Combination Of Nab-paclitaxel Research Articles

Serial single-cell profiling analysis of metastatic TNBC during Nab-paclitaxel and pembrolizumab treatment.

Immunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy. Both patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3weeks (after cycle 1, chemotherapy alone) and 6weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing. ScRNA-seq analysis showed significant baseline heterogeneity of tumor-infiltrating immune cell populations between the two patients as well as modulation of the tumor microenvironment by chemotherapy and immunotherapy. In the responding patient there was a population of PD-1high-expressing T cells which significantly decreased after nab-paclitaxel plus pembrolizumab treatment as well as a presence of tissue-resident memory T cells (TRM). In contrast, tumors from thepatientwith rapid disease progressionshowed a prevalent and persistent myeloid compartment. Our study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor.

Abstract 5535: SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.

Study protocol for an open-label, single-arm, phase Ib/II study of combination of toripalimab, nab-paclitaxel, and gemcitabine as the first-line treatment for patients with unresectable pancreatic ductal adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a fatal disease with a dismal response to single-use of immune checkpoint inhibitors (ICIs). ICIs combined with systemic therapy has shown efficacy and safety in various solid tumors. Nab-paclitaxel and gemcitabine (AG), as the standard first-line treatment for advanced PDAC, has been widely used in recent years. The combination of ICIs and AG chemotherapy appears to be a promising option in the treatment of PDAC.MethodsThis is an open-label, single-arm, and single-center phase Ib/II trial. The enrolled subjects are the unresectable (locally advanced or metastatic) PDAC patients without previous systemic treatments. All subjects receive an intravenous injection of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 on day 1 and day 8, along with toripalimab 240 mg at day 1 every 3 weeks. The subjects may discontinue the treatment because of progression disease (PD), intolerable toxicities, requirements of patients or researchers. For local advanced patients who are evaluated as partial response (PR), surgeons need to assess the surgical possibility. The primary objective of this trial is to evaluate the safety and overall survival (OS) of this combination therapy; and the secondary objective is related to the assessment of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and the rate of resection or R0 resection after receiving toripalimab plus AG treatment. Besides, we expect to identify the predictive biomarkers (such as MMR protein and PD-L1 expression, the number of TILs, the small RNA of EBV and so on) and explore the correlation between these biomarkers and tumor response to this combined regimen.DiscussionThis trial is the first attempt to evaluate the efficacy and safety of the combination of toripalimab plus AG chemotherapy as a first-line treatment for unresectable PDAC patients. The results of this phase Ib/II study will provide preliminary evidence for further assessment of this combined therapeutic regimen for unresectable PDAC patients.Trial registrationTrial registration: ChiCTR (ChiCTR2000032293). Registered 25 April 2020 - Retrospectively registered.

Adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine alone for resected pancreatic ductal adenocarcinoma: A single center experience in China.

Nab-paclitaxel plus gemcitabine (AG) has resulted in higher tumor response and survival rates for metastatic or advanced pancreatic ductal adenocarcinoma (PDAC) compared with gemcitabine (GEM) alone. To examine the feasibility and safety of AG adjuvant chemotherapy of resectable PDAC. We retrospectively analyzed patients with resected PDAC who received AG or GEM as postoperative adjuvant treatment between January 2013 and December 2016 at the Chinese People's Liberation Army General Hospital, Beijing, China. The patients adopted combined nab-paclitaxel (125 mg/m2) and GEM (1 g/m2) or GEM (1 g/m2) alone treatment, on days 1 and 8 every 3 wk for six cycles, unless intolerable adverse events or disease progression occurred. The disease-free survival, overall survival (OS) and adverse events of the two groups were statistically analyzed. Compared with GEM, median disease-free survival (12.2 mo vs 15.8 mo, P = 0.039) and OS (20.6 mo vs 28.3 mo, P = 0.028) were significantly improved in the AG group. The 2-year OS rates were 63.3% and 43.3% in the AG and GEM groups, respectively. However, the incidence of sensory neuropathy was increased significantly in the AG than the GEM group (53.3% vs 23.3%, P < 0.001). In our initial experience, AG significantly improved disease-free survival and OS of patients with resected PDAC. AG may be a potential option for postoperative adjuvant chemotherapy of resectable PDAC.

Комбинация гемцитабина и наб-паклитаксела у больных местнораспространенным и генерализованным раком поджелудочной железы

Комбинация гемцитабина и наб-паклитаксела у больных местнораспространенным и генерализованным раком поджелудочной железы

Metastatic triple-negative breast cancer: Established and emerging treatments.

Metastatic triple-negative breast cancer (mTNBC) patients tend to have a poor overall survival. The primary goals of treatment focus on palliation of symptoms and improvement in overall survival (OS). Single-agent sequential chemotherapy with anthracycline or taxane has remained the cornerstone of treatment for many years. The FDA has approved newer agents such as poly-adenosine diphosphate-ribose polymerase (PARP) inhibitors upfront in germline BRCA (gBRCA) 1/2 mutation carriers; atezolizumab and nab-paclitaxel combination frontline in patients with PD-L1 expression >1%; and sacituzumab govitecan (IMMU-132), an antibody-drug conjugate in heavily pretreated mTNBC patients.

Immune Checkpoint Blockade in Patients with Triple-Negative Breast Cancer.

Triple-negative breast cancer constitutes ~ 15% of all breast cancer subtypes. Because of the negative hormone receptor and human epidermal growth factor receptor 2 status, therapy is mainly based on chemotherapy with a poor median overall survival in the metastatic setting of ~ 18months. Compared to other breast cancer subtypes, triple-negative breast cancer is characterized by a higher mutational load, which renders the tumor immunogenic and amenable to immunotherapeutic intervention. Based on the promising results of immunotherapy in other cancer entities, including melanoma or non-small cell lung cancer, a vast number of studies are currently assessing immunotherapeutic approaches in patients with triple-negative breast cancer. While monotherapies with antibodies against programmed death-1 and programmed death ligand-1 have shown little efficacy in patients with heavily pretreated metastatic triple-negative breast cancer, treatment efficacy likely depends on the therapeutic setting, the treatment line, and the combination of immunotherapies with other anticancer drugs. Several studies are currently evaluating the safety and efficacy of immune checkpoint inhibition in combination with chemotherapy, angiogenesis inhibitors, poly(ADP-ribose) polymerase inhibitors, as well as radiotherapy in the metastatic and (neo-)adjuvant settings. The US Food and Drug Administration approval of nab-paclitaxel in combination with atezolizumab in 2019 presented a landmark therapeutic development for patients with triple-negative breast cancer, given the limited treatment options available for this highly aggressive disease. In this review, we provide an overview on important ongoing and completed immunotherapeutic studies in triple-negative breast cancer and their possible implications for clinical practice.

Pharmacoeconomic analysis of atezolizumab plus nab-paclitaxel in the treatment of the advanced or metastatic triple-negative breast cancer

Objective.To determine the pharmacoeconomical feasibility of using a combination of atezolizumab + nab-paclitaxel in the 1st line of therapy for locally advanced or metastatic triple negative breast cancer (TNBC) in adult PDL1 positive patients in the Russian healthcare system.Materials and methods.A decision analysis model was used followed by Markov modelling for the economic evaluation of the drugs in the treatment of metastatic TNBC. We used the «cost-effectiveness» analysis and the «impact on the budget» (BIA) analysis. Two therapeutic approaches were evaluated: the use of combined therapy with atezolizumab + nab-paclitaxel and monotherapy with nab-paclitaxel. The analysis included direct costs. Additionally, the obtained pharmacoeconomical indicators of the use of a combination of atezolizumab and nab-paclitaxel and other drugs for the treatment of locally advanced and metastatic breast cancer were compared.Results. The use of the estimated therapeutic approaches in the treatment of metastatic TNBC was characterized by the following costs: with a modelling horizon of 1 year, the cost of using atezolizumab in combination with nab-paclitaxel was 5,076,321 rubles per patient. The costs for the use of single agent nab-paclitaxel with was 60 % less than: — 2 020 038,78 RUB. At the same time, the effectiveness of therapy with a combination of atezolizumab and nab-paclitaxel clinically significantly exceeded that of nab-paclitaxel monotherapy: a 38 % reduction in the risk of death or progression, a 10-fold increase in the frequency of complete response to therapy (10 vs 1 %), and a 7-month increase in the median overall survival (25 vs 18 months). The economic evaluation of the combination of atezolizumab with nab-paclitaxel was carried out with the calculation of the incremental cost-effectiveness ratios (ICER) — the calculation of the additional cost for each additional year of life in comparison with standard therapy. Due to the fact that currently in Russia for patients with metastatic TNBC no similar performance modes of therapy ICER for the combination atezolizumab + nab-paclitaxel compared with the ICER for palbociclib in combination with fulvestrant (drugs, showed improved overall survival in clinical research and included in clinical guidelines for the treatment of diseases of the same class ICD-10 in locally advanced and metastatic breast cancer). The ICER for overall survival at the end of the first year of follow-up for atezolizumab + nab-paclitaxel and palbociclib + fulvestrant was 30.5 million rubles and 47.4 million rubles, respectively. For the combination of atezolizumab + nab-paclitaxel, ICER is lower than the similar ICER for the palbociclib + fulvestrant mode by 36 %. Analysis of trends in the weighted average cost of systemic pathogenetic treatment of breast cancer (breast cancer) shows the following: increased use of the combination of atezolizumab + nab-paclitaxel for the treatment of patients with metastatic TNBC doesn’t lead to a considerable growth in the cost of therapy in patients with breast cancer — providing therapy to 1400 patients that includes the entire target population of patients with TNBC and expression of PD-L1 in Russia changes in the costs of chemotherapy and immunotherapy of breast cancer will remain within 2.6 %.Conclusion. Pharmacoeconomic indicators of the use of atezolizumab in combination with nab-paclitaxel are more cost-effective in comparison with other expensive schemes for the treatment of breast cancer, and tumors of other localities that are actively used in current practice, which suggests the acceptability and feasibility of introducing and expanding the use of this therapeutic option in the target population.

Atezolizumab in the treatment of metastatic triple-negative breast cancer

ABSTRACT Introduction Triple-negative breast cancer (TNBC) accounts for approximately 10%-15% of all diagnosed breast cancers and is associated with an aggressive natural history and poor clinical outcomes. Immunotherapy using immune checkpoint inhibitors has emerged as an effective therapeutic option for TNBC. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel in the first-line treatment of patients with unresectable locally advanced or metastatic, PD-L1-positive TNBC. Areas covered This article summarizes the clinical development and ongoing research on atezolizumab in the treatment of metastatic TNBC. Results of atezolizumab monotherapy trials and data from combination studies with chemotherapy in the advanced setting are reviewed, with special focus on the design, methods, and key findings of the IMpassion130 trial. Expert opinion The approval of atezolizumab plus nab-paclitaxel represents an important advance in the treatment of metastatic TNBC. This combination has a favorable risk-benefit profile and is associated with clinically meaningful outcomes. However, further research is needed to identify better predictive biomarkers of response as well as novel immunotherapeutic strategies with atezolizumab and other anticancer drugs.

A phase I trial of nab-paclitaxel/bevacizumab (AB160) nano-immunoconjugate therapy for unresectable stage IV malignant melanoma (MM): MC1371 (NCT02020707).

e22020 Background: The combination of nab-paclitaxel (NP) and bevacizumab (BEV) in patients with MM has shown promising clinical activity. AB160 is a 160 nm nano-immunoconjugate of NP nanoparticles non-covalently coated with BEV for targeted delivery into high VEGF expressing tissues. Preclinical data showed that AB160 improved tumor targeting/ tumor inhibition more than NP followed by BEV. Methods: A 3+3 phase I trial was conducted in patients (pts) with MM who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. Dose level 1 (DL1) was 125 mg/m2 NP /50 mg/m2 BEV. Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT &lt; 25,000, serum creatinine ≥ 2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Tumor evaluations (RECIST) were conducted every 8 weeks. Treatment continued until progression or intolerability. Results: 21 pts (11 ♀) aged 36-78 years old were enrolled. One of the first 3 pts on DL1 developed a G2 colonic perforation; this was considered a DLT. One of the next 3 pts on DL1 had a DLT: G4 neutropenia. Of the 3 pts on DL-1 (100 mg/m2 NP/40 mg/m2 BEV), 2 had no DLTs and 1 died of sepsis after C1D1 dose. Enrollment was suspended until an amendment modifying the eligibility criteria was approved by the IRB. The trial reopened. One of the 4 pts on DL-1 and 1 of the 5 pts on DL1 had a DLT: G3 pain and G3 fatigue, respectively. Enrollment ended after 2 of the 3 pts on DL2 (150 mg/m2 NP/ 60 mg/m2 BEV) developed G4 neutropenia. Thus, MTD is DL1. A median of 3 cycles was administered. Treatment ended due to progression (9), intolerability (9), refusal (2) and death (1). There were no objective tumor responses. Common G3-4 toxicities were: neutropenia (33%) and thromboembolic events (19%). Conclusions: AB160 was found to have insufficient clinical benefit in patients with previously treated MM to justify further development. However, parallel phase I testing in gynecologic cancers suggests clinical benefit (abstract #300225). Clinical trial information: NCT02020707.

A real-world comparison of efficacy and toxicity of FOLFIRINOX and gemcitabine to nab-paclitaxel in treatment of advanced stage pancreatic cancer.

e16728 Background: Pancreatic adenocarcinoma is a dreaded malignancy accounting for 7% of all cancer related deaths in the United States. The two most used chemotherapeutic regimens are a combination of 5- fluorouracil, leucovorin, oxaliplatin and irinotecan (FFX) and a combination of gemcitabine nab paclitaxel (GN). Both improve survival when compared to gemcitabine alone but have not been compared directly. Methods: Retrospective chart review of 83 chemotherapy naïve patients with metastatic cancer of exocrine pancreas who underwent chemotherapy between February 2011 and June 2017. Patients who completed at least one cycle of chemotherapy regimen were included. Characteristics, efficacy and adverse events between the two regimens were compared using appropriate statistical analyses. Results: 83 patients met selection criteria. 39 patients received FFX and 44 received GN. Mean age of FFX and GN patients was 69.7 (SD 8.7) (Median 66) and 72.3 (SD 8.8) (Median 69) yrs respectively (p = 0.100). The proportion of patients with ECOG performance scale ≤1 receiving FFX vs. GN was 50.8% vs. 49.2% and &gt; 2 receiving FFX vs. GN was 33.3% vs 66.7% (p = .286). Of the 23 patients &gt; 75 yrs., 7 received FFX and 16 received GN (p = .086). Median overall survival was 10.1 months (95% CI: 5.4-18.7) in FFX and 7.2 months in GN (95% CI: 5.4-11.3) [p = 0.037]. Median survival based on site of tumor was 10.2 months (95% CI: 6.7-13.8) in head and 10.1 months (95% CI: 4.3-14.7) in body and tail tumors [p = 0.776]. Incidence of vomiting in FFX / GN was 94.1% / 73.7% (p =.027), vomiting requiring hospital admission was 55.9% / 21.1% (p = 0.003). Other events requiring admission included: diarrhea 31.4% / 17.9%; anemia 5.7% / 10.3%; thrombocytopenia 11.4% / 7.7%; febrile neutropenia 28.6% / 12.8% and acute kidney injury 25.7% / 15.4%; no statistically significant differences between groups. Conclusions: Patients treated with FFX had a longer survival in this retrospective review. FFX is associated with an increased incidence of vomiting requiring hospitalization. FFX remains a preferred regimen in treating patients with good performance status regardless of age.

Phase I study of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

TPS4671 Background: SEA-CD40 is an investigational non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40, a co-stimulatory receptor expressed on antigen-presenting cells (APCs). Activation of CD40 on APCs upregulates cytokine production and co-stimulatory receptors, enhancing tumor antigen presentation to T cells. Preclinical data indicate that treatment of PDAC with chemotherapy in conjunction with a CD40 agonist could enhance antigen presentation and initiate an antitumor immune response (Byrne KT and Vonderheide RH, Cell Rep 2016;15, 2719–32). An ongoing Phase 1 study (SGNS40-001) is evaluating SEA-CD40 as monotherapy and in combination with pembrolizumab in patients with advanced solid or hematologic malignancies. A new cohort is enrolling to evaluate the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in PDAC. Methods: The cohort consists of patients with metastatic PDAC who have had no prior therapy for metastatic disease. Patients must be ≥18 years old, with (neo)adjuvant therapy completed &gt;4 months prior to enrollment, ECOG status ≤1, adequate renal, hepatic, and hematologic function, and measurable disease per RECIST v 1.1 criteria. A standard regimen of gemcitabine and nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle is administered with SEA-CD40 IV on Day 3. Pembrolizumab is administered every 42 days starting on Day 8. The primary objective is antitumor activity; secondary objectives are safety and tolerability and SEA-CD40 and pembrolizumab pharmacokinetics. Efficacy endpoints are confirmed RECIST ORR per investigator (primary), disease control rate (response or stable disease ≥16 weeks), duration of response, PFS, and OS. Disease is assessed every 8 weeks using RECIST and immune-based RECIST (iRECIST). Treatment continues until occurrence of unacceptable toxicity, progressive disease per iRECIST, consent withdrawal, or study closure. Assessment of dose-limiting toxicity will occur initially in groups of 6 patients to identify the recommended phase 2 dose of SEA-CD40 for the cohort. Enrollment to this cohort began in November 2019. Clinical trial information: NCT02376699 .

Atezolizumab for the treatment of breast cancer

ABSTRACTIntroduction: In March 2019, atezolizumab became the first immune checkpoint inhibitor to receive a breast cancer-specific approval. Based on a significant improvement in progression-free survival as well as a 10-month improvement in overall survival (on interim analysis) seen in the IMpassion 130 trial, the combination of atezolizumab and nab-paclitaxel was approved for patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC).Areas covered: This article reviews current data and ongoing research on atezolizumab for the treatment of breast cancer. Results of atezolizumab monotherapy trials in the context of other early immune checkpoint blockade trials in breast cancer are discussed as well as data from combination clinical trials with chemotherapy in both early-stage and metastatic breast cancer. We focus on the safety and efficacy analyses from the phase III IMpassion trial that led to FDA and EMA approval of atezolizumab and nab-paclitaxel in patients whose tumor tested positive for PD-L1 by the Ventana SP142 companion diagnostic immunohistochemical assay.Expert opinion: The FDA and EMA approvals of atezolizumab mark an important advance for treatment of metastatic TNBC. However, ongoing investigations need to define better biomarkers of response, determine resistance mechanisms, and identify strategies to increase response rates.

ABLE: single-arm trial of nab-paclitaxel with ANTI-PD1 in advanced urothelial cancer.

520 Background: Anti-PD1 immune checkpoint inhibitor monotherapy is standard in cisplatin ineligible advanced urothelial cancer (aUC) patients (pts) that is PDL1 positive as well as in platinum refractory aUC. Nab-paclitaxel (Abraxane) monotherapy showed an overall response rate (ORR) of 27.7% in platinum refractory aUC. We conducted a single-arm trial of nab-paclitaxel and pembrolizumab in platinum refractory or cisplatin ineligible aUC (NCT03240016). Methods: Eligible pts had RECIST 1.1 measurable disease, grade 1 or lower neuropathy and adequate organ function. Study therapy consisted of nab-paclitaxel at starting dose of 125 mg/m2 IV on days 1 and day 8 and pembrolizumab 200 mg IV on day 1 in 21-day cycles until progression, intolerable toxicity, death or consent withdrawal. Primary endpoint was ORR by RECIST 1.1criteria. Secondary endpoints included safety/toxicity, progression free survival, overall survival, complete response proportion, duration of response (DOR) and duration of therapy (DOT). Results: Seventeen pts were enrolled between 02/2018 to 04/2019; 16 were response evaluable. Seven were of upper tract origin, 14/17 men, mean age 70.9 yrs (52 – 83), 71% pure urothelial, 8/17 platinum refractory; 9/17 cisplatin ineligible by Galsky criteria, and ECOG PS was 0, 1 or 2 in 6, 8 and 3 pts respectively. Unconfirmed ORR was 9/16 (56.25%: 95% CI [30-80%]), confirmed in 7; 14 pts experienced some tumor shrinkage; 2 pts had CR and 7 pts PR. Median DOR was 18 wks (95% CI: 6-NR) and median PFS 5.4 m (95% CI: 3.9-5.7). Pts received a median 6 cycles (range 1-11) with median DOT 4.4 m (0.7-7.6). Median follow up was 5.1 m. Grade ≥3 adverse events (AE) occurred in 15/17 pts including fatigue (n=5), peripheral neuropathy (n=3), anemia (n=3) and oral mucositis (n=3). Five pts had immune mediated AEs including 1 encephalitis; 5 pts discontinued treatment due to AEs, all attributed to nab-paclitaxel. Conclusions: The combination of nab-paclitaxel and pembrolizumab in advanced urothelial cancer exhibited promising activity but with moderate toxicity. A follow-up expansion study with nab-paclitaxel starting dose at 100 mg/m2 in 19 additional pts is being initiated. Correlative studies including PD-L1 expression and TILs are underway. Clinical trial information: NCT03240016.

Abstract PD5-02: Effective and globally reproducible digital pathologist training program on PD-L1 immunohistochemistry scoring on immune cells as a predictive biomarker for cancer immunotherapy in triple negative breast cancer

Abstract BACKGROUND: The VENTANA PD-L1 (SP142) Assay (SP142 assay) is the FDA-approved companion diagnostic for the combination of TECENTRIQ (atezolizumab) and nab-paclitaxel for the treatment of patients with unresectable, locally advanced, or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 - defined as PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥ 1 percent of the tumor area. Accurate and reproducible assessment of IC PD-L1 staining with the SP142 assay by pathologists is important to ensure the right treatment decisions for patients are made. Analytical studies have demonstrated variable agreement rates for PD-L1 IC scoring with the SP142 assay, ranging from low, moderate, strong and near-perfect agreement depending on tumor type, cut-off and prior training. The Roche International Pathologist Training Program has trained over 1000 pathologists globally for the SP142 assay in the indications of non-small cell lung cancer, urothelial carcinoma and TNBC. Here we present results from the TNBC training program. METHODS: The glass-slide based training program for pathologists participating in clinical trials leading to the approval of the SP142 assay was adapted to enable live training to be conducted using a novel digital training platform (Pathomation) which was customized for Roche with a rapid, user-friendly interface, facilitating monitoring of scores and reporting. Feedback and endorsement from a Pathologist Training Expert Committee led to a global Train-the Trainer program which enabled regional training sessions to be conducted using the digital platform. Training content was developed around the FDA-approved 1% IC cut-off and was conducted over a 1-day program. Didactic instruction was followed by case reviews and a final proficiency test consisting of 28 cases, with a passing score of ≥85%. RESULTS: Between 17th November, 2018 and 19th June 2019, 432 pathologists from 58 countries participated in the TNBC training program for the SP142 assay. This includes 1 PTEC, 10 Train-the Trainer Sessions and 24 Regional Training sessions. The passing rate for trainees was 99.1%. Overall percent agreement (OPA) was 98.2%, with positive percent agreement (PPA) 99.4% and negative percent agreement (NPA) 96.6%. CONCLUSION: This is the first formal PD-L1 training program for practicing pathologists to be developed for the assessment of PD-L1 on ICs in TNBC. The SP142 assay training utilizing a novel digital platform demonstrates robust, reproducible and excellent pathologist concordance scores in this real-world program. Citation Format: Eslie Dennis, Mark Kockx, Greg Harlow, Zhuangyu Cai, Ken Bloom, Ehab ElGabry. Effective and globally reproducible digital pathologist training program on PD-L1 immunohistochemistry scoring on immune cells as a predictive biomarker for cancer immunotherapy in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-02.

Abstract MS1-1: Immunotherapy in breast cancer: enhancing response to checkpoint blockade

Abstract Historically, breast tumors have been categorized as non-immunogenic in part due to a paucity of tumor infiltrating lymphocytes (TIL) when compared to other histologies. Multiple studies have now demonstrated an endogenous immune response against breast cancer with tumors having TIL present in the tumor and surrounding stroma. The extent of TIL infiltrate is dictated by the subtype of disease being highest in triple negative breast cancer (TNBC) and lowest in hormone receptor positive, HER2 negative (HR+/HER2-) disease. Recent studies have shown that immunotherapy, in the form of immune checkpoint blockade, can be effective in treating breast cancer patients. Specifically, the IMpassion 130 trial, a phase III study that enrolled over 900 patients with metastatic TNBC and randomized them to the immune checkpoint blockade agent atezolizumab plus nab-paclitaxel versus placebo plus nab-paclitaxel, demonstrated benefit to the addition of immunotherapy with respect to progression free survival as well as overall survival; a difference that was greater in patients with PD-L1 positive disease. Based on these data, the combination of atezolizumab plus nab-paclitaxel was approved for use in patients with PD-L1+ metastatic TNBC. More recently, data from a large phase III trial evaluating the use of the immune checkpoint blockade agent pembrolizumab in the neoadjuvant setting for TNBC patients showed a significant improvement in the rates of pathologic complete response. Based in part on these successes, there is significant enthusiasm for using immunotherapy to treat breast cancer patients. It must be recognized however, that a minority of patients respond. Additional work must therefore be done to expand the number of patients with TNBC who respond as well as to identify strategies for successfully employing immunotherapy for HER2+ and HR+ positive breast cancer. Development of these strategies requires understanding of the cancer immunity cycle and how it can be altered to enhance endogenous immune responses to breast cancer as well as improved understanding of the immune aspects of the tumor microenvironment and how standard of care therapies alter that microenvironment. As an example, there is emerging data showing that PARP inhibition leads to cytoplasmic DNA which activates the STING pathway leading to increased expression of release of type 1 interferons, increased MHC expression and antigen presentation and increased infiltration of effector T cells. Ongoing trials are therefore evaluating those agents in combination with immunotherapy. Our lab has shown that PARP inhibition further modifies the tumor microenvironment suggesting additional therapeutic targets. In addition, there is mounting evidence regarding potential mechanisms behind why some subtypes of breast cancer mount a robust immune response while others remain immunologically “cold”. Differences in antigen processing and presentation likely contribute and understanding how HR+ tumors “hide” from immune recognition could contribute to developing strategies to make these tumors susceptible to immunotherapy. Finally, our group has recently published data demonstrating a difference in susceptibility to immune checkpoint blockade based on age suggesting that a patient’s systemic immune status could predict therapeutic response and potentially be manipulated to enhance that response. Citation Format: E Mittendorf. Immunotherapy in breast cancer: enhancing response to checkpoint blockade [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr MS1-1.

Abstract P2-15-09: Systemic corticosteroid use in patients with metastatic triple-negative breast cancer treated with first-line therapy in the United States

Abstract Background: Corticosteroids (CS) have immunosuppressive properties that may diminish the efficacy of cancer immunotherapy (CIT). In retrospective analyses of clinical trial data, the use of CS for immune-mediated adverse events after starting CIT does not clearly appear to adversely affect outcomes; however, patients (pts) receiving CS at the start of CIT may have shorter overall and progression-free survival (Arbour, J Clin Oncol, 2018). With the increasing use of CIT for pts with metastatic triple-negative breast cancer (mTNBC) following the approval of atezolizumab in combination with nab-paclitaxel, it is important to understand the landscape of CS use as part of first-line (1L) treatment. Here we describe patterns of CS use in pts receiving 1L therapy for mTNBC, with a focus on taxanes. Methods: A total of 974 pts with confirmed mTNBC diagnosed from Jan 1, 2011, to Jul 5, 2018, and treated in the 1L setting from the de-identified Flatiron Health electronic health record-derived database were included in the study. Pts were categorized as having no CS use during 1L treatment, CS use at the start of 1L treatment or CS use after the start of 1L treatment. Results: The median age at mTNBC diagnosis was 60 years. The majority of pts were female (99%), treated at community centers (94%), and had recurrent disease (59%). Among the most common regimens in 1L were those containing capecitabine (n=208), paclitaxel (n=204), or nab-paclitaxel (n=131) (Table 1). Capecitabine was administered as monotherapy more frequently than paclitaxel and nab-paclitaxel (86% vs 67% and 52%, respectively). Most pts receiving capecitabine did not receive CS during 1L therapy (79%), whereas the majority of pts receiving paclitaxel and nab-paclitaxel did (&amp;gt;95% and 78%, respectively). However, among pts treated with nab-paclitaxel, CS use during 1L was more common in pts receiving combination regimens (88%) than those receiving monotherapy (67%). In general, pts who were treated with paclitaxel or nab-paclitaxel and initiated CS use at the start of 1L treatment continued it throughout their 1L treatment. CS was given (orally or intravenously) with 92% of paclitaxel administrations, 67% of nab-paclitaxel monotherapy administrations, 77% of nab-paclitaxel combination therapy administrations, and 81% of administrations when agents were given in combination with capecitabine. Among pts who received nab-paclitaxel monotherapy, pts who used CS during 1L tended to be younger and less likely to have visceral metastases or recurrent disease than pts who did not use CS. Conclusions: Overall, CS use was common at 1L initiation of most regimens used for the treatment of mTNBC, with the exception of capecitabine. Among pts who were treated with taxanes, those who initiated CS at 1L treatment tended to continue CS treatment for the duration of 1L. Despite the lack of requirement for the use of CS with nab-paclitaxel, the majority of pts treated with nab-paclitaxel monotherapy still received CS at the start of 1L treatment, suggesting use as premedication. None of the assessed pt characteristics were associated with CS use in pts who were treated with nab-paclitaxel monotherapy; however, due to widespread use of CS in the population and small sample size, definitive conclusions are difficult. Larger data sets with reasons for CS use are needed to further understand the observed patterns. Table 1CapecitabinePaclitaxelNab-Paclitaxel Othera(n=208)(n=204)(n=431)MonotherapyCombination(n=63)(n=68)Key baseline characteristicsAge at mBC diagnosis, median (IQR), years63 (53, 74)62 (53, 71)63 (57, 72)60 (52, 67)58 (61, 67)White, non-Hispanic, n (%)133 (64)115 (56)35 (56)41 (60)260 (60)De novo mBC, n (%)35 (17)106 (52)22 (35)23 (34)142 (33)mBC diagnosis later than 2015, n (%)112 (54)111 (54)42 (33)38 (56)261 (61)Bone-only mets at diagnosis, n (%)44 (21)38 (19)&amp;lt;5 (&amp;lt;8)11 (16)62 (14)Visceral mets at diagnosis, n (%)118 (57)121 (59)45 (71)37 (54)266 (62)Time from initial to mBC diagnosis (recurrent), median (IQR), months33 (20, 68)40 (23, 83)47 (24, 86)44 (27, 86)30 (17, 57)1L regimen typeMonotherapy, n (%)179 (86)68 (33)63 (100)0 (0)159 (37)Combination therapy, n (%)29 (14)136 (67)068 (100)272 (63)Duration, median (IQR), months3.9 (2.1, 7.0)3.2 (2.0, 4.8)3.2 (1.8, 5.0)5.0 (3.1, 7.3)2.8 (1.6, 4.4)CS use, n (%)No use during 1L164 (79)&amp;lt;6 (&amp;lt;3)21 (33)8 (12)88 (20)Use during 1L44 (21)&amp;gt;198 (&amp;gt;97)42 (67)60 (88)343 (80)Chemotherapy administrations with CS given on the same day, n (%)No39 (19)b177 (8)285 (33)231 (23)820 (27)Yes163 (81)b2104 (92)587 (67)780 (77)2236 (73)a Top 5 other regimens were carboplatin + gemcitabine (n=77), cyclophosphamide + doxorubicin (n=56), eribulin (n=25), carboplatin + docetaxel (n=23), and docetaxel (n=19).b These numbers comprise capecitabine combination regimens only, as chemotherapy administrations did not capture oral capecitabine monotherapy.1L, first-line; CS, corticosteroid; IQR, interquartile range; IV, intravenous injection administration; mBC, metastatic breast cancer; met, metastasis. Citation Format: MK Downer, Patricia Luhn, David Miles, Matthew Kent, Kenneth Russell, Joyce O’Shaughnessy. Systemic corticosteroid use in patients with metastatic triple-negative breast cancer treated with first-line therapy in the United States [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-09.

Multicenter phase I/II study of intravenous gemcitabine + nab-paclitaxel combined with intraperitoneal paclitaxel for pancreatic ductal adenocarcinoma patients with peritoneal metastasis.

702 Background: Pancreatic ductal adenocarcinoma (PDAC) patients with peritoneal metastasis (peritoneal deposits and/or positive peritoneal cytology) have an extremely poor prognosis, and an effective treatment strategy remains elusive. Methods: The aim of this study were to determine the recommended dose (RD) for a combination of intravenous (IV) gemcitabine, intravenous nab-paclitaxel, and intraperitoneal (IP) paclitaxel in chemotherapy-naive PDAC patients with peritoneal metastasis and to evaluate the clinical efficacy and safety. Gemcitabine and nab-paclitaxel was administered IV combined with paclitaxel IP on days 1, 8 and 15, followed by 1 week of rest. The frequency of dose-limiting toxicity was evaluated and the RD was determined. The primary endpoint of the phase II part was 1-year overall survival (OS) rate. The secondary endpoints were antitumor effect, symptom relief effect, safety and OS. Results: In the phase I part, RD for IV gemcitabine, IV nab-paclitaxel and IP paclitaxel were determined as 800 mg/m2, 75 mg/m2, and 20 mg/m2, respectively. A total of 46 patients were enrolled in the phase II part and drugs were delivered at the RD. All patients had positive intraperitoneal cytology and 29 patients (63.0%) had the peritoneal dissemination. The median treatment period was 6.0 (0-22.6) months. The response rate and disease control rate were 45.7% and 95.7%, respectively. Ascites disappeared in 40.0% and cytology turned negative in 67.4%. Median CA19-9 decrease ratio was 84.4 (16.9-99.1) %. The median survival time was 12.8 (3.1-32.7) months, and the 1-year survival rate was 52.2%. Finally, conversion surgery was performed in 8 (17.4%) patients and those who received conversion surgery survived significantly longer than those who did not (not reached vs. 11.7 months, P = 0.0070). Grade 3/4 hematologic toxicities occurred in 76.0% and nonhematologic adverse events in 15.0%, of which 6.5% were bowel obstructions. Conclusions: This regimen has shown promising clinical efficacy with acceptable tolerability in chemotherapy-naive PDAC patients with peritoneal metastasis. Clinical trial information: 000018878.

Risk factors for severe neutropenia among pancreatic cancer patients receiving nab-paclitaxel and gemcitabine combination therapy.

684 Background: Albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine combination therapy (GnP therapy) significantly extends overall survival in patients with metastatic pancreatic cancer, compared to conventional gemcitabine monotherapy. However, severe neutropenia (Grade ≥ 3) occurred in 67.6% of patients in the Japanese phase I/II trials of GnP therapy, and is often a limiting factor. The purpose of this study was to identify the risk factors for severe neutropenia in pancreatic patients receiving GnP therapy in clinical settings. Methods: A retrospective study of 222 consecutive patients with pancreatic cancer who received GnP therapy at the Cancer Institute Hospital from December 2014 to December 2016 was conducted. Univariate and multivariate analyses were used to compare blood test values and patients’ characteristics between patients with no neutropenia or Grade 1/2 (non-serious) neutropenia and those with Grade ≥ 3 (severe) neutropenia. Results: There were 19 patients (8.6%) with modified FOLFIRINOX in the previous treatment history. The median doses of nab-paclitaxel and gemcitabine were 192.5 mg (range 134-277.5) and 1,545 mg (range 1,000-2,220), respectively. Severe neutropenia and febrile neutropenia occurred in 118 patients (53.2%) and 15 patients (6.8%), respectively. Multivariate logistic regression analysis indicated that ANC (absolute neutrophil count) &lt; 3.03 x 103 /μL (OR: 4.806, 95% CI: 2.416-9.558, p = 0.000), T-Bil ≥ 0.6 mg/dl (OR: 1.964, 95% CI: 1.040-3.708, p = 0.037) and CRP &lt; 0.13 mg/dl (OR: 2.607, 95% CI: 1.331-5.106, p = 0.005) were significant risk factors for severe neutropenia. The incidence rate of severe neutropenia was 85.7% (18/21) in patients with all three identified factors, while it was 27.7% (13/47) in patients with none of them. Age was not a risk factor in either univariate or multivariate analysis. Conclusions: Low ANC, high T-Bil, and low CRP were found to be risk factors for severe neutropenia in patients receiving GnP therapy. It would be desirable to monitor patients with these risk factors carefully, even if their values are within the standard ranges.

Conversion surgery for advancedgastric cancer with peritoneal metastasis.

450 Background: Patients with peritoneal metastasis have significantly poor prognosis. We have performed pretherapeutic staging laparoscopy (SL) to diagnose peritoneal metastasis for patients with large type 3, type 4 or serosa-invasive gastric cancer. When peritoneal metastasis disappears by chemotherapy for patients with positive peritoneal cytology (CY1) or peritoneal dissemination (P1), we perform the conversion surgery (CS). Methods: We retrospectively analyzed clinical outcomes of 134 patients with advanced gastric cancer who underwent SL between 2005 from 2016. We examined safety and usefulness of CS for patients with CY1 or P1. Results: CY0P0, CY1P0 and P1 were found in 67, 28 and 39 patients, respectively. The median survival time (MST) of patients with CY0P0, CY1P0 and P1 were 39, 21 and 11 months (CY0P0 vs CY1P0; p = 0.029, CY0P0 vs P1; p&lt;0.001, CY1P0 vs P1; p&lt;0.001). In patients with CY1P0, 20 of 26 patients who received chemotherapy underwent the second look SL, and 14 patients (54%) underwent CS (R0) as peritoneal cytology turned negative. These regimens of chemotherapy were S-1/CDDP (n = 9), Docetaxel/CDDP/S-1 (n = 2), SOX (n = 2) and S-1/Docetaxel (n = 1) and the median number of treatment courses was5courses. The MSTs of patients with or without CS were 40 months and 11 months (p&lt;0.001). Then, there was no difference in overall survival between patients with CS and patients with CY0P0 at the first SL (p = 0.866). All patients with P1received chemotherapy, and 11 of these patients underwent the second look SL. As peritoneal metastasis of 7 patients (18%) disappeared by chemotherapy, they underwent CS (R0). The MSTs of patients with or without CS were 31 months and 9 months (p = 0.026). Regarding complications after CS, surgical-site infection and interstitial pneumonia each occurred in one patient (grade II), and intestinal obstruction (grade IIIa) occurred in one patient. There was no mortality. Conclusions: This study suggests that CS is probably safe and may contribute to improve the survival rate of patients with peritoneal metastasis. Moreover, we developed the NSOX regimen, comprised of a combination nab-paclitaxel, S-1 and oxaliplatin, and have performed a phase I/II trial using the NSOX regimen (UMIN000030909).