Mahipal, Amit

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.

Objectives Prognostic factors for solid pseudopapillary neoplasms (SPN) of the pancreas have been incompletely defined in the literature. We aimed to use the National Cancer Database to describe survival and characterize prognostic factors in patients with pancreatic pseudopapillary neoplasms. Methods We identified 304 patients with pancreatic SPN diagnosed between 2004 and 2012 using the National Cancer Database. All patients were included in the survival analysis. Kaplan-Meier method, χ 2 , and log-rank tests were used for statistical analysis. Cox proportional hazard regression model was used for multivariate analysis. Results The median age at diagnosis was 36.5 years. Eighty-five percent of patients were female, 69% were white, and 25% were black. Metastases were observed in 5% of patients. Median tumor size was 5.1 cm. Ninety-two percent of patients underwent primary tumor resection. At 60 months, 98% of patients who underwent resection were alive, and 40% who did not undergo resection were alive. On multivariate analysis, female sex, resection of primary tumor, and absence of metastasis were correlated with improved survival. Conclusions Patients with SPN who undergo resection have an excellent survival at 5 years. Surgery should be considered in all patients with this diagnosis.

Pancreatic cancer is the third most common cause of cancer deaths in the United States. Surgical resection with negative margins still constitutes the cornerstone of potentially curative therapy, but is possible only in 15–20% of patients at the time of initial diagnosis. Accumulating evidence suggests that the neoadjuvant approach may improve R0 resection rate in localized resectable and borderline resectable diseases, and potentially downstage locally advanced disease to achieve surgical resection, though the impact on survival is to be determined. Despite advancements in the last decade in developing effective combinational chemo-radio therapeutic options, preoperative treatment strategies, and better peri-operative care, pancreatic cancer continues to carry a dismal prognosis in the majority. Prodigious efforts are currently being made in optimizing the neoadjuvant therapy with a better toxicity profile, developing novel agents, imaging techniques, and identification of biomarkers for the disease. Advancement in our understanding of the tumor microenvironment and molecular pathology is urgently needed to facilitate the development of novel targeted and immunotherapies for this setting. In this review, we detail the current literature on contemporary management of resectable, borderline resectable and locally advanced pancreatic cancer with a focus on future directions in the field.