Citations

3554 Background: There is considerable variability in the outcomes between second line (SL) trials in mCRC. The aim of this analysis is to compare the outcomes of patients (pts) with mCRC treated either on SAFL, with protocol defined SL treatment, or DSLT. Methods: Individual pt data was available on pts with mCRC enrolled in 1 of 10 trials (7 DSLT, 3 SAFL) in the ARCAD database. Regimens included FOLFIRI, FOLFOX, and irinotecan (IRI), since pts did not receive biologic agents in SL on SAFL. For pts on a SAFL, PFS and OS were defined as time from initiation of SL treatment to second progression (SP)/death and death, respectively. Descriptive statistics and multivariable Cox models were used to assess differences in PFS and OS. Results: 5,076 pts were included; 63% were male; median age was 62. See Table for treatment details. Pts treated on SAFL had shorter OS (0.7-1.5 months (mos>) shorter) and PFS (0.6-2.6 mos shorter), compared to those treated on DSLT. These findings were statistically significant and differences in OS did not attenuate after adjustment for age, gender, and prior treatment. PFS differences in FOLFOX became insignificant after multivariable adjustment. Conclusions: There are modest differences in both PFS and OS between pts with mCRC treated on SAFL and those on DSLT, suggesting differences in these pt populations. Caution is needed when applying these data to pts, as we were unable to control for potential confounders (ECOG PS, number and sites of metastases) at initiation of SL in SAFL, which may impact outcomes. [Table: see text]

3551 Background: Cutaneous toxicity is a known adverse effect of multikinase inhibitors and has been associated with clinical outcomes (Granito 2016). In the phase 3 CORRECT trial (NCT01103323), the multikinase inhibitor regorafenib significantly improved overall survival (OS) vs placebo in patients with mCRC (hazard ratio [HR] 0.77, 95% CI 0.64, 0.94; 1-sided P = 0.0052). This retrospective analysis explored whether HFSR was associated with outcomes in CORRECT. Methods: Patients randomized to receive regorafenib 160 mg/day during the first 3 weeks of each 4-week cycle were divided into subgroups based on whether or not they had HFSR. Estimates of OS and progression-free survival (PFS) (95% CI) were calculated using the Kaplan–Meier method. Patients who were randomized, but not treated, were included in the no HFSR group for the analysis of survival. Results: Of the 505 randomized patients, 500 received at least one dose of regorafenib. Among the treated patients, 47% (n = 235) had HFSR of any grade and 17% (n = 83) had HFSR grade 3. Of the patients who had HFSR, 69% (n = 162) had their first HFSR event (any grade) during the first treatment cycle. There was some imbalance in baseline characteristics between groups (Table). Survival was improved in patients who had HFSR at any time vs those who did not (Table). The OS benefit was also observed in patients who had the first HFSR event during Cycle 1 vs those who did not (median OS 7.2 vs 5.7 months; HR 0.66, 95% CI 0.51, 0.87). Conclusions: This post-hoc exploratory analysis suggests that patients who had HFSR had a greater treatment benefit from regorafenib. Since HFSR and survival are post-baseline assessments, results may be confounded by baseline factors or other unknown factors. Clinical trial information: NCT01103323. [Table: see text]

3535 Background: CRC is known to be a heterogeneous disease. This study quantifies within pt heterogeneity in early lesion change rate (LCR) in the era of targeted agents compared to chemo alone and its potential impact on survival. Methods: Pts with 2-10 lesions measured at baseline were included. For each lesion, the early LCR was defined as the change in size (shrinking or growing) from baseline to 12 weeks on treatment. Within pt heterogeneity in early LCR among lesions was estimated by standard deviation (STD). A larger value of STD indicates larger variation of LCR per pt. Stratified multivariate Cox models were used to assess the associations between LCR STD with overall survival (OS). Adjusted hazard ratios (HRadj) and 95% confidence intervals (CIs) are reported. Results: Data were available on 9,092 mCRC pts (median age 61; 60% male, 55% ECOG PS 0; 61% 2+ metastatic sites) enrolled in 16 1st-line randomized trials, with 44%, 42%, and 10% of pts received chemo alone, + a VEGF inhibitor (VEGFi) or an EGFR inhibitor (EGFRi), respectively. LCR heterogeneity is the highest among pts received EGFRi but lowest among pts received VEGFi (Table). Overall, higher heterogeneity is associated with worst OS (HRadj1.22, 95% CI (1.16, 1.27)). The effect is most pronounced in pts received VEGFi (interaction p=0.0012). Conclusions: There was heterogeneity observed in lesion size changes within pts. Its magnitude varies across treatment approaches, and was associated with poor survival. This preliminary result reveals the great potentials to define novel response endpoint and refine treatment decision-making by incorporating heterogeneities in lesion changes. [Table: see text]

3529 Background: Cancer stem cells are considered to be fundamentally important for resistance, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mCRC pts was done to confirm the RP2D and signs of anti-cancer activity of napabucasin in combination with FOLFIRI +/- Bev. Pts received napabucasin 240 mg PO BID with bi-weekly FOLFIRI IV +/- Bev 5 mg/kg until disease progression or other discontinuation criterion. Results: 82 pretreated mCRC pts were enrolled (ITT); including 32 (39%) previously treated with FOLFIRI +/- bev. Of the 82 pts, 48 received FOLFIRI and 34 FOLFIRI plus bev in combination with napabucasin. There was no dose-limiting or unexpected toxicity or significant PK interactions. Most common adverse events (AEs) included grade 1/2 diarrhea, cramping, nausea, vomiting, fatigue and anorexia with grade 4 diarrhea in 1 pt and 27 pts with grade 3 AEs including: diarrhea (15), fatigue (5), dehydration (1), electrolyte imbalance (4), abdominal pain (1), vomiting (1) and weight loss (1), which resolved with dose reduction and supportive care. Disease control (CR+PR+SD) was observed in 55 of 66 pts who received RECIST evaluation (83%), with 1 CR (1.5%), 13 PR (20%) (33-100% regression) and 27 SD with tumor regression (41%). Conclusions: This phase Ib/II study confirmed that napabucasin can be safely combined with FOLFIRI +/- bev, and shows encouraging signs of efficacy in pretreated mCRC pts, including pts previously treated with FOLFIRI +/- bev. Clinical trial information: NCT02024607. [Table: see text]

LBA1 The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Sunday, June 4, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.

Abstract Background In the phase III CORRECT trial, regorafenib significantly improved survival in treatment-refractory metastatic colorectal cancer (mCRC). The CONSIGN study was designed to further characterize regorafenib safety and allow patients access to regorafenib before market authorization. Methods This prospective, single-arm study enrolled patients in 25 countries at 186 sites. Patients with treatment-refractory mCRC and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤1 received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoint was safety. Progression-free survival (PFS) per investigator assessment was the only efficacy evaluation. Results In total, 2,872 patients were assigned to treatment and 2,864 were treated. Median age was 62 years, ECOG PS 0/1 was 47%/53%, and 74% had received at least three prior regimens for metastatic disease. Median treatment duration was three cycles. Treatment-emergent adverse events (TEAEs) led to dose reduction in 46% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 9%. Grade 5 regorafenib-related TEAEs occurred in <1%. The most common grade ≥3 regorafenib-related TEAEs were hypertension (15%), hand–foot skin reaction (14%), fatigue (13%), diarrhea (5%), and hypophosphatemia (5%). Treatment-emergent grade 3–4 laboratory toxicities included alanine aminotransferase (6%), aspartate aminotransferase (7%), and bilirubin (13%). Ongoing monitoring identified one nonfatal case of regorafenib-related severe drug-induced liver injury per DILI Working Group criteria. Median PFS (95% confidence interval [CI]) was 2.7 months (2.6–2.7). Conclusion In CONSIGN, the frequency and severity of TEAEs were consistent with the known safety profile of regorafenib. PFS was similar to reports of phase III trials. ClinicalTrials.gov: NCT01538680. Implications for Practice Patients with metastatic colorectal cancer (mCRC) who fail treatment with standard therapies, including chemotherapy and monoclonal antibodies targeting vascular endothelial growth factor or epidermal growth factor receptor, have few treatment options. The multikinase inhibitor regorafenib was shown to improve survival in patients with treatment-refractory mCRC in the phase III CORRECT (N = 760) and CONCUR (N = 204) trials. However, safety data on regorafenib for mCRC in a larger number of patients were not available. The CONSIGN trial, carried out prospectively in more than 2,800 patients across 25 countries, confirmed the safety profile of regorafenib from the phase III trials and reinforced the importance of using treatment modifications to manage adverse events.