Citations

Abstract Background: PD-L1 blockade with durvalumab (D) is approved as second-line therapy in platinum-refractory metastatic urothelial cancer (mUC). Adding CTLA-4 blockade with tremelimumab (T) may improve responses, particularly in pts with low PD-L1 expression. Here we report safety and efficacy in the mUC cohort of the dose-expansion phase of a phase I, multicenter, open-label study of D+T in pts with advanced solid tumors (NCT02261220). Methods: Pts with platinum-refractory mUC received D 20 mg/kg + T 1 mg/kg Q4W for 4 months, followed by D 10 mg/kg Q2W for a total of 12 months of treatment. The primary objectives were safety in the mUC cohort and antitumor activity in the subgroup with tumor cell and immune cell PD-L1 expression <25% (assessed by SP263 IHC assay). Secondary objectives included antitumor activity per RECIST v1.1 in other subgroups. Results: As of Oct 20 2017, 168 pts received treatment and had ≥24 weeks' follow-up. Median age was 65.5 yr (range, 35-85), 78.0% were male, 81.0% had visceral metastases (32.1% liver metastases) and 32.1% had received >1 prior line of chemotherapy. Median duration of follow-up was 11.6 mo. Treatment-related AEs occurred in 75.6% of pts and were Grade 3-4 in 28.6%. One pt died due to a treatment-related AE (pulmonary hemorrhage). Treatment-related AEs led to discontinuation of therapy in 11.9% of pts. Confirmed objective response rate (ORR) was 35/168 (20.8%) including 4 CRs. Responses occurred early (median 1.8 mo) and are durable (median DOR not reached, range 1.9-24.9 mo). At 6 months, the PFS rate was 25.4% and the OS rate was 60.9%. Median PFS was 1.9 mo and median OS was 9.5 mo. Clinical activity was seen regardless of PD-L1 status, but patients with either tumor or immune cell expression ≥25% had numerically higher response rates (29.4% vs 15.1%) and 6-month OS rates than those with <25% expression (Table). Conclusions: D+T had a manageable safety profile and encouraging antitumor activity and survival rate in previously treated mUC regardless of PD-L1 status. Response and survivalPD-L1 ≥25% (n=68)PD-L1 <25% (n=86)PD-L1 unknown (n=14)Total (N=168)Confirmed ORR (CR+PR)(95% CI), %29.4 (19.0-41.7)15.1 (8.3-24.5)14.3 (1.8-42.8)20.8 (15.0-27.8)Ongoing ORR, %60.092.310074.3Disease control rate (CR+PR+SD≥24 weeks) (95% CI), %32.4 (21.5-44.8)24.4 (15.8-34.9)42.9 (17.7-71.1)29.2 (22.4-36.7)Median PFS, months (95% CI)3.5 (1.9-3.7)1.8 (1.8-1.9)4.9 (1.8-NE)1.9 (1.8-3.4)PFS 6-month rate, %26.122.638.525.4Median OS, months (95% CI)*18.9 (8.1-NE)8.0 (4.8-10.0)16.4 (7.3-16.4)9.5 (8.1-18.9)OS 6-month rate, %66.451.991.760.9NE, not estimable *Should be interpreted with caution due to limited follow-up at data cutoff Citation Format: Arjun V. Balar, Amit Mahipal, Enrique Grande, Victor M. Villalobos, Sebastien Salas, Taek Won Kang, Se Hyun Kim, Thomas Powles, Frank Tsai, Aung Naing, Albiruni Razak, Yohann Loriot, Ji Youl Lee, Sang Joon Shin, Rafael Morales-Barrera, Natasha Angra, Feng Xiao, Shaad Abdullah, Michiel S. Van der Heijden. Durvalumab + tremelimumab in patients with metastatic urothelial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT112.

Abstract Background: In stage IV non-small cell lung cancer (NSCLC), survival has significantly improved with the use of novel therapies and better supportive care. Despite such trends, it has been noted that patients (pts) frequently refuse cancer treatment. Therefore, we explored the factors associated with treatment refusal in pts with stage IV NSCLC. Methods: Utilizing the National Cancer Database (NCDB), we identified all incident cases with stage IV NSCLC from 2004 to 2014. Patients who received cancer treatment outside of the reporting facility or died before receiving treatment were excluded. Multivariable logistic regression models were used to determine associations with treatment refusal. Results: A total of 341,993 pts were identified. On average, 5.4% of pts refused radiation therapy and 10.3% refused chemotherapy despite provider recommendations. The proportion of pts refusing radiation and chemotherapy increased over the study period from 4.2% to 7.3% and 7.9% to 15%, respectively (p<0.001 for both). In multivariable analysis, men were less likely to refuse radiation or chemotherapy compared to women (OR: 0.82, 95%CI: 0.76-0.83, p<0.001; OR: 0.84, 95%CI: 0.81-0.86, p<0.001, respectively). Factors associated with radiation therapy refusal included: Medicaid or Medicare as primary insurance (OR: 1.95, 95%CI: 1.76-2.15, p<0.001; OR: 1.25, 95%CI: 1.17-1.34, p<0.001, respectively) or a >2 Charlson Comorbidity Index (OR: 1.97, 95%CI: 1.85-2.10, p<0.001). Moreover, receiving care at an academic center (OR: 0.57, 95%CI: 0.53-0.62, p<0.001) was associated with less likelihood of refusing radiation. Regarding chemotherapy, uninsured pts (OR: 2.45, 95%CI: 2.26-2.66, p<0.001), pts with Medicaid as primary insurance (OR: 2.17, 95%CI: 2.03-2.32, p<0.001) or with a high comorbidity index (OR: 1.76, 95%CI: 1.68-1.84, p<0.001) were more likely to refuse chemotherapy. Contrary to findings from previous studies, Non-Hispanic Blacks and Hispanics were less likely to refuse chemotherapy compared to non-Hispanic whites (OR: 0.86, 95%CI: 0.82-0.91, p<0.001; OR: 0.78, 95%CI: 0.72-0.89, p<0.001). Patients receiving care at an academic center and residing in high income neighborhoods were less likely to refuse chemotherapy (OR: 0.76, 95%CI: 0.72-0.80, p<0.001; OR: 0.76, 95%CI: 0.71-0.81, p<0.001, respectively). Distance from residence to treating facility and living in a rural county did not affect treatment refusal. Conclusions: Socioeconomic factors rather than race/ethnicity appear to influence refusal of cancer treatment in pts with stage IV NSCLC in the NCDB. Assessing socioeconomic challenges should be an essential part of patients' evaluation when discussing treatment options. Citation Format: Narjust Duma, Urshila Durani, Ryan Frank, Jonas Paludo, Gustavo Westin, Yanyan Lou, Leventakos Konstantinos, Julian Molina, Ronald Go, Aaron Mansfield, Sikander Ailawadhi, Alex Adjei. Influence of sociodemographic factors on treatment decisions in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4230.

Abstract Background. Mutation of the BRAF(V600E) oncogene occurs in ~8% of human colorectal cancers (CRC) and its inhibition is associated with treatment resistance that is due, in part, to paradoxical re-activation of MEK/ERK signaling. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. We determined whether CDK1 antagonism can enhance the efficacy of MEK inhibition in BRAFV600E CRC cell lines. Methods. Manipulation of gene expression was achieved by siRNA and/or ectopic expression, or using isogenic cell pairs. Cells were treated with the CDK1 selective inhibitor RO-3306 or dinaciclib (CDK1,2,5,9 inhibitor) alone or combined with the MEK inhibitor cobimetinib. Apoptosis was quantified by Annexin V staining with flow cytometry; apoptotic signaling was analyzed by immunoblotting of caspase-8 phosphorylation and caspase cleavage. Long-term cell survival was evaluated by clonogenic assay. In vivo efficacy of the drug combination was determined in a murine flank xenograft model. Results. BRAFV600E CRC cell lines expressed CDK1 whose siRNA knockdown or pharmacological inhibition by RO-3306 or dinaciclib was shown to sensitize them to apoptosis (annexin V labeling). The combination of RO-3306 or dinaciclib with cobimetinib cooperatively enhanced apoptosis and reduced clonogenic survival compared to drug monotherapy. Cells isogenic or ectopic for BRAFV600E displayed apoptosis resistance to CDK inhibitors, as did cells with ectopic expression of constitutively active MEK. CDK1 inhibition by RO-3306 or dinaciclib induced a caspase-8-dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib-induced caspase-3 cleavage. Furthermore, CDK inhibitors suppressed procaspase-8 phosphorylation at S387 shown by drug withdrawal that restored phospho-S387 and increased cell mitosis. In a CRC xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase-dependent apoptosis than did either drug alone. Analysis of TCGA datasets revealed overexpression of CDK1 in human CRCs compared to normal colonic tissue. An inverse relationship existed between expression of CDK1 and the cell cycle inhibitor p16. In CRC cells, ectopic p16 was shown to downregulate CDK1 expression. In conclusion, our data establish CDK1 as a novel mediator of apoptosis resistance in BRAFV600E CRC cells lines whose combined targeting with CDK and MEK/ERK inhibitors may represent an effective therapeutic strategy. Citation Format: Peng Zhang, Hisato Kawakami, Weizhen Liu, Xiangyu Zeng, Klaus Stebhardt, Kaixiong Tao, Shengbing Huang, Frank A. Sinicrope. Targeting CDK1 and MEK/ERK overcomes apoptosis resistance in BRAFV600E human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2336.

Background Balloon catheter sinuplasty (BCS) for chronic rhinosinusitis (CRS) was found to be successful in adults. The safety and feasibility of BCS in children has been recently established. The purpose of this study was to study the outcome of this technology in CRS in children. Methods A prospective, multicenter, nonrandomized evaluation was performed on patients with CRS. Thirty-two children between the ages of 2 and 11 years were enrolled. Safety was assessed by rate of adverse events. Effectiveness was assessed using the Sino-Nasal (SN)-5 quality-of-life questionnaire for children with CRS at 52 weeks follow-up. Results Thirty-two children were enrolled of which 24 completed their 52 weeks follow-up. No adverse events were reported because of the procedure. SN-5 score improved from a mean of 4.9 at baseline to a mean of 2.95 at 52 weeks (p < 0.0001). Twelve (50%) children had a significant improvement of their SN-5 (> – 1.5), 7 (29%) had moderate improvement (> –1.0 and < –1.5), 2 (8%) had mild improvement (> –0.5 and < –1.0), 1 (4%) remained the same, and 2 (8%) had worsening scores. Conclusions Balloon catheter dilation of the sinus ostia in children was safe and a significant number showed improvement of their SN-5 at 1 year follow-up. Additional studies comparing balloon sinuplasty to other modalities of treatment in children are needed to determine its efficacy in the treatment of CRS in children.

Abstract BACKGROUND Reducing length of stay (LOS) in a safe manner has the potential to save significant costs for the care of patients undergoing elective lumbar spine surgery. Due to the relative absence on weekends of staff required for discharging patients to rehabilitation or nursing facilities, we hypothesize that patients undergoing lumbar surgery later in the week have a longer LOS than their counterparts. OBJECTIVE To analyze the effect of day of the week for lumbar surgery on LOS. METHODS Patients undergoing surgery for lumbar degenerative disease were prospectively enrolled in the multicenter quality and outcomes database registry. A multivariable proportional odds regression model was built with LOS as the outcome of interest and patient and surgical variables as covariates. RESULTS A total of 11 897 patients were analyzed. Among those discharged home, the regression analysis demonstrated significantly higher odds of longer LOS for patients undergoing surgery on Friday as compared to Monday ( P < .001). Among those discharged to a facility, there were significantly higher odds of longer LOS for patients undergoing surgery on Wednesday ( P < .001), Thursday ( P < .001), and Friday ( P = .002) as compared to Monday. CONCLUSION The findings of this study suggest that lumbar patients undergoing fusions and those discharged to a facility have longer LOS when surgery is later in the week. Scheduling these patients for surgery earlier in the week and ensuring adequate resources for patient disposition on weekends may lead to LOS reduction and cost savings for hospitals, payers, and patients alike.

Background and objectives In the 3-year Tolvaptan Efficacy and Safety in Management of ADPKD and Its Outcomes (TEMPO) 3:4 and 1-year Replicating Evidence of Preserved Renal Function: an Investigation of Tolvaptan Safety and Efficacy in ADPKD (REPRISE) trials, tolvaptan slowed the decline of eGFR in patients with autosomal dominant polycystic kidney disease at early and later stages of CKD, respectively. Our objective was to ascertain whether the reduction associated with the administration of tolvaptan is sustained, cumulative, and likely to delay the need for kidney replacement therapy. Design, setting, participants, & measurements One hundred and twenty-eight patients with autosomal dominant polycystic kidney disease participated in clinical trials of tolvaptan at the Mayo Clinic. All had the opportunity to enroll into open-label extension studies. Twenty participated in short-term studies or received placebo only. The remaining 108 were analyzed for safety. Ninety seven patients treated with tolvaptan for ≥1 year (mean±SD, 4.6±2.8; range, 1.1–11.2) were analyzed for efficacy using three approaches: ( 1 ) comparison of eGFR slopes and outcome (33% reduction from baseline eGFR) to controls matched by sex, age, and baseline eGFR; ( 2 ) Stability of eGFR slopes with duration of follow-up; and ( 3 ) comparison of observed and predicted eGFRs at last follow-up. Results Patients treated with tolvaptan had lower eGFR slopes from baseline (mean±SD, −2.20±2.18 ml/min per 1.73 m 2 per year) and from month 1 (mean±SD, −1.97±2.44 ml/min per 1.73 m 2 per year) compared with controls (mean±SD, −3.50±2.09 ml/min per 1.73 m 2 per year; P <0.001), and lower risk of a 33% reduction in eGFR (risk ratio, 0.63; 95% confidence interval, 0.38 to 0.98 from baseline; risk ratio, 0.53; 95% confidence interval, 0.31 to 0.85 from month 1). Annualized eGFR slopes of patients treated with tolvaptan did not change during follow-up and differences between observed and predicted eGFRs at last follow-up increased with duration of treatment. Conclusions Follow-up for up to 11.2 years (average 4.6 years) showed a sustained reduction in the annual rate of eGFR decline in patients treated with tolvaptan compared with controls and an increasing separation of eGFR values over time between the two groups.