Citations

e21054 Background: Up to 50% of patients undergoing resection for advanced melanoma experience recurrence. Identification of preoperative prognostic biomarkers is needed to ascertain risk of relapse and guide postoperative management. Lactate dehydrogenase (LDH) represents a strong prognostic factor in unresectable metastatic (stage IV) melanoma, but its relevance in patients with resected stage III or IV disease remains unknown. Methods: We retrospectively analyzed data from patients with stage III and IV melanoma who had undergone complete resection of disease and received follow-up treatment at Mayo Clinic, Rochester between January 1, 2000 and January 31, 2012. Clinical data were collected from electronic records. Survival data were estimated using the Kaplan-Meier method. Associations of preoperative LDH with time to relapse and death were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals. Results: A total of 154 subjects with resectable stage III or IV melanoma were included in the study. Median age at the time of resection was 58; 54 (35.1%) were female. One-hundred sixteen (75.3%) patients were classified as stage III and 38 (24.7%) stage IV. Adjuvant systemic treatment was administered in 75 (48.7%) patients and adjuvant radiation in 32 (20.7%). Median duration of follow-up was 4.0 years. Sixteen (10.3%) patients had preoperative LDH above the upper limit of normal. Each 50-unit increase in LDH was associated with a 15% increased risk of relapse (HR 1.15; p = 0.040) and 23% increased risk of death (HR 1.23; p = 0.001). After adjusting for age, gender, stage, number of sites, adjuvant systemic treatment, and adjuvant radiation, preoperative LDH remained associated with time to death (HR 1.25; p = 0.002). Preoperative LDH greater than the upper limit of normal was associated with increased hazard of death, both with univariate (HR 2.44; p = 0.005) and multivariate (HR 2.17; p = 0.017) analyses. Conclusions: This study supports the role of elevated preoperative LDH as a predictor of inferior outcomes in patients with advanced melanoma. Further study to correlate LDH to outcomes in the era of adjuvant immunotherapy is required.

e16003 Background: Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. While radical cystectomy (RC) is currently viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) combining transurethral resection of bladder tumor, chemotherapy for radiation sensitization and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, we compared the oncological outcomes between patients managed by RC or TMT using a propensity-score matched cohort analysis. Methods: Patients seen in our multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were retrospectively reviewed. Those who received TMT for MIBC were identified and matched (for gender, cT and cN stage, ECOG status, Charlson comorbidity score, treatment date, age, CIS, hydronephrosis) using propensity scores, to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox Proportional hazards modeling and competing risk analysis, respectively. Results: 112 patients with MIBC were included after matching, 56 treated with TMT and 56 by RC. Median age was 68.0 years and 29.5% were cT3/cT4. At a median follow up of 4.51 years, there were 20 (35.7%) deaths (13 from BC) in the RC group and 22 (39.3%) deaths (13 from BC) in the TMT group. 5 year DSS was 73.2% and 76.6%, in the RC and TMT groups, respectively (p = 0.49). Salvage cystectomy was performed in 6/56 TMT patients (10.7%). Conclusions: In the setting of a MDBCC, TMT yielded survival outcomes similar to matched RC patients. Appropriately selected MIBC patients should be offered the opportunity to discuss various treatment options including organ-sparing TMT.

4106 Background: Cancer stem cells are fundamentally important for resistance to therapy, 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). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m2 and gem 1000 mg/m2for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is >7.1 and >10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]

TPS4148 Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutic agents, including nab-PTX and gem. Encouraging anticancer activity in mPDAC was observed in a phase Ib (El-Rayes et al, ASCO 2016) study of 37 pts, reporting 93% (28/30) disease control rate (DCR) and 50% (15/30) overall response rate (ORR), with 1 complete and 14 partial responses and prolonged disease control ( > 24 wks) in 57% (17/30) of pts who have had a RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia and Asia. Methods: This study (ClinicalTrials.gov NCT02993731) will assess the efficacy of napabucasin+nab-PTX+gem vs nab-PTX+gem in pts with mPDAC (n = 1132). Pts must have been diagnosed with mPDAC < 6 weeks prior to randomization and not have received treatment for metastatic disease. Pts are randomized in a 1:1 ratio to receive napabucasin 240 mg PO twice daily continuously plus nab-PTX+gem IV weekly for 3 out every 4 weeks, or nab-PTX+gem IV weekly for 3 out every 4 weeks. Pts will be stratified by geography, performance status and presence of liver metastases. Treatment will continue until disease progression, death, intolerability or patient/investigator decision to stop. Primary endpoint is overall survival (OS) in the general study population (HR 0.80 for OS improvement from 8.5 to 10.63 months); secondary endpoints include progression free survival (PFS), OS and PFS in the biomarker positive sub-population, ORR and DCR, safety and quality of life. In addition, blood and tumor archival tissue will be assessed for pharmacokinetic and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02993731.

3541 Background: Pembrolizumab (PEM) has activity in patients with deficient mismatch repair (dMMR) colorectal cancer (CRC). Oxaliplatin (OX) and 5FU lead to immunogenic cell death and increased antigen presentation. We hypothesized that combining mFOLFOX6 and PEM may enhance immunogenic cell death and improve outcome in patients with CRC irrespective of MMR status. Methods: Subjects ≥18 years old with untreated, unresectable CRC were assigned to a single arm study. The study had a safety run in cohort of six patients (OX 85 mg/m2, leucovorin 400 mg/m2, 5FU 400 mg/m2, 5FU infusion 2400 mg/m2over 46 hours) and PEM 200 mg Q 3 weeks, followed by a phase II cohort. The primary objective was median progression free survival (mPFS), with secondary objectives: safety and toxicity per CTCAE V4.03, median overall survival, response rate, immune related response, disease control rate, and molecular correlates. Results: Between 4/2015 and 9/2016, 30 subjects were enrolled with following characteristics: 11 female, 26 Caucasian, median age: 45 years (25-75), 3 with dMMR, 22 MMR-proficient, and 5 with no available data. During the safety run in, 2 patients had G3 febrile neutropenia (FN) and 1 G4 neutropenia. The data safety monitoring committee recommended dose reduction of mFOLFOX6 to OX 68 mg/m2, leucovorin 400 mg/m2, 5FU of 320 mg/m2, 5FU infusion of 1920 mg/m2over 46 hours and PEM 200 mg Q 3 weeks. At the data cut off (12/29/16), median follow up was 24 weeks (10-66) and 27 patients remained on study. Rate of G3/4 toxicity associated with FOLFOX/PEM and PEM alone was 36.7% and 13.2%, respectively. No further FN was observed. No grade 5 toxicity was seen on study. Best response was recorded as: 1 complete response, 15 partial response (CR +PR = 53%), and 14 stable disease, with 100% DCR at 8 weeks. One patient with dMMR had resection after 2 months of therapy with complete pathologic response. MPFS has not been reached (95% CI: 5.5 months, NR). Conclusions: Based on these preliminary results, PEM/mFOLFOX6 has acceptable toxicity though demonstrated a suggestion of increased neutropenia in the initial cohort. Clinical activity was seen in patients with untreated advanced CRC including those with proficient MMR. Clinical trial information: NCT02375672.

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]

3503 Background: 80405 found no OS or Progression Free Survival (PFS) difference when bevacizumab (BV) or cetuximab (Cet) was added to 1st-line FOLFOX or FOLFIRI in All RAS wild type (wt) mCRC pts. There was a significant 1° side by biologic interaction (P int: OS = 0.008, PFS = 0.001) favoring pts with left-sided (L) 1°. Analyses of 1° tumors beyond All RAS includes Consensus Molecular Subtype (CMS), BRAF and MSI. (CMS results - see Lenz et al; BRAF -see Innocenti et al) We asked whether 1° tumor location - L vs right (R) - is an independent prognostic marker when these other molecular features are considered. Methods: We used a Cox proportional hazard model stratified by prior XRT and +/- adjuvant chemo; adjusted for age, gender, synchronous vs metachronous, CMS, MSI and BRAF status. Pts with transverse (T) tumors were excluded in this analysis. Results: Sidedness was determined in 782 pts (L - 472; R - 256; T -54). Molecular data from 728 pts (with L - and R-sided 1°s) was available as follows: KRAS -- 291, NRAS -393, BRAF - 393, MSI - 378, CMS - 533. L vs R mOS: 32.9 v 19.6 months (mo) (p < 0.0001). See Table for OS results in All RAS / BRAF wt and BRAF mutant (mut) pts. Sidedness (R vs L) is an independent prognostic marker even after adjusting for all these molecular features: HR = 1.392 (1.032, 1.878), p = 0.031. Conclusions: Primary tumor location is an independent prognostic factor when adjusted for age, gender, synchronous/metachronous, CMS, MSI and BRAF status. We are exploring clinical variables such as tumor burden, metastatic sites and measurability of disease in an attempt to explain the impact of sidedness. Support: U10CA188021, U10CA180882. Eli Lilly and Co, Genentech/Roche, Pfizer, Sanofi. Clinical trial information: NCT002655850. [Table: see text]