Correction: Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal. RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively. CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

Direct therapeutic targeting of immune checkpoint PD-1 in pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) hijacks innate cellular processes to promote cancer growth. We hypothesized that PC exploits PD-1/PD-L1 not only to avoid immune responses, but to directly enhance growth. We also hypothesized that immune checkpoint inhibitors (ICIs) have direct cytotoxicity in PC. We sought to elucidate therapeutic targeting of PD-1/PD-L1. METHODS: PD-1 was assessed in PC cells, patient-derived organoids (PDOs), and clinical tissues. Then, PC cells were exposed to PD-L1 to evaluate proliferation. To test PD-1/PD-L1 signaling, cells were exposed to PD-L1 and MAPK was examined. Radio-immunoconjugates with anti-PD-1 drugs were developed to test uptake in patient-derived tumor xenografts (PDTXs). Next, PD-1 function was assessed by xenografting PD-1-knockdown cells. Finally, PC models were exposed to ICIs. RESULTS: PD-1 expression was demonstrated in PCs. PD-L1 exposure increased proliferation and activated MAPK. Imaging PDTXs revealed uptake of radio-immunoconjugates. PD-1 knockdown in vivo revealed 67% smaller volumes than controls. Finally, ICI treatment of both PDOs/PDTXs demonstrated cytotoxicity and anti-MEK1/2 combined with anti-PD-1 drugs produced highest cytotoxicity in PDOs/PDTXs. CONCLUSIONS: Our data reveal PCs innately express PD-1 and activate druggable oncogenic pathways supporting PDAC growth. Strategies directly targeting PC with novel ICI regimens may work with adaptive immune responses for optimal cytotoxicity.

Hydration requirements with emetogenic chemotherapy: granisetron extended-release subcutaneous versus palonosetron.

AIM: This retrospective analysis evaluated chemotherapy-induced nausea and vomiting (CINV)-related hydration needs with palonosetron or granisetron extended-release subcutaneous (GERSC), approved in 2016 for CINV prevention. MATERIALS & METHODS: At a community practice, CINV-related hydration per chemotherapy cycle was determined following highly (HEC) or moderately emetogenic chemotherapy (MEC) and a guideline-recommended antiemetic regimen: NK-1 receptor antagonist, dexamethasone and either palonosetron only, GERSC only, or palonosetron switched to GERSC. RESULTS: Palonosetron-only patients (n = 93) had a significantly higher mean (standard deviation) hydration rate (0.9 [1.1]) than GERSC-only patients (n = 91; 0.3 [0.6]; p < 0.0001). Switched patients' (n = 48) hydration rates were significantly higher in the HEC subgroup with palonosetron (0.7 [1.2]) versus GERSC (0.5 [1.0]; p = 0.028). CONCLUSION: GERSC in a three-drug antiemetic regimen may reduce hydration needs following HEC or MEC. [Formula: see text].

APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy.

AIM: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. METHODS: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). RESULTS: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. CONCLUSION: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

Comprehensive Genomic Profiling of Advanced Esophageal Squamous Cell Carcinomas and Esophageal Adenocarcinomas Reveals Similarities and Differences.

BACKGROUND: Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. CASES: The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations. METHODS: Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of >650× for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanism-driven clinical trials. RESULTS: There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years. All ESCCs and EACs were at an advanced stage at the time of sequencing. All 71 ESCCs and 231 EACs featured GAs on profiling, with 522 GAs in ESCC (7.4 per sample) and 1,303 GAs in EAC (5.6 per sample). The frequency of clinically relevant GAs in ESCC was 94% (2.6 per sample) and 93% in EAC (2.7 per sample). CRGAs occurring more frequently in EAC included KRAS (23% EAC vs. 6% ESCC) and ERBB2 (23% EAC vs. 3% ESCC). ESCC samples were enriched for CRGA in PIK3CA (24% ESCC vs. 10% EAC), PTEN (11% ESCC vs. 4% EAC), and NOTCH1 (17% ESCC vs. 3% EAC). Other GAs that differed significantly between histologic tumor types included SMAD4 (14% EAC vs. 1% ESCC), RB1 (14% ESCC vs. 2% EAC), SOX2 (18% ESCC vs. 1% EAC), and NFE2L2 (24% ESCC vs. 1% EAC). CONCLUSION: ESCC and EAC share similarly high frequencies of overall and clinically relevant genomic alterations; however, the profiles of genomic alterations in the two diseases differ widely, with KRAS and ERBB2 far more frequently altered in EAC compared with ESCC and with mammalian target of rapamycin (MTOR) pathway genes (PIK3CA and PTEN) and NOTCH1 more frequently altered in ESCC compared with EAC. Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.

Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma.

Patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) are treated with salvage regimens and may be considered for high-dose chemotherapy and autologous stem cell transplantation if disease is chemosensitive. Bendamustine is active in indolent B cell lymphomas and chronic lymphocytic leukemia but has not been extensively studied in aggressive lymphomas. This trial examines the combination of bendamustine and rituximab in patients with relapsed and refractory DLBCL. Patients received bendamustine at 90 mg/m² (n = 2) or 120 mg/m² (n = 57) on days 1 and 2 and rituximab at 375 mg/m² on day 1 every 28 days for up to 6 cycles. The study evaluated objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and treatment safety. Fifty-nine patients were treated, and 48 were evaluable for response. Median age was 74; 89 % had stage III or IV disease, and 63 % had high revised International Prognostic Index scores; the median number of prior therapies was 1. Based on analysis using the intent-to-treat population, the ORR was 45.8 % (complete response, 15.3 %; partial response, 30.5 %). The median DOR was 17.3 months, and the median PFS was 3.6 months. Grade 3 or 4 hematological toxicities included neutropenia (36 %), leukopenia (29 %), thrombocytopenia (22 %), and anemia (12 %). The combination of bendamustine and rituximab showed modest activity in patients with relapsed and refractory DLBCL and has an acceptable toxicity profile.

Granisetron Extended-Release Subcutaneous Injection versus Palonosetron Infusion for CINV Prevention: Cost Comparison of Unscheduled Hydration.

Background: Granisetron extended-release subcutaneous (SC) injection is a novel formulation of granisetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Palonosetron is administered intravenously and is indicated for CINV prevention in acute and delayed phases after the use of moderately emetogenic chemotherapy (MEC) and in the acute phase after highly emetogenic chemotherapy (HEC). No data are available regarding the impact of SC granisetron on the cost of unscheduled hydration compared with other antiemetic drugs, specifically the older-generation palonosetron. Objective: To compare the costs of unscheduled hydration associated with breakthrough CINV after SC granisetron versus palonosetron administration in patients receiving MEC or HEC. Methods: This retrospective analysis was based on electronic medical records data from a single multicenter, community-based practice involving patients receiving MEC or HEC with a 3-drug antiemetic regimen, including a neurokinin-1 receptor antagonist, dexamethasone, and either SC granisetron or palonosetron. A cost-of-care analysis for SC granisetron and palonosetron was based on the maximum per-unit Medicare reimbursement amounts for the use of unscheduled hydration, administration of rescue antiemetic drugs, laboratory tests, and patient office evaluations. Results: A total of 182 patient records were evaluated, 91 for patients receiving SC granisetron and 91 receiving palonosetron. The mean per-patient cost of care related to unscheduled hydration in patients receiving HEC or MEC was significantly lower with SC granisetron ($296) than palonosetron ($837; P <.0001), including subset analysis of patients requiring additional care (SC granisetron [$691], N = 39; palonosetron [$1058], N = 72; P = .0260). The mean hydration costs per patient receiving HEC or MEC were lower with SC granisetron ($62) than with palonosetron ($253; P <.0001). The hydration costs per patient receiving only HEC were lower with SC granisetron ($66) than palonosetron ($280; P <.0001). The per-patient costs were lower when SC granisetron was administered than when palonosetron was administered as part of the antiemetic regimen, except for the cost of rescue antiemetic drug in patients receiving MEC. Fewer median unscheduled hydration therapies per patient were used with SC granisetron versus palonosetron (HEC, 3 vs 5; MEC, 2 vs 3). Conclusion: The use of SC granisetron reduced the total per-patient costs of care associated with unscheduled hydration compared with palonosetron in patients receiving HEC or MEC for breakthrough CINV events.

Granisetron Extended-Release Subcutaneous Injection versus Palonosetron Infusion for CINV Prevention: Cost Comparison of Unscheduled Hydration.

Background: Granisetron extended-release subcutaneous (SC) injection is a novel formulation of granisetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV). Palonosetron is administered intravenously and is indicated for CINV prevention in acute and delayed phases after the use of moderately emetogenic chemotherapy (MEC) and in the acute phase after highly emetogenic chemotherapy (HEC). No data are available regarding the impact of SC granisetron on the cost of unscheduled hydration compared with other antiemetic drugs, specifically the older-generation palonosetron. Objective: To compare the costs of unscheduled hydration associated with breakthrough CINV after SC granisetron versus palonosetron administration in patients receiving MEC or HEC. Methods: This retrospective analysis was based on electronic medical records data from a single multicenter, community-based practice involving patients receiving MEC or HEC with a 3-drug antiemetic regimen, including a neurokinin-1 receptor antagonist, dexamethasone, and either SC granisetron or palonosetron. A cost-of-care analysis for SC granisetron and palonosetron was based on the maximum per-unit Medicare reimbursement amounts for the use of unscheduled hydration, administration of rescue antiemetic drugs, laboratory tests, and patient office evaluations. Results: A total of 182 patient records were evaluated, 91 for patients receiving SC granisetron and 91 receiving palonosetron. The mean per-patient cost of care related to unscheduled hydration in patients receiving HEC or MEC was significantly lower with SC granisetron ($296) than palonosetron ($837; P <.0001), including subset analysis of patients requiring additional care (SC granisetron [$691], N = 39; palonosetron [$1058], N = 72; P = .0260). The mean hydration costs per patient receiving HEC or MEC were lower with SC granisetron ($62) than with palonosetron ($253; P <.0001). The hydration costs per patient receiving only HEC were lower with SC granisetron ($66) than palonosetron ($280; P <.0001). The per-patient costs were lower when SC granisetron was administered than when palonosetron was administered as part of the antiemetic regimen, except for the cost of rescue antiemetic drug in patients receiving MEC. Fewer median unscheduled hydration therapies per patient were used with SC granisetron versus palonosetron (HEC, 3 vs 5; MEC, 2 vs 3). Conclusion: The use of SC granisetron reduced the total per-patient costs of care associated with unscheduled hydration compared with palonosetron in patients receiving HEC or MEC for breakthrough CINV events.

Safety Profile of HTX-019 Administered as an Intravenous Infusion in Patients With Cancer: A Retrospective Analysis.

HTX-019 is a neurokinin 1 receptor antagonist approved for prevention of acute and delayed chemotherapy-induced nausea and vomiting in patients with cancer receiving moderately and highly emetogenic chemotherapy. When administered as a 30-minute intravenous (IV) infusion, HTX-019 has displayed a tolerable and favorable safety profile in healthy subjects. This is the first study to evaluate the safety profile of multiple HTX-019 infusions in patients with cancer. This retrospective analysis shows that HTX-019 administered via IV infusion has a favorable safety profile in patients with cancer, and no new treatment-emergent adverse events were identified.

An open-label, dose-ranging study of Rolontis, a novel long-acting myeloid growth factor, in breast cancer.

This randomized, open-label, active-controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long-acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 µg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to <1.5 × 109 /L. Up to four cycles of TC were investigated. The difference in DSN (time from ANC <0.5 × 109 /L to ANC recovery ≥2.0 × 109 /L) between the Rolontis and pegfilgrastim groups was -0.28 days (confidence interval [CI]: -0.56, -0.06) at 270 µg/kg, 0.14 days (CI: -0.28, 0.64) at 135 µg/kg, and 0.72 days (CI: 0.19, 1.27) at 45 µg/kg. Noninferiority to pegfilgrastim was demonstrated at 135 µg/kg (P = 0.002) and 270 µg/kg (P < .001), with superiority demonstrated at 270 µg/kg (0.03 days; P = 0.023). The most common treatment-related adverse events (AEs) were bone pain, myalgia, arthralgia, back pain, and elevated white blood cell counts, with similar incidences across groups. All doses of Rolontis were well tolerated, and no new or significant treatment-related toxicities were observed. In Cycle 1, Rolontis demonstrated noninferiority at the 135 µg/kg dose and statistical superiority in DSN at the 270 µg/kg dose when compared to pegfilgrastim.

Poly-ligand profiling differentiates trastuzumab-treated breast cancer patients according to their outcomes.

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.

Health-Related Quality of Life in Patients with Metastatic Pancreatic Cancer.

PURPOSE: Due to its clinical course and often-late detection, many patients with metastatic pancreatic cancer (mPC) experience poor quality of life (QoL). This pilot project assessed real-world QoL in patients with mPC at different stages of treatment. METHODS: A cross-sectional survey was conducted in the following groups of patients with mPC: before initiation of first-line (1L) chemotherapy (no treatment); with partial response (PR) or stable disease (SD) upon receipt of ≥3 cycles of 1L nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine PR or SD); and with disease progression during ≥1L chemotherapy and not currently receiving nab-paclitaxel (≥1L PD). Eligible participants completed three QoL instruments, EORTC QLQ-C30, the pancreatic cancer module of EORTC QLQ-PAN26, and the EQ-5D, during their clinical visits at 14 clinics across the USA. RESULTS: Demographic characteristics were similar among groups (no treatment, n = 29; nab-paclitaxel plus gemcitabine PR or SD, n = 26; ≥1L PD, n = 17). Patients in the nab-paclitaxel plus gemcitabine PR or SD group had lower mean pain scores by EORTC-QLQ-C30 (27.6 vs 47.1; P = 0.02) and lower mean pancreatic pain scores by EORTC-QLQ-PAN26 (27.9 vs 45.4; P = 0.02) compared with the no treatment group. The groups did not differ significantly in QoL as measured by the EQ-5D. CONCLUSIONS: Patients who experienced PR or SD with 1L nab-paclitaxel plus gemcitabine had improved general and pancreatic pain scores and no clinically meaningful deterioration in QoL compared with patients who had not yet initiated chemotherapy.

APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide-based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial.

BACKGROUND: APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. PATIENTS AND METHODS: This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24-120 hours) complete response (CR). RESULTS: APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0-120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. CONCLUSION: APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging.

The organomercurial 4-aminophenylmercuric acetate, independent of matrix metalloproteinases, induces dose-dependent activation/inhibition of platelet aggregation.

Matrix metalloproteinases (MMPs) play an important role in many biological and pathological processes including tissue remodeling, wound healing, inflammation, atherosclerosis, and cancer. Numerous publications have supported the concept that activated MMP-2 enhances agonist-induced platelet aggregation and activated MMP-9 inhibits platelet aggregation. In this study, we demonstrated that the organomercurial compound, 4-aminophenyl mercuric acetate (APMA), which is routinely employed to activate latent MMPs at a concentration of 1000 microM, induces platelet aggregation at low concentration (5 microM) and inhibits agonist-induced platelet aggregation at concentrations >or= 50 microM. Activated MMP-2, MMP-1, and MMP-9, following removal of APMA by ultrafiltration through an anisotropic membrane, exert no independent effect on platelet aggregation. Acetylsalicylic acid and BAPTA inhibited APMA-induced platelet aggregation indicating that the APMA mediated pathway of platelet activation is dependent upon thromboxane and calcium signaling. Zinc chelation with 1,10-phenanthroline, which inhibits zinc-dependent proteins including metalloproteinases, also abrogated platelet functional responses to APMA. Additional studies will be required to clarify the mechanism of the biphasic effect of APMA on platelet aggregation.