Results of a Randomized, Double-Blind, Placebo-Controlled, Phase 1b/2 Trial of Nabpaclitaxel + Gemcitabine ± Olaratumab in Treatment-Naïve Participants with Metastatic Pancreatic Cancer.

The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Impact of Recombinant Granulocyte Colony-Stimulating Factor During Neoadjuvant Therapy on Outcomes of Resected Pancreatic Cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by chronic inflammation and a tolerogenic immune response. The granulocyte colony-stimulating factor (G-CSF)-neutrophil axis promotes oncogenesis and progression of PDAC. Despite frequent use of recombinant G-CSF in the management and prevention of chemotherapy-induced neutropenia, its impact on oncologic outcomes of patients with resected PDAC is unclear. PATIENTS AND METHODS: This cohort study assessing the impact of G-CSF administration was conducted on 351 patients with PDAC treated with neoadjuvant therapy (NAT) and pancreatic resection at a high-volume tertiary care academic center from 2014 to 2019. Participants were identified from a prospectively maintained database and had a median follow-up of 45.8 months. RESULTS: Patients receiving G-CSF (n=138; 39.3%) were younger (64.0 vs 66.7 years; P=.008), had lower body mass index (26.5 vs 27.9; P=.021), and were more likely to receive 5-FU-based chemotherapy (42.0% vs 28.2%; P<.0001). No differences were observed in baseline or clinical tumor staging. Patients receiving G-CSF were more likely to have an elevated (>5.53) post-NAT neutrophil-to-lymphocyte ratio (45.0% vs 29.6%; P=.004). G-CSF recipients also demonstrated higher circulating levels of neutrophil extracellular traps (+709 vs -619 pg/mL; P=.006). On multivariate analysis, G-CSF treatment was associated with perineural invasion (hazard ratio [HR], 2.65; 95% CI, 1.16-6.03; P=.021) and margin-positive resection (HR, 1.67; 95% CI, 1.01-2.77; P=.046). Patients receiving G-CSF had decreased overall survival (OS) compared with nonrecipients (median OS, 29.2 vs 38.7 months; P=.001). G-CSF administration was a negative independent predictor of OS (HR, 2.02; 95% CI, 1.45-2.79; P<.0001). In the inverse probability weighted analysis of 301 matched patients, neoadjuvant G-CSF administration was associated with reduced OS. CONCLUSIONS: In patients with localized PDAC receiving NAT prior to surgical extirpation, G-CSF administration may be associated with worse oncologic outcomes and should be further evaluated.

Defining the Values and Quality of Life of Cancer Survivors Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An International Survey Study.

BACKGROUND: Advances in treatment of peritoneal surface malignancies including cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS±HIPEC) have led to long-term survivorship, yet the subsequent quality of life (QOL) and values of these patients are unknown. PATIENTS AND METHODS: Survivors were offered surveys via online support groups. Novel items assessed how patients prioritized experience, costs, longevity, and wellbeing. RESULTS: Of the 453 gastrointestinal/hepatobiliary (GI/HPB) surgical patients that responded, 74 underwent CRS±HIPEC and were 54±12 years old, 87% female, and 93% white. Respondents averaged 29 months from diagnosis, with a maximum survival of 20 years. With a moderate level of agreement (W = 39%), rankings of value metrics among respondents were predictable (p < 0.001). Longevity and functional independence were ranked highest; treatment experience and cost of treatment were ranked lowest (p < 0.001). Those who underwent CRS±HIPEC or other GI/HPB surgeries reported the same rank order. QOL in CRS±HIPEC survivors, both mental (M-QOL) (44±13) and physical (P-QOL) (41±11) were lower than in the general population (50±10); p < 0.001. Impairments persisted throughout survivorship, but M-QOL improved over time (p < 0.05). When comparing CRS±HIPEC with other GI/HPB cancer surgery survivors, M-QOL (43±13 versus 43±14, p = 0.85) and P-QOL (40±11 versus 42±12, p = 0.41) were similar. CONCLUSIONS: Although CRS±HIPEC survivors experience long-term mental and physical health impairments, they were similar to those experienced by survivors of other GI/HPB cancer surgeries, and their QOL improved significantly throughout survivorship. As CRS±HIPEC survivors prioritize longevity above all other metrics, survival benefit may outweigh a temporary reduction in QOL.

Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration.

PURPOSE: Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting. EXPERIMENTAL DESIGN: Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing. RESULTS: Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome. CONCLUSIONS: Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

No survival benefit with suboptimal CA19-9 response: defining effective neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer.

BACKGROUND/PURPOSE: Neoadjuvant chemotherapy (NAC) is gaining popularity over a surgery-first (SF) approach in treating resectable and borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, what constitutes effective neoadjuvant chemotherapy is unknown. METHODS: We retrospectively analyzed resectable and borderline resectable PDAC patients who underwent pancreaticoduodenectomy (2010-2019) at a single institution. Optimal CA19-9 response was defined as normalization AND >50% reduction. We utilized Kaplan-Meier and multivariable-adjusted Cox models and competing risk subdistribution methods for statistical analysis. RESULTS: 586 patients were included in this study. The multivariable-adjusted analysis demonstrated OS benefit in the NAC group only when OS was calculated from diagnosis (HR = 0.72, p = 0.02), but not from surgery (HR = 0.81, p = 0.1). However, in 59 patients who achieved optimal CA19-9 response, OS is significantly longer than the 134 patients with suboptimal CA19-9 response (39.3 m vs. 21.5 m, p = 0.005) or the 117 SF patients (39.3 m vs. 19.5 m, p < 0.001). Notably, a suboptimal CA19-9 response conferred no OS advantage compared to SF patients. The accumulative incidence of liver metastases (but not other metastases) was significantly reduced only in patients with optimal CA19-9 response to NAC (multivariable-adjusted subdistribution HR = 0.26, p = 0.03). CONCLUSION: CA19-9 response to NAC may serve as the marker for effective NAC. These findings warrant validation in a multi-institutional study.

The use of angiotensin system inhibitors correlates with longer survival in resected pancreatic adenocarcinoma patients.

BACKGROUND: Activities and inhibition of the Renin-Angiotensin-Aldosterone System (RAAS) may affect the survival of resected pancreatic ductal adenocarcinoma (PDAC) patients METHOD: A single-institution retrospective analysis of resected PDAC patients between 2010 and 2019. To estimate the effect of angiotensin system inhibitors (ASIs) on patient survival, we performed Kaplan Meier analysis, Cox Proportional Hazards model, Propensity Score Matching (PSM), and inverse probability weighting (IPW) analysis. RESULTS: 742 patients were included in the analysis. The average age was 67.0 years, with a median follow-up of 24.1 months. The use of ASI was associated with significantly longer overall survival in univariate (p = 0.004) and multivariable (HR = 0.70 [0.56-0.88],p = 0.003) adjusted analysis. In a propensity score-matched cohort of 400 patients, ASI use was again associated with longer overall survival (p = 0.039). Lastly, inverse probability weighting (IPW) analysis suggested that the use of ASI was associated with an average treatment effect on the treated (ATT) of HR = 0.68 [0.53-0.86],p = 0.002) for overall survival. CONCLUSION: In this single-institution retrospective study focusing on resected PDAC patients, the use of ASI was associated with longer overall survival in multiple statistical models. Prospective clinical trials are needed before routine clinical implementation of ASI as an adjuvant to existing therapy can be recommended.

Evaluation of Adjuvant Chemotherapy Survival Outcomes Among Patients With Surgically Resected Pancreatic Carcinoma With Node-Negative Disease After Neoadjuvant Therapy.

Importance: Neoadjuvant therapy (NAT) is rarely associated with a complete histopathologic response in patients with pancreatic ductal adenocarcinoma (PDAC) but results in downstaging of regional nodal disease. Such nodal downstaging after NAT may have implications for the use of additional adjuvant therapy (AT). Objectives: To examine the prognostic implications of AT in patients with node-negative (N0) disease after NAT and to identify factors associated with progression-free (PFS) and overall survival (OS). Design, Setting, and Participants: A retrospective review was conducted using data from 2 high-volume, tertiary care academic centers (University of Pittsburgh Medical Center and the Medical College of Wisconsin). Prospectively maintained pancreatic cancer databases at both institutes were searched to identify patients with localized PDAC treated with preoperative therapy and subsequent surgical resection between 2010 and 2019, with N0 disease on final histopathology. Exposures: Patients received NAT consisting of chemotherapy with or without concomitant neoadjuvant radiation (NART). For patients who received NART, chemotherapy regimens were gemcitabine or 5-fluoururacil based and included stereotactic body radiotherapy (SBRT) or intensity-modulated radiation therapy (IMRT) after all intended chemotherapy and approximately 4 to 5 weeks before anticipated surgery. Adjuvant therapy consisted of gemcitabine-based therapy or FOLFIRINOX; when used, adjuvant radiation was commonly administered as either SBRT or IMRT. Main Outcomes and Measures: The association of AT with PFS and OS was evaluated in the overall cohort and in different subgroups. The interaction between AT and other clinicopathologic variables was examined on Cox proportional hazards regression analysis. Results: In this cohort study, 430 consecutive patients were treated between 2010 and 2019. Patients had a mean (SD) age of 65.2 (9.4) years, and 220 (51.2%) were women. The predominant NAT was gemcitabine based (196 patients [45.6%]), with a median duration of 2.7 cycles (IQR, 1.5-3.4). Neoadjuvant radiation was administered to 279 patients (64.9%). Pancreatoduodenectomy was performed in 310 patients (72.1%), and 160 (37.2%) required concomitant vascular resection. The median lymph node yield was 26 (IQR, 19-34); perineural invasion (PNI), lymphovascular invasion (LVI), and residual positive margins (R1) were found in 254 (59.3%), 92 (22.0%), and 87 (21.1%) patients, respectively. The restricted mean OS was 5.2 years (95% CI, 4.8-5.7). On adjusted analysis, PNI, LVI, and poorly differentiated tumors were independently associated with worse PFS and OS in N0 disease after NAT, with hazard ratios (95% CIs) of 2.04 (1.43-2.92; P < .001) and 1.68 (1.14-2.48; P = .009), 1.47 (1.08-1.98; P = .01) and 1.54 (1.10-2.14; P = .01), and 1.90 (1.18-3.07; P = .008) and 1.98 (1.20-3.26; P = .008), respectively. Although AT was associated with prolonged survival in the overall cohort, the effect was reduced in patients who received NART and strengthened in patients with PNI (AT × PNI interaction: hazard ratio, 0.55 [95% CI, 0.32-0.97]; P = .04). Conclusions and Relevance: The findings of this cohort study suggest a survival benefit for AT in patients with N0 disease after NAT and surgical resection. This survival benefit may be most pronounced in patients with PNI.

Neoadjuvant Therapy Versus Upfront Resection for Nonpancreatic Periampullary Adenocarcinoma.

BACKGROUND: In contrast to pancreatic ductal adenocarcinoma (PDAC), neoadjuvant therapy (NAT) for periampullary adenocarcinomas is not well studied, with data limited to single-institution retrospective reviews with small cohorts. We sought to compare outcomes of NAT versus upfront resection (UR) for non-PDAC periampullary adenocarcinomas. PATIENTS AND METHODS: Using the National Cancer Database (NCDB), we identified patients who underwent surgery for extrahepatic cholangiocarcinoma, ampullary adenocarcinoma, or duodenal adenocarcinoma from 2006 to 2016. We compared outcomes between NAT versus UR groups for each tumor subtype with 1:3 propensity score matching. Cox regression was used to identify predictors of survival. RESULTS: Among 7656 patients who underwent resection for non-PDAC periampullary adenocarcinoma, the proportion of patients who received NAT increased from 6 to 11% for cholangiocarcinoma (p < 0.01), 1 to 4% for ampullary adenocarcinoma (p = 0.01), and 5 to 8% for duodenal adenocarcinoma (p = 0.08). Length of stay, readmission, and 30-day mortality were comparable between NAT and UR. All tumor subtypes were downstaged following NAT (p < 0.01). The R0 resection rate was significantly higher in patients with extrahepatic cholangiocarcinoma who received NAT, and these patients had improved median overall survival (38 vs 26 months, p < 0.001). After adjustment for clinicopathologic factors and adjuvant chemotherapy, use of NAT was associated with improved survival in patients with cholangiocarcinoma [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.54-0.89, p = 0.004] but not duodenal or ampullary adenocarcinoma. The survival advantage for cholangiocarcinoma persisted after propensity matching. CONCLUSION: This national cohort analysis suggests, for the first time, that neoadjuvant therapy is associated with improved survival in patients with extrahepatic cholangiocarcinoma.

Adaptive Dynamic Therapy and Survivorship for Operable Pancreatic Cancer.

Importance: Neoadjuvant therapy is increasingly used in localized pancreatic carcinoma, and survival is correlated with carbohydrate antigen 19-9 (CA19-9) levels and histopathologic response following neoadjuvant therapy. With several regimens now available, the choice of chemotherapy could be best dictated by response to neoadjuvant therapy (as measured by CA19-9 levels and/or pathologic response), a strategy defined herein as adaptive dynamic therapy. Objective: To evaluate the association of adaptive dynamic therapy with oncologic outcomes in patients with surgically resected pancreatic cancer. Design, Setting, and Participants: This retrospective cohort study included patients with localized pancreatic cancer who were treated with either gemcitabine/nab-paclitaxel or fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) preoperatively between 2010 and 2019 at a high-volume tertiary care academic center. Participants were identified from a prospectively maintained database and had a median follow-up of 49 months. Data were analyzed from October 17 to November 24, 2020. Exposures: The adaptive dynamic therapy group included 219 patients who remained on or switched to an alternative regimen as dictated by CA19-9 response and for whom the adjuvant regimen was selected based on CA19-9 and/or pathologic response. The nonadaptive dynamic therapy group included 103 patients who had their chemotherapeutic regimen selected independent of CA19-9 and/or tumoral response. Main Outcomes and Measures: Prognostic implications of dynamic perioperative therapy assessed through Kaplan-Meier analysis, Cox regression, and inverse probability weighted estimators. Results: A total of 322 consecutive patients (mean [SD] age, 65.1 [9] years; 162 [50%] women) were identified. The adaptive dynamic therapy group, compared with the nonadaptive dynamic therapy group, had a more pronounced median (IQR) decrease in CA19-9 levels (-80% [-92% to -56%] vs -45% [-81% to -13%]; P < .001), higher incidence of complete or near-complete tumoral response (25 [12%] vs 2 [2%]; P = .007), and lower median (IQR) number of lymph node metastasis (1 [0 to 4] vs 2 [0 to 4]; P = .046). Overall survival was significantly improved in the dynamic group compared with the nondynamic group (38.7 months [95% CI, 34.0 to 46.7 months] vs 26.5 months [95% CI, 23.5 to 32.9 months]; P = .03), and on adjusted analysis, dynamic therapy was independently associated with improved survival (hazard ratio, 0.73; 95% CI, 0.53 to 0.99; P = .04). On inverse probability weighted analysis of 320 matched patients, the average treatment effect of dynamic therapy was to increase overall survival by 11.1 months (95% CI, 1.5 to 20.7 months; P = .02). Conclusions and Relevance: In this cohort study that sought to evaluate the role of adaptive dynamic therapy in localized pancreatic cancer, selecting a chemotherapeutic regimen based on response to preoperative therapy was associated with improved survival. These findings support an individualized and in vivo assessment of response to perioperative therapy in pancreatic cancer.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis.

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .

The Role of Adjuvant Chemotherapy Following Right Hemicolectomy for Non-metastatic Mucinous and Nonmucinous Appendiceal Adenocarcinoma.

BACKGROUND: Appendiceal adenocarcinoma (AA) represents a heterogenous group of neoplasms with distinct histologic features. The role and efficacy of adjuvant chemotherapy (AC) in non-metastatic disease remain controversial. The aim of this study was to ascertain the role of AC in non-metastatic AA in a national cohort of patients. METHODS: The National Cancer Database (NCDB) was queried to identify patients diagnosed with stage I-III mucinous and nonmucinous AA who underwent right hemicolectomy between 2006 and 2016. Kaplan-Meier and Cox regression analyses were used to evaluate the impact of AC on overall survival (OS) stratified by each pathologic stage. RESULTS: A total of 1433 mucinous and 1954 nonmucinous AA were identified; 578 (40%) and 722 (40%) received AC respectively. In both AC groups, there was a higher proportion of T4 disease, lymph node metastasis, pathologic stage III, and poorly/undifferentiated grade (all P<0.05). On unadjusted analysis, there was no significant association between AC and OS for stage I-III mucinous AA. For nonmucinous AA, AC significantly improved OS only for stage II and III disease. On adjusted analysis, AC was independently associated with an improved OS for stage III nonmucinous AA (HR: 0.61, 95%CI 0.45-0.84, P=0.002), while for mucinous AA, AC was associated with worse outcomes for stage I/II disease (HR: 1.4, 95%CI 1.02-1.91, P=0.038) and had no significant association with OS for stage III disease. CONCLUSION: This current analysis of a national cohort of patients suggests a beneficial role for AC in stage III nonmucinous AA and demonstrates no identifiable benefit for stage I-III mucinous AA.

Non-functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size.

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.

Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome.

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

Encouraging long-term survival following autophagy inhibition using neoadjuvant hydroxychloroquine and gemcitabine for high-risk patients with resectable pancreatic carcinoma.

INTRODUCTION: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort. METHODS: A review of patients enrolled between July 2010 and February 2013 in the completed phase I/II single arm (two doses of fixed-dose gemcitabine (1500 mg/m2 ) in combination with oral hydroxychloroquine administered for 31 consecutive days until the day of surgery for high-risk pancreatic cancer) was undertaken. Progression-free survival (PFS) and overall survival analysis (OS) using Kaplan-Meier estimates were performed. RESULTS: Of 35 patients initially enrolled, 29 patients underwent surgical resection (median age at diagnosis: 62 years, 45% females). Median duration of follow-up was 7.5 years. There was a median 15% decrease in the serum CA19-9 levels following completion of neoadjuvant therapy and 83% of the cohort underwent a pancreaticoduodenectomy, 7 (24%) patients had a concomitant venous resection. On histopathology, 14 (48%) patients had at least a partial treatment response. The median PFS and OS were 11 months (95% Confidence interval [CI]: 7-28) and 31 months (95% CI: 13-47), respectively, while 9 (31%) patients survived beyond 5 years from diagnosis; a rate that compares very favorably with contemporaneous series. CONCLUSION: Compared to historical data, neoadjuvant autophagy inhibition with HCQ plus gemcitabine is associated with encouraging long-term survival for patients with PDAC.

Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Liposomal Irinotecan.

BACKGROUND: The NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this. METHODS: This real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology. RESULTS: There were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score <2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively. CONCLUSIONS: Patients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit.

Optimal management of patients with operable pancreatic head cancer: A Markov decision analysis.

INTRODUCTION: Neoadjuvant therapy (NAT) is an emerging strategy for operable pancreatic ductal adenocarcinoma (PDAC). While NAT increases multimodal therapy completion, it risks functional decline and treatment dropout. We used decision analysis to determine optimal management of localized PDAC and consider risks faced by elderly patients. METHODS: A Markov cohort decision analysis model evaluated treatment options for a 60-year-old patient with resectable PDAC: (1) upfront pancreaticoduodenectomy or (2) NAT. One-way and probabilistic sensitivity analyses were performed. A subanalysis considered the scenario of a 75-year-old patient. RESULTS: For the base case, NAT offered an incremental survival gain of 4.6 months compared with SF (overall survival: 26.3 vs. 21.7 months). In one-way sensitivity analyses, findings were sensitive to recurrence-free survival for NAT patients undergoing adjuvant, probability of completing NAT, and probability of being resectable at exploration after NAT. On probabilistic analysis, NAT was favored in a majority of trials (97%) with a median survival benefit of 5.1 months. In altering the base case for the 75-year-old scenario, NAT had a survival benefit of 3.8 months. CONCLUSIONS: This analysis demonstrates a significant benefit to NAT in patients with localized PDAC. This benefit persists even in the elderly cohort.