Tag: Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with Pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced Pancreatic cancer has been dismal, with a 5-year survival rate for metastatic Pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2020.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label, Phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy (N=151), ONIVYDE® plus 5-FluoroUracil (N=117) or 5-FU with Leucovorin (N=149). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group). Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. Treatment groups were well balanced. The Primary study endpoint was Overall Survival and Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR). The authors in this publication reported the updated Overall Survival analysis from a longer follow up in the NAPOLI-1 trial, as well as baseline characteristics associated with long term survivors (survival of 1 year or more) in the NAPOLI-1 trial. The authors also provided the updated safety and tolerability data.

The combination of ONIVYDE®, 5-FU and Leucovorin maintained its median OS of 6.2 months compared with 4.2 months with 5-FU and Leucovorin alone, with an unstratified Hazard Ratio of 0.75 (P=0.04), and stratified Hazard Ratio of 0.63 (P=0.002). The estimated one-year survival rates were 26% in the ONIVYDE®, 5-FU and Leucovorin arm versus 16% in the 5-FU and Leucovorin combination control arm. Patient characteristics associated with long term survival in the ONIVYDE®, 5-FU and Leucovorin combination arm included Karnofsky Performance Status of 90 or more, age 65 years or less, lower serum CA19-9 levels, Neutrophil-to-Lymphocyte ratio of 5 or less and no liver metastases. There was again no OS advantage with ONIVYDE® monotherapy, when compared with 5-FU and Leucovorin (4.9 versus 4.2 months). The median PFS was 3.1 months in patients receiving ONIVYDE®, 5-FU and Leucovorin and 1.5 months in those receiving 5-FU and Leucovorin combination alone (HR=0.57; P < 0.0001), and was 2.7 months for ONIVYDE® monotherapy compared with 1.6 months for 5-FU and Leucovorin combination control group. The ORR was significantly higher with ONIVYDE®, 5-FU and Leucovorin combination (17%) compared with 1% for the 5-FU and Leucovorin combination (P < 0.0001) and the Disease Control Rate was also higher with ONIVYDE®, 5-FU and Leucovorin combination (52%) versus 24% for the 5-FU and Leucovorin combination control group. No new safety concerns were detected in the current updated analysis.

The authors concluded that for patients with metastatic Pancreatic adenocarcinoma, a combination of ONIVYDE®, 5-FU and Leucovorin improves Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate, with an acceptable safety profile, and represents a new standard of care following Gemcitabine-based therapy. This updated analysis also identified prognostic markers associated with longer survival. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: Final overall survival analysis and characteristics of long-term survivors. Wang-Gillam A, Hubner RA, Siveke JT, et al. European Journal of Cancer 2019;108:78-87

SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2020.

BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively. They control cell growth by repairing DNA damage and thus prevent tumor development. Mutations in these genes predispose an individual to develop malignant tumors. It is well established that the presence of BRCA1 and BRCA2 mutations can significantly increase the lifetime risk for developing breast and ovarian cancer, as high as 85% and 40% respectively. BRCA1/2 mutations have been detected in 4-7% of patients with pancreatic cancer, with a 2-6 fold increase in risk, associated with these mutations. These patients tend to be younger. Among pancreatic cancer patients with Ashkenazi Jewish ancestry, the prevalence of BRCA1/2 mutations is 6-19%, with mutations more common for BRCA2. NCCN guideline recommends that germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.

BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). The BRCA gene plays an important role in DNA repair via Homologous Recombination (HR). Mutation of BRCA gene results in loss of BRCA function and likely deregulates Homologous Recombination (HR) pathway. Majority of patients with Germline BRCA mutations (gBRCA) have HR Deficiency (HRD) resulting in inability to repair double strand breaks. HRD can also occur due to other mechanisms, such as germline mutations, somatic mutations and epigenetic modifications of other genes involved in the HR pathway. Patients with HRD exhibit specific clinical behaviors, and improved responses to treatments, such as platinum-based chemotherapy and PARP Inhibitors.

The PARP (Poly ADP Ribose Polymerase) family of enzymes include PARP1 and PARP2, which repair damaged DNA. LYNPARZA® is a first-in-class PARP enzyme inhibitor that causes cell death in tumors that already have a DNA repair defect, such as those with BRCA1 and BRCA2 mutations, through the concept of synthetic lethality. Malignancies such as epithelial ovarian cancers with Homologous Recombination Deficiency have demonstrated sensitivity to PARP inhibitors. Recent studies have confirmed that PARP inhibitors are effective not only in ovarian cancers displaying germline or somatic BRCA mutations but also in cancers with HRD caused by other underlying etiologies. LYNPARZA® in a Phase II trial, demonstrated antitumor activity in heavily pretreated metastatic pancreatic cancer patients with a germline BRCA mutation. Maintenance treatment with LYNPARZA® in BRCA mutated ovarian cancer patients resulted in significant improvement in Progression Free Survival.

The POLO (Pancreas Cancer Olaparib Ongoing) trial was conducted to evaluate the efficacy of maintenance therapy with LYNPARZA® in metastatic pancreatic adenocarcinoma patients with a germline BRCA mutation whose disease had not progressed during first-line platinum-based chemotherapy. In this international, multicenter, randomized, double-blind, placebo-controlled Phase III study, 154 patients with BRCA mutant disease were randomly assigned in a 3:2 ratio, to receive maintenance LYNPARZA® tablets 300 mg twice daily (N=92) or matching placebo (N=62). The median patient age was 57 years. Eligible patients should have received at least 16 weeks of continuous first-line platinum-based chemotherapy for metastatic pancreatic cancer and maintenance treatment was initiated 4-8 weeks after the last dose of first-line chemotherapy had been administered. Maintenance intervention was continued until disease progression. Crossover to LYNPARZA® was not permitted during this trial. The Primary end point was Progression Free Survival and Secondary end points included Objective Response Rate (ORR) and Quality of Life.

The median PFS was significantly longer in the LYNPARZA® group compared to the placebo group (7.4 months versus 3.8 months; HR for disease progression or death=0.53; P=0.004). This suggested a 47% reduction in the risk of disease progression or death. At 2 years, 22% of the patients in the LYNPARZA® group did not have disease progression compared with 9.6% of patients in the placebo group. The interim analysis of Overall Survival showed no significant difference, with a median 18.9 months for the LYNPARZA® group and 18.1 months for the placebo group (HR=0.91; P=0.68). Health-related Quality of Life scores were also not significantly different. Grade 3 or higher adverse events were 40% in the LYNPARZA® group and 23% in the placebo group and 5% and 2% of the patients, respectively, discontinued therapy because of an adverse event.

It was concluded that among metastatic pancreatic cancer patients with germline BRCA mutation and whose cancer has not progressed during platinum-based chemotherapy, Progression Free Survival was significantly longer with maintenance LYNPARZA® than with placebo. This study allows identifying patients with metastatic pancreatic cancer who will likely benefit from PARP inhibition. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. Golan T, Hammel P, Reni M, et al. N Engl J Med 2019; 381:317-327

SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcomes for patients with advanced pancreatic cancer, has been dismal with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%.

The ASCO Expert Panel in 2016 published a guideline to assist in clinical decision making in metastatic pancreatic cancer for initial assessment after diagnosis, first and second-line treatment options, palliative and supportive care, and follow-up. This present update incorporated new evidence related to second-line therapy, published between June 2015 and January 2018, for patients who have experienced disease progression or intolerable toxicities during first-line therapy.

INITIAL ASSESSMENT

Recommendation 1.1: A multiphase CT scan of the Chest, Abdomen, and Pelvis should be performed to assess extent of disease. Other staging studies should be performed only as dictated by symptoms.

Recommendation 1.2: The baseline Performance Status, symptom burden, and comorbidity profile of a patient with metastatic pancreatic cancer should be evaluated carefully.

Recommendation 1.3: The goals of care including a discussion of an advance directive, patient preferences, as well as support systems, should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers.

Recommendation 1.4: Multidisciplinary collaboration to formulate treatment and care plans and disease management for patients with metastatic pancreatic cancer should be the standard of care.

Recommendation 1.5: Every patient with pancreatic cancer should be offered information about clinical trials, which include therapeutic trials in all lines of treatment as well as palliative care, biorepository/biomarker, and observational studies.

FIRST-LINE TREATMENT

Recommendation 2.1: FOLFIRINOX (Leucovorin, Fluorouracil, Irinotecan, and Oxaliplatin) is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 2.2: Gemcitabine plus NAB-Paclitaxel is recommended for patients who meet all of the following criteria: an ECOG PS of 0-1, a relatively favorable comorbidity profile, and patient preference and a support system for relatively aggressive medical therapy.

Recommendation 2.3: Gemcitabine alone is recommended for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy. The addition of either Capecitabine or Erlotinib to Gemcitabine may be considered in this setting.

Recommendation 2.4: Patients with an ECOG PS 3 or more or with poorly controlled comorbid conditions despite ongoing active medical care should be offered cancer-directed therapy only on a case-by-case basis. The major emphasis should be on optimizing supportive care measures.

SECOND-LINE TREATMENT

Recommendation 3.1: Routine testing for dMMR or MSI-H is recommended, using IHC, PCR, or NGS for patients who are considered to be candidates for checkpoint inhibitor therapy.

Recommendation 3.2: PD-1 immune checkpoint inhibitor pembrolizumab is recommended as second-line therapy for patients who have tested positive for dMMR or MSI-H.

Recommendation 3.3: Gemcitabine plus NAB-Paclitaxel can be offered as second-line therapy to patients who had received first-line treatment with FOLFIRINOX, have an ECOG PS of 0-1, with a relatively favorable comorbidity profile, and patient preference and a support system for aggressive medical therapy.

Recommendation 3.4: Fluorouracil plus nanoliposomal Irinotecan, or Fluorouracil plus Irinotecan where the former combination is unavailable, is preferred as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Recommendation 3.5: Fluorouracil plus Oxaliplatin may be considered as second-line therapy for patients who meet all of the following criteria: first-line treatment with Gemcitabine plus NAB-Paclitaxel, an ECOG PS of 0-1, a relatively favorable comorbidity profile, patient preference and a support system for aggressive medical therapy, and access to chemotherapy port and infusion pump management services.

Qualifying statement for Recommendations 3.4 and 3.5: A recent phase III trial comparing mFOLFOX6 with FU + LV demonstrated a higher rate of grade 3 or 4 adverse events and significantly reduced OS within the mFOLFOX6 arm of the trial. However, previous phase III data have demonstrated a benefit with the OFF regimen compared with FU + LV. Considering the inconsistency of these results, although Fluorouracil plus nanoliposomal Irinotecan is preferred, the Expert Panel continues to support the use of Fluorouracil plus Oxaliplatin as an option where the availability of Fluorouracil plus nanoliposomal Irinotecan is limited or where residual toxicity from first-line therapy or comorbidities preclude the use of Fluorouracil plus nanoliposomal Irinotecan.

Recommendation 3.6: Gemcitabine or Fluorouracil can be considered as second-line therapy for patients who have either an ECOG PS of 2 or a comorbidity profile that precludes more aggressive regimens and who wish to pursue cancer-directed therapy.

Recommendation 3.7: No data are available to recommend third-line (or greater) therapy with a cytotoxic agent. Clinical trial participation is encouraged

PALLIATIVE CARE

Recommendation 4.1: Patients with metastatic pancreatic cancer should have a full assessment of symptom burden, psychological status, and social supports as early as possible, preferably at the first visit. In most cases, this assessment will indicate a need for a formal palliative care consult and services.

TREATMENT of PAIN and SYMPTOMS

Recommendation 5.1: Patients with metastatic pancreatic cancer should be offered aggressive treatment of the pain and symptoms of the cancer and/or the cancer-directed therapy.

FOLLOW-UP/SURVEILLANCE

Recommendation 6.1: For patients on active cancer-directed therapy outside a clinical trial, imaging to assess first response should be offered at 2-3 months from the initiation of therapy. CT scans with contrast are the preferred modality. Thereafter, clinical assessment, conducted frequently during visits for cancer-directed therapy, should supplant imaging assessment. The routine use of PET scans for the management of patients with pancreatic cancer is not recommended. CA19-9 is not considered an optimal substitute for imaging for the assessment of treatment response.

Recommendation 6.2: No data exist on the duration of cancer-directed therapy. An ongoing discussion of goals of care and assessment of treatment response and tolerability should guide decisions to continue or to hold or terminate cancer-directed therapy.

Metastatic Pancreatic Cancer: ASCO Clinical Practice Guideline Update. Sohal DPS, Kennedy EB, Khorana A, et al. J Clin Oncol. 2018;36:2545-2556.

SUMMARY: The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with pancreatic cancer and about 44,330 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcomes for patients with advanced pancreatic cancer, has been dismal. Diagnosis is often made late in the course of the disease, as patients are often asymptomatic and early tumors cannot be detected during routine physical examination. Research has been underway evaluating the role of modifiable risk factors, early screening biomarkers, and tumor microenvironment and their influence on outcomes.

Recent published studies have shown the influence of gut microbiome alterations, in the carcinogenesis of pancreatic cancer. A commensal microbiome in a healthy individual maintains a symbiotic relationship conferring protection by its inflammatory-modulating activity, detoxification, hormonal homeostatic and metabolic effects of bacterial metabolites. An imbalanced microbiome can result in dysbiosis, and microbiome alteration has been reported to contribute to carcinogenesis of multiple malignancies. One classic example of influence of microbiome alteration contributing to carcinogenesis is Helicobacter pylori (H. pylori). Eradication of H. pylori causes regression of MALT lymphoma and decreases risk of metachronous gastric carcinoma after endoscopic resection for early stage gastric cancer.

An abundance and alteration of certain microbiomes has been shown to suppress monocytic cellular differentiation in pancreatic cancer leading to T-cell anergy. Targeting the microbiome and bacterial ablation has been shown to be associated with immunogenic reprogramming of the pancreatic tumor microenvironment, by reducing the myeloid-derived suppressor cells and increasing macrophage differentiation. Additionally, bacterial ablation also upregulates PD-1 expression, and enables the efficacy for checkpoint-based immunotherapy and reverses intratumoral immune tolerance. These findings have led to the conclusion that, endogenous microbiota promote immune suppression, characteristic of pancreatic ductal adenocarcinoma, and targeting microbiome potentially can modulate disease progression.

The present study was based on preclinical findings that cancerous pancreas harbors a population of bacteria that is a 1000 fold more, compared with normal pancreas in both mice and humans, and these select bacteria are differentially increased in the tumorous pancreas compared with the gut. The authors in this study noted that bacteria that are more abundant in pancreatic cancers include proteobacteria, actinobacteria, and fusobacteria species. These bacteria release cell membrane components such as lipopolysaccharides and proteins such as flagellins that shift macrophages into immune suppression and prevent the immune system from attacking tumor cells. Their study showed that eliminating these bacteria using antibiotics restored the ability of immune cells to recognize cancer cells, slowed pancreatic tumor growth, and reduced the cancer cell tumor burden by 50% in study animals. Specifically, it was noted that eradicating these bacteria from the gut and pancreas, by treating mice with antibiotics, slowed cancer growth and allowed the recognition of tumor cells by the immune system. Oral antibiotics also increased the efficacy of checkpoint inhibitors roughly 3 fold, thereby strongly improving antitumor immunity.

The researchers further pointed out that even though alterations in genes such as KRAS can result in abnormal cell growth and development of pancreatic cancer, the present study showed that bacteria can change the immune environment around cancer cells and facilitate rapid tumor growth in some patients more so than others, despite their similar genetic alterations. The authors hypothesized that changes in the genes that cause abnormal cell growth in the pancreas might also change the immune response, favoring the growth of different bacterial species, other than those found in healthy individuals. Environmental factors like diet, other medical conditions, or common medications, might also cause bacterial changes in the gut, that influence the pancreatic microbiome.

It was concluded that in pancreatic cancer, a distinct and abundant group of bacteria provide an immune suppressed environment, and addition of antibiotics improved the efficacy of a checkpoint inhibitor, in a mouse model of pancreatic ductal adenocarcinoma, as demonstrated by an increase in T cells that could attack the tumor. Studies are planned to evaluate the role of antibiotic combinations such as Ciprofloxacin and Metronidazole and their benefit in improving the efficacy of PD-1 inhibitors, in patients with pancreatic ductal adenocarcinoma. The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression. Pushalkar S, Hundeyin M, Daley D, et al. DOI: 10.1158/2159-8290.CD-17-1134

SUMMARY: The American Cancer Society estimates that in 2018, about 55,440 people will be diagnosed with pancreatic cancer and about 44,330 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcomes for patients with advanced pancreatic cancer, has been dismal. Diagnosis is often made late in the course of the disease, as patients are often asymptomatic and early tumors cannot be detected during routine physical examination. Further, precursors of pancreatic cancer evolve as microscopic lesions in the ducts and are often not visualized on imaging studies. Based on the National Cancer Institute Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease, and 1% for those with Stage IV disease. Early detection and cancer prevention is therefore critical. 

Pancreatic adenocarcinoma can also develop from mucin-producing Pancreatic Cystic Lesions (PCLs) and these neoplasms include Intraductal Papillary Mucinous Neoplasms (IPMNs) and Mucinous Cystic Neoplasms. These neoplasms comprise 10-50% of Pancreatic Cystic Lesions (PCLs). It should be noted that PCLs also encompass intrinsically benign tumors such as serous cystic neoplasms and inflammatory pseudocysts. With the rising use of abdominal MRI, partly due to concerns about ionizing radiation inherent to other exams such as CT scans, PCLs are incidentally discovered in up to 20% of these imaging studies in adults and these individuals are asymptomatic. Imaging techniques that are presently available cannot distinguish between benign, premalignant, and malignant PCLs. The same is true for currently available Endoscopic Ultrasound (EUS)-guided Fine Needle Aspiration (FNA) of Pancreatic Cystic Lesions and evaluation of cyst fluid for cytology and quantification of CarcinoEmbryonic Antigen (CEA). A high risk lesion in the pancreas would require surgical intervention with associated risks. Identifying benign from premalignant and malignant PCLs, as well as determining the epithelial subtype of IPMNs is therefore critical. The risk of malignancy is highest for Pancreatobiliary-type IPMNs with somewhat better prognosis for Intestinal-type IPMNs, whereas Gastric-type IPMNs tend to be indolent.

The authors in this study utilized targeted Mass Spectrometry (MS) to identify and quantitate proteins in the cystic fluid samples. Targeted quantitation of proteins by Mass Spectrometry provides a next-generation platform that overcomes many of the limitations of Western blotting and provides new capabilities for protein analysis. This sensitive technique is used to detect, identify and quantitate protein molecules in a given sample, based on their mass-to-charge ratio, enabling targeted protein measurement.

Using pancreatic cyst fluid samples obtained by routine EUS-guided FNA, biomarker candidates for malignant potential and high-grade dysplasia/cancer were identified via an explorative proteomic approach, in an initial cohort of 24 patients. Subsequently, a quantitative analysis using 30 heavy-labeled peptides from the biomarkers and parallel reaction monitoring mass spectrometry was devised, and tested, in a training cohort of 80 patients, and prospectively evaluated in a validation cohort of 68 patients. Patients with solid-pseudopapillary neoplasm and neuroendocrine tumor were excluded. The Primary objective of this study was to devise and validate a targeted, quantitative proteomic analysis to identify and distinguish between premalignant Pancreatic Cystic Lesions (PCLs) and Cystic neoplasms with manifest high-grade dysplasia /cancer. A Secondary aim was to find and evaluate markers for different epithelial subtypes of IPMNs, which may be used to predict the risk of malignant transformation.

It was noted that the optimal set of markers for detecting malignant potential was a panel of peptides from Mucin-5AC and Mucin-2, which could distinguish premalignant/malignant lesions from benign, with an accuracy of 97% in the validation cohort , compared with 61% using pancreatic cyst fluid CarcinoEmbryonic Antigen (P< 0.001) and 84% using Cytology (P=0.02). A combination of proteins Mucin-5AC and Prostate Stem Cell Antigen (PSCA) could identify high-grade dysplasia/cancer with an accuracy of 96% and detected 95% of malignant/severely dysplastic lesions, compared with 35% and 50% for CarcinoEmbryonic Antigen and Cytology (P<0.001 and P=0.003, respectively).

The authors concluded that Targeted Mass Spectrometry analysis of three pancreatic cyst fluid biomarkers provides highly accurate identification and assessment of cystic precursors to pancreatic adenocarcinoma. It remains to be seen whether this methodology will be beneficial for early diagnosis as well as prevention of development of pancreatic adenocarcinoma. Highly Accurate Identification of Cystic Precursor Lesions of Pancreatic Cancer Through Targeted Mass Spectrometry: A Phase IIc Diagnostic Study. Jabbar KS, Arike L, Hansson GC, et al. J Clin Oncol 2018;36:367-375

SUMMARY: The American Cancer Society estimates that in 2017, about 53,670 people will be diagnosed with pancreatic cancer in the United States and about 43,090 patients will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use, in combination with GEMZAR® (Gemcitabine), for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved Overall Survival (OS) and Progression Free Survival (PFS) with this combination, when compared to single agent GEMZAR®, in a multicenter, international, open-label, randomized trial (MPACT study).

PEGPH20 is a PEGylated form of recombinant human Hyaluronidase, for the potential systemic treatment of tumors that accumulate Hyaluronan (HA). PEGPH20 is an enzyme that temporarily degrades Hyaluronan, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells and potentially constrict blood vessels and there by impede treatment access to tumor tissue. It is estimated that 35% to 40% of patients with pancreatic cancer have high expression of Hyaluronan and this biomarker may predict response to PEGPH20.

HALO-202 is a phase 2 multicenter, randomized clinical trial, in which PEGPH20 in combination with ABRAXANE® and GEMZAR® (N=166) – PAG, was compared with ABRAXANE® and GEMZAR® – AG (N=113), in treatment-naive patients, with metastatic pancreatic carcinoma. In this study, following enrollment of 146 patients in the first stage of the trial, the study was placed on hold to address concerns regarding thromboembolic events, in the group receiving PEGPH20. The protocol was amended to exclude those at high risk for a thromboembolic event and prophylaxis with Low Molecular Weight Heparin was required. One hundred thirty-three patients (N=133) were enrolled into the second stage of the trial for a total of 279 patients. Patients enrolled in stage 2 received Low Molecular Weight Heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to prevent thromboembolic events. Each 4-week treatment cycle consisted of 3 weekly treatments and 1 week off. PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. ABRAXANE® and GEMZAR® were administered weekly at their standard FDA-approved doses of 125 mg/m2 and 1,000 mg mg/m2 respectively. Tumor biopsy samples for the Hyaluronan analysis were available for 138 patients treated with PEGPH20 and 79 patients treated in the control group, across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had Hyaluronan expression of 50% or more. The Primary endpoint of the study was Progression Free Survival (PFS) across the entire treatment group. Following change in the treatment protocol, a second Primary endpoint was added to assess thromboembolic event rate. Secondary endpoints included Objective Response Rate, PFS by Hyaluronan level, and Overall Survival. The second stage of this study was also utilized to validate a companion diagnostic for Hyaluronan (HA) levels.

It was noted that across the overall study population, there was a statistically significant increase in Progression Free Survival (PFS) in the PEGPH20 group compared to the control group (6 months versus 5.2 months; HR=0.73; P=0.49). In patients with high levels of Hyaluronan (HA-High), the PFS was 9.2 months among those treated with PEGPH20 plus ABRAXANE® and GEMZAR® versus 5.2 months among patients receiving ABRAXANE® and GEMZAR® alone (HR = 0.51, P = 0.048). The additional Primary endpoint of a reduction in the rate of thromboembolic events was achieved, in the PEGPH20 group. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the ABRAXANE® and GEMZAR® group. These events were lower in those receiving Low Molecular Weight Heparin at 1 mg/kg/day dose versus 40 mg/day (6% vs 10%, respectively). The most common adverse events were cytopenias.

The authors concluded that the addition of PEGPH20 to ABRAXANE® and GEMZAR® resulted in significant improvement in Progression Free Survival compared with ABRAXANE® plus GEMZAR® alone, in treatment naïve patients with advanced pancreatic cancer. Patients with high levels of expression of the biomarker Hyaluronan, had the best outcomes suggesting that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to standard chemotherapy. A phase III study is underway, evaluating PEGPH20 in combination with ABRAXANE® and GEMZAR® in patients with metastatic pancreatic cancer, with high Hyaluronan levels. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. Hingorani SR, Zheng L, Bullock AJ, et al. DOI: 10.1200/JCO.2017.74.9564 Journal of Clinical Oncology – published online before print December 12, 2017

SUMMARY: The American Cancer Society estimates that in 2017, about 53,670 people will be diagnosed with pancreatic cancer in the United States and about 43,090 patients will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved Overall Survival (OS) and Progression Free Survival (PFS), in a multicenter, international, open-label, randomized trial (MPACT study), when compared to single agent GEMZAR®.

PEGPH20 is a PEGylated form of recombinant human Hyaluronidase, for the potential systemic treatment of tumors that accumulate Hyaluronan (HA). PEGPH20 is an enzyme that temporarily degrades Hyaluronan, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells and potentially constrict blood vessels and there by impede treatment access to tumor tissue. It is estimated that 35% to 40% of patients with pancreatic cancer have high expression of Hyaluronan and this biomarker may predict response to PEGPH20.

HALO 202 (Halo 109-202) is a phase 2 multicenter, randomized clinical trial, in which PEGPH20 in combination with ABRAXANE® and GEMZAR® was compared with ABRAXANE® and GEMZAR® alone, in treatment naive patients with metastatic pancreatic carcinoma. In this study, following enrollment of 146 patients in the first stage of the trial, the study was placed on hold to address concerns regarding thromboembolic events, in the group receiving PEGPH20. The protocol was amended to exclude those at high risk for a thromboembolic event and prophylaxis with Low Molecular Weight Heparin was required. One hundred thirty-three patients (N=133) were enrolled into the second stage of the trial for a total of 279 patients. Patients enrolled in stage 2 received Low Molecular Weight Heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to prevent thromboembolic events. PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. ABRAXANE® and GEMZAR® were administered at their standard FDA-approved doses. Tumor biopsy samples for the Hyaluronan analysis were available for 138 patients treated with PEGPH20 and 79 patients treated in the control group across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had Hyaluronan expression of 50% or more. The primary endpoint of the study was Progression Free Survival (PFS) across the entire treatment group. Following change in the treatment protocol, a second primary endpoint was added to assess thromboembolic event rate. Secondary endpoints included Objective Response Rate, PFS by Hyaluronan level, and Overall Survival. The second stage of this study was also utilized to validate a companion diagnostic for Hyaluronan (HA) levels.

It was noted that across the overall study population, there was a statistically significant increase in Progression Free Survival (PFS) in patients with high levels of Hyaluronan (HA-High) treated with PEGPH20 plus ABRAXANE® and GEMZAR®, compared to HA-High patients receiving ABRAXANE® and GEMZAR® alone. Among the patients in the second stage of this study, there was a 91% improvement in median PFS for HA-High patients in the PEGPH20 group compared to the control group (8.6 months versus 4.5 months) and the additional primary endpoint of a reduction in the rate of thromboembolic events was achieved, in the PEGPH20 group. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the ABRAXANE® and GEMZAR® group. These events were lower in those receiving Low Molecular Weight Heparin at 1 mg/kg/day dose versus 40 mg/day (6% vs 10%, respectively). The most common adverse events were cytopenias.

The authors concluded that the addition of PEGPH20 to ABRAXANE® and GEMZAR® resulted in significant improvement in Progression Free Survival compared with ABRAXANE®/GEMZAR® alone, in treatment naïve patients with advanced pancreatic cancer. Patients with high levels of expression of the biomarker Hyaluronan, had the best outcomes suggesting that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to standard chemotherapy. A phase III study is underway, evaluating PEGPH20 in combination with ABRAXANE® and GEMZAR® in patients with metastatic pancreatic cancer, with high Hyaluronan levels. Countouriotis A. Study 202 Overall Results and Stage 2 Results [webcast]. Halozyme Investor Call; January 5, 2017. Final analysis of stage 1 data from a randomized phase II study of PEGPH20 plus nab-Paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients (pts), utilizing Ventana companion diagnostic assay. Bullock AJ, Hingorani SR, Wu XW, et al. J Clin Oncol 34, 2016 (suppl; abstr 4104)