 mg/kg IV) plus FOLFIRI or PBO plus FOLFIRI every 2 weeks until PD, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Planned sample size of 1,050 pts ensured 85% power to demonstrate statistical significance at an overall two-sided alpha of 0.05, assuming a hazard ratio (HR) of 0.8. Results: Between Dec 2010 and Aug 2013, 1,072 eligible pts were randomized (RAM 536; PBO 536). Baseline pt characteristics were similar between treatment arms. The OS HR was 0.84 (95% CI: 0.73, 0.98; log-rank p=0.0219). Median OS was 13.3months (m) for RAM vs 11.7m for PBO. The PFS HR was 0.79 (95% CI: 0.70, 0.90; log-rank p = 0.0005). Median PFS with RAM was 5.7m and 4.5m for PBO. ORR was 13.4% RAM; 12.5% PBO (p = 0.6336). Subgroup results were consistent with the OS and PFS results. Grade ≥3 adverse events (AEs) occurring in >5% of pts in RAM+FOLFIRI were: neutropenia (RAM 38.4% vs PBO 23.3% ), hypertension (11.2% vs 2.8%), diarrhea (10.8% vs 9.7%), and fatigue (11.5% vs 7.8%). Conclusions: RAISE met its primary end-point, demonstrating a statistically significant improvement in OS for RAM and FOLFIRI vs PBO and FOLFIRI in second-line mCRC pts. Benefits were similar across important clinical subgroups and no unexpected AEs were identified. Clinical trial information: NCT01183780.

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.