Cutsem, Eric Van

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.

224 Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p < 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p < 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p < 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.

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]

666 Background: Early tumor shrinkage (ETS; ≥20% decrease from baseline) and early objective tumor response (EOTR; CR/PR by RECIST) are associated with improved PFS/OS to a similar extent than best overall response (BOR), confirmed response (ConfR) and non-progression rate (NPR; CR/PR/SD by RECIST) at the individual level in first-line mCRC (ASCO 2014, abstr 3538/3578). We assessed these RBEs at the trial level. Methods: Data were available on 12,185 pts enrolled in a total of 17 randomized trials of chemotherapy (CT) alone or with targeted agents (TAs). ETS, EOTR and NPR were assessed at 6/8/9 and 12 weeks (wks), whereas BOR and ConfR were ascertained within 26 wks from randomization. Association between treatment effects on RBEs and on PFS/OS was assessed by coefficients of determination (R2, adjusted for estimation errors) using a copula model). Results: None of the RBEs had consistently strong correlations with PFS or OS (Table). The number of trials was insufficient to obtain reliable estimates for antiangiogenics and anti-EGFR separately. Conclusions: Despite their individual-level associations with PFS and OS, RBEs do not appear to be surrogate endpoints in first-line mCRC, given their poor predictive ability. [Table: see text]

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]

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

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.