Lenz, Heinz‐Josef

e16076 Background: Median overall survival (mOS) of patients (pt) with metastatic colorectal cancer (mCRC) has improved steadily over the past two decades. However, epidemiological data suggest that cancer outcomes for rural compared to urban dwelling pts are worse. In this study, we retrospectively compared progression free survival (PFS) and OS among mCRC pts residing in urban versus rural areas enrolled in N9741 (1997-2004) and CALGB 80405 (2005-2012) clinical trials. Methods: Zip code data from the Centers for Disease Control (CDC) were used to classify pts into rural or urban dwellers. Chi-square and Kruskal Wallis analyses were used to compare the groups. Survival outcomes were evaluated using Kaplan-Meier estimates, compared by stratified log rank and cox proportional hazards models. Results: In N9741 and 80405 respectively, 217 (35%) and 521 (21%) pts resided in rural areas. Median age of mCRC pts at diagnosis was 60.5 yrs. (rural) compared to 58.6 yrs. (urban) in 80405 (P < 0.01) and 59.6 yrs. to 60.2 yrs. in N9741 (P = 0.4). In 80405, pts in rural areas were less likely to be female (35% vs 43%, P < 0.01) black (6.6% vs 15.1%, P < 0.01), unmarried (51% vs 62%, P < 0.01), and to have private insurance (PI) (45% vs 50%, P = 0.03) when compared to pts in urban areas. In N9741, gender (P = 0.8) and PI (P = 0.3) distribution was similar; pts in rural areas were less likely to be black (1.4% vs 9.1%, P < 0.01). Rural vs urban pt PFS was no different in either trial. MOS was worse in pts in rural areas when compared to urban dwellers in 80405 (Table). OS outcomes stratified based on the use of cetuximab based regimen in 80405 showed worse outcomes for pts in rural compared to urban dwellers (21.9 vs 26.3 mo. HR: 1.22 (1.03-1.44), P = 0.02). Conclusions: MCRC pts from rural areas had a significantly worse mOS when compared to pts in urban areas in 80405. Furthermore, mOS with cetuximab based regimens was 4.4 months shorter in rural pts. The observed rural vs urban dweller mOS disparities in 80405 pts justifies additional research searching for causal factors and the necessity to identify actionable approaches in order to improve pt outcomes in rural areas. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA180830; Pfizer, Sanofi, BMS, Genentech, https://acknowledgments.alliancefound.org . ClinicalTrials.gov Identifier: NCT00003594, NCT00265850. [Table: see text]

4086 Background: The randomized phase III CALGB/SWOG 80405 trial found no difference in overall survival (OS) in first-line mCRC pts treated with either bevacizumab (Bev) or cetuximab (Cet) combined with the same chemotherapy. We investigated the potential prognostic and predictive value of HER2 amplification and HER2 gene expression using NGS and Nanostring data. Methods: Primary tumor DNA from 559 patients (pts) was profiled for HER2 amplification by NGS (Foundation One). Tumor tissue from 925 pts was tested for Nanostring gene expression using an 800 gene panel. OS and progression free survival (PFS) were the endpoints as time-to-event variables. Cox proportional hazard models with gene expression fitted with linear spline (one internal knot at median) were used, adjusting for pts baseline characteristics, treatment assignment, and molecular features (microsatellite instability, BRAF, all RAS). Results: Of 505 tumors with both NGS and Nanostring data, 16 harbored HER2 amplification (copy number variation > 6), limited to microsatellite stable tumors and significantly associated with HER2 expression ( P < 0.001) and wild-type RAS ( P = 0.036). HER2 amplification was neither prognostic nor predictive for OS or PFS. Conversely, HER2 expression higher than median was associated with longer PFS ( P = 0.018) but not OS ( P = 0.13). Among pts with HER2 not amplified, higher HER2 expression was associated with better OS (hazard ratio [HR], 0.83; 95%CI, 0.72-0.97; P = 0.016) and PFS (HR, 0.85; 95%CI, 0.74-0.98; P = 0.027) when the expression was less than median. Additionally, in pts with no HER2 amplification and HER2 expression lower than median, treatment with Cet was associated with worse PFS compared to Bev (HR, 1.46; 95%CI, 1.12-1.90; P = 0.005). This effect was not observed with expression higher than median regardless of HER2 amplification status. Conclusions: To our knowledge, this is the largest analysis of HER2 amplification and gene expression in mCRC pts treated with standard therapy. Our results provide novel insight on the predictive and prognostic value of HER2 gene expression in pts treated with Cet- and Bev-based regimens. Upon validation, these findings could inform pts selection and the design of more effective treatment options for pts with low HER2 expression. Clinical trial information: NCT00265850.

4032 Background: PNET has long had few effective therapies other than chemotherapy. Placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <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 was 50 patients, with interim analysis for futility 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: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, 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. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.

3637 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progression-free survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n=505) or P (n=255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n=500, P n=253). The mean ± SD treatment duration was 12.1 ± 9.7 weeks for REG and 7.8 ± 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ≥10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ≥3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323. [Table: see text]

3514 Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p=0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p=0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p<0.001; PIGF: HR 1.81, p=0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p<0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.

4047 Background: PNET has long had few effective therapies other than chemotherapy. Recent placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/ PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <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 for futility 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 13 of the first 25 (52%) evaluable patients. 21 of 25 (84%) patients were progression-free at 6 months. Both endpoints exceeded the protocol-defined criteria to continue enrollment. For 36 evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (14%), leukopenia (11%), lymphopenia (11%), hyperglycemia (11%), mucositis (8%), hypokalemia (8%), and fatigue (8%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 52%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 84% in a population of patients with RECIST criteria progression within 7 months of study entry. Accrual is ongoing.

3636 Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progression-free survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ≥3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ≥65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n=505) or Pla (n=255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts <65 years (307 evaluable for safety) and 196 pts ≥65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56–0.91) in pts <65 years and 0.86 (95% CI 0.61–1.19) in pts ≥65 years (interaction p-value = 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts <65 years, and 6.0 vs 5.6 months, respectively, in pts ≥65 years. Most pts experienced drug-related AEs (<65 years: 93.8%; ≥65 years: 91.7%). The rates of grade ≥3 REG-related AEs of interest and dose modifications are shown in the Table. In pts <65 years vs ≥65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6–15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6–160.0) vs 160.0 mg (137.5–160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts <65 years and ≥65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. [Table: see text]

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]

4020 Background: Adjuvant chemotherapy (AC) presents a substantial patient education challenge to medical oncologists (MOs). Findings from our 2005 pilot survey suggest that a significant fraction of colorectal cancer (CRC) survivors are willing to undergo AC for modest treatment benefits, but their understanding of risks and benefits may be suboptimal. This project attempted to validate these findings by surveying patients with CRC (Pts) who previously received AC. Methods: 150 Pts who received AC for CRC in the last 5 years were recruited to listen to an audio program on AC featuring interviews with clinical investigators (CIs) and Pts who received AC. Based on this input, Pts were asked whether they would undergo the same AC again for varying absolute treatment benefits. A corresponding survey asked 24 CRC CIs and 150 MOs to predict how patients would respond. The survey also queried Pts about their expectations of and experiences with AC side effects. Results: About 1/3 of Pts would be treated again with AC for a 1% absolute reduction in recurrence risk (ARRR), and about 2/3 believed a 5% ARRR would justify treatment. There were no statistically significant differences between responses of males and females or between Pts receiving oxaliplatin (OX) and those receiving other regimens. ( Table 1 ) The corresponding estimates of CIs and MOs were lower. Additionally, AC side effects were different than expected: 57% and 66% of Pts experienced less GI toxicity and alopecia, respectively, while 38% and 46% of Pts receiving OX experienced greater cold intolerance and numbness. Conclusions: Many potential obstacles exist in communicating with Pts about AC including heterogeneity in Pts’ attitudes towards risk/benefit trade-offs and preconceptions about treatment side effects. The next step in this initiative will be to examine these issues prospectively by evaluating the impact of an audio/web education supplement on the decision-making process. [Table: see text] No significant financial relationships to disclose.

11586 Background: Hand-foot skin reaction (HFSR) is the most common regorafenib adverse event. However, no intervention has demonstrated efficacy in preventing or palliating this adverse event, short of modulating the regorafenib dose. Methods: The Regorafenib Dose Optimization Study (ReDOS) was a randomized trial ( https://clinicaltrials.gov/ct2/show/NCT02368886 ); here we describe an a priori secondary analysis of ReDOS with the goal of assessing whether clobetasol 0.05% cream (a potent corticosteroid) applied to the palms and soles twice per day is more effective when prescribed pre-emptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the 1st 2 cycles of regorafenib. Results: Among 116 evaluable patients, 61 received pre-emptive clobetasol, and 55 reactive clobetasol. Baseline demographics were comparable between groups. During the 1st regorafenib cycle, 46% and 52% of patients developed HFSR with pre-emptive and reactive clobetasol, respectively (p = 0.52). However, during the 2nd cycle, 56% (of 47 total patients) and 80% (of 41 total patients), developed this toxicity with pre-emptive and reactive clobetasol, respectively (p = 0.02). Of note, during the 2nd cycle, rates of grade 1,2, and 3 HFSR were 40%, 11%, and 4% (pre-emptive) and 45%, 25%, and 10% (reactive) (p = 0.07). A sensitivity analysis to examine rates of no HFSR over all 2 regorafenib cycles showed that no HFSR occurred in 33% (of 61 total patients) with pre-emptive clobetasol versus 15% (of 55 total patients) with reactive clobetasol (p = 0.02). Patient-reported outcomes showed HFSR compromised activities of daily living, including getting dressed, preparing meals, walking, and even driving, with seemingly worse descriptive outcomes in patients who received reactive therapy. No adverse events from clobetasol were reported. Conclusions: Compared to reactive therapy, pre-emptive topical clobetasol might lessen regorafenib-induced HFSR. Clinical trial information: NCT02368886.