Tag: Pancreatic Cancer

Early Detection of Pancreatic Cancer with an Exosome-Based Liquid Biopsy

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SUMMARY: The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with pancreatic cancer and 51,750 people will die of the disease. Detecting cancer at early stages can significantly increase survival rates and outcomes.

Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer, however, is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is NOT recommended by the FDA for screening, as it may be elevated in several benign conditions. Currently, there are no general screening strategies to detect asymptomatic, early-stage PDAC and there is therefore a significant unmet need in this patient group.

Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and released by tumors into the bloodstream. They mediate intercellular signaling by shuttling mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. MicroRNAs play a role in regulating gene expression and have been implicated in various cancer types due to their stability and specific expression patterns associated with tumor presence. Exosomes retain the cytoplasmic content of the cell from which they were shed, essentially replicating the biology of their tissue of origin. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.

The researchers developed an exosome-based liquid biopsy signature as a diagnostic tool to detect pancreatic cancer through the analysis of circulating biomarkers in blood samples. This signature utilizes two primary types of biomarkers – Eight microRNAs unique to exosomes shed from pancreatic cancer cells, combined with five cell-free DNA (cfDNA) markers such as mutations or alterations in DNA methylation patterns found in the blood of patients with pancreatic cancer.

In previous work, researchers had tested an exosome-based liquid biopsy signature on a cohort of 95 individuals from either the United States or Japan. This initial study reported an impressive 98% detection rate for pancreatic cancer. Building on this success, the latest research aimed to validate this liquid biopsy approach in larger, more diverse populations across multiple institutions and countries.

The most recent study involved a comprehensive, multi-cohort evaluation to assess the performance of the exosome-based liquid biopsy signature. The study enrolled participants from four countries, each contributing both pancreatic cancer patients and healthy donors:
• Japan: 150 individuals with pancreatic cancer and 102 healthy donors
• United States: 139 individuals with pancreatic cancer and 193 healthy donors
• South Korea: 184 individuals with pancreatic cancer and 86 healthy donors
• China: 50 individuals with pancreatic cancer and 80 healthy donors

The research methodology involved training the liquid biopsy signature using data from the Japanese cohort. Machine learning algorithms were likely used to train and validate the diagnostic model, optimizing its sensitivity and specificity. After training the signature on the Japanese cohort, the researchers validated its performance using data from cohorts in the United States, South Korea, and China. Each of these cohorts included a mix of pancreatic cancer patients and healthy controls, allowing for an assessment of the signature’s performance across diverse populations.

The performance of the liquid biopsy signature across different cohorts was as follows:
• United States Cohort: The test detected 93% of pancreatic cancers.
• South Korean Cohort: The test detected 91% of pancreatic cancers.
• Chinese Cohort: The test detected 88% of pancreatic cancers.

These validation results demonstrated the signatures robustness and effectiveness in detecting pancreatic cancer across different ethnic and geographic backgrounds, although there was a noted decrease in detection rates with different cohorts.

To enhance the diagnostic accuracy, the researchers combined their exosome-based signature with the traditional pancreatic cancer marker CA 19-9, a carbohydrate antigen often elevated in pancreatic cancer but is less sensitive for detecting early-stage disease. The combination of the exosome-based signature with CA 19-9 improved the detection rate of early-stage pancreatic cancers (Stage I and II) to 97% in the U.S. cohort. This suggests that the combination approach offers a more comprehensive evaluation than CA 19-9 alone.

In conclusion, the exosome-based liquid biopsy signature represents a significant advancement in the early detection of pancreatic cancer. By leveraging the unique properties of exosomal microRNAs and cfDNA, the researchers have developed a diagnostic tool with high sensitivity and specificity. The successful validation in multiple cohorts underscores its potential utility in clinical practice. This assay may be helpful for early detection of pancreatic cancer in certain groups with a high risk for pancreatic cancer such as a family history of pancreatic cancer, germline BRCA mutations, new-onset diabetes, chronic pancreatitis or pancreas precancer lesion such as intraductal papillary mucinous neoplasm. However, addressing the limitations and further optimizing the technology will be crucial for its widespread adoption and effectiveness in diverse populations.

An exosome-based liquid biopsy for non-invasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter and prospective study. Xu C, Xu Y, Han H, et al. AACR Annual Meeting 2024. Abstract 3899. Presented April 8, 2024.

FDA Approves ONIVYDE® for First-Line Treatment of Metastatic Pancreatic Adenocarcinoma

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SUMMARY: The FDA on February 13, 2024, approved ONIVYDE® (Irinotecan liposome) with Oxaliplatin, Fluorouracil, and Leucovorin, for the first-line treatment of metastatic Pancreatic adenocarcinoma. The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with Pancreatic cancer and 51,750 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 10%. 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. Majority of patients with Pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

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.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic Pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic Pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic Pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Approximately 80% of patients had liver metastases. Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.83; P=0.04). The 12 months OS rate was 45.6% versus 39.5%, and 18 months OS rate was 26.2% versus 19.3% respectively. There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.69; P=0.0001). The 12 months PFS rate was 27.4% versus 13.9%, and 18 months PFS rate was 11.4% versus 3.6% respectively. This OS and PFS benefit was observed across subgroups.

The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and the median Duration of Response was 7.3 months versus 5.0 months respectively. A lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and included a higher incidence of diarrhea, nausea and hypokalemia.

It was concluded that first-line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic Pancreatic ductal adenocarcinoma.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Wainberg ZA, Melisi D, Macarulla T, et al. The Lancet. 2023;402: 1272-1281.

Significant Survival Benefit with NALIRIFOX in Previously Untreated Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2023, about 64,050 people will be diagnosed with Pancreatic cancer and 50,550 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 10%. 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. Majority of patients with Pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

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.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic Pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic Pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic Pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Approximately 80% of patients had liver metastases. Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.83; P=0.04). The 12 months OS rate was 45.6% versus 39.5%, and 18 months OS rate was 26.2% versus 19.3% respectively. There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.69; P=0.0001). The 12 months PFS rate was 27.4% versus 13.9%, and 18 months PFS rate was 11.4% versus 3.6% respectively. This OS and PFS benefit was observed across subgroups.

The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and the median Duration of Response was 7.3 months versus 5.0 months respectively. A lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and included a higher incidence of diarrhea, nausea and hypokalemia.

It was concluded that first-line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic Pancreatic ductal adenocarcinoma.

Liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): 12- and 18-month survival rates from the phase 3 NAPOLI 3 trial. O’Reilly EM, Melisi D, Macarulla T, et al. J Clin Oncol. 2023;41(suppl 16):4006. doi:10.1200/JCO.2023.41.16_suppl.4006

NALIRIFOX Improves Overall Survival in Patients with Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 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 10%. 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. Majority of patients with pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

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.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.84; P=0.04). There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.70; P=0.0001). This OS and PFS benefit was observed across subgroups. The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and a lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and consistent with the drug profiles in this regimen.

It was concluded that first line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Wainberg ZA, Melisi D, Macarulla T, et al. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco. Abstract LBA661.

Association Between Polycystic Ovary Syndrome and Risk of Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 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 10%. 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.

Majority of patients with pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months. Clinical surveillance is recommended for individuals at high risk, although pancreatic cancer has relatively few established risk factors.

Polycystic Ovary Syndrome (PCOS) is a hormone disorder affecting 7-10% of women of childbearing age and is the most common cause of infertility. In the United States, an estimated 5-6 million women have PCOS and is the most common hormonal disorder among women of reproductive age. The etiology of PCOS is unknown and the signs and symptoms of PCOS have been attributed to abnormal levels of Luteinizing Hormone (LH) and androgen excess, which interfere with normal function of the ovaries. Hyperinsulinemia and insulin resistance can lead to the development of Type 2 diabetes and worsen androgen excess. A previously published study using Swedish register data suggested several carcinogenic processes associated with PCOS, with a 3.4-fold increased risk of pancreatic cancer, in small group of women with PCOS (JAMA Oncol. 2019;5(1):106-107).

To confirm these findings, the authors conducted a case-control study using data from the Memorial Sloan Kettering Cancer Center Pancreatic Tumor Registry. The study population included 446 women (N=446) who were 21 years of age or older and had pathologically or cytologically confirmed pancreatic adenocarcinoma. The control group consisted of visitors accompanying patients to Memorial Sloan Kettering Cancer Center clinics or spouses of patients with pancreatic cancer with no personal history of cancer (N=209). The researchers followed STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guideline to report their observational research findings and used multivariable logistic regression to estimate Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the association between PCOS and risk of pancreatic cancer. The median age of the study population was 60 years.

The researchers noted a positive association between PCOS and risk of pancreatic cancer, after adjusting for age, race and ethnicity, BMI, and estrogen use (OR=1.88 – 88% more likely). The Odds Ratio remained significant at 1.78 after adjusting for potential mediator Type 2 diabetes, in addition to all the above factors. Excluding those with pancreatic cancer diagnosed less than 5 years after PCOS diagnosis, history of pancreatitis and a history of familial pancreatic cancer did not materially alter risk estimates. These findings suggested that this association of PCOS and risk of pancreatic cancer was independent of BMI, and not driven by Type 2 diabetes or other variables. The researchers hypothesized that these data suggest some individuals may have unknown metabolic derangements that may underly the development of both conditions.

The authors concluded that in this case-control study, PCOS was strongly associated with increased risk of pancreatic cancer. They added that diagnosis of PCOS may warrant increased education and clinical vigilance for pancreatic cancer, although prospective studies are needed to examine underlying biologic mechanisms and confirm this study findings.

Association Between Polycystic Ovary Syndrome and Risk of Pancreatic Cancer. Peeri NC, Landicino MV, Saldia CA, et al. JAMA Oncol. Published online October 6, 2022. doi:10.1001/jamaoncol.2022.4540

Late Breaking Abstract – ASCO 2022: Nimotuzumab Significantly Improves Overall Survival in K-Ras Wild-Type Advanced Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 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 10%. 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.

Majority of patients with pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months. In patients with pancreatic ductal adenocarcinoma, the main driver is the KRAS oncogene, which is mutationally activated in over 90% of cases, and is more common in older (50 years or more) and female patients. However approximately 8-12% of patients with pancreatic ductal adenocarcinoma do not harbor KRAS mutations.

Nimotuzumab is a humanized anti-EGFR monoclonal antibody, that binds to EGFR (Epidermal Growth Factor Receptor) and disrupts the interaction of the EGFR with its ligand, specifically blocking the EGFR signaling pathway, and mediating Antibody-Dependent Cellular Cytotoxicity (ADCC) and other immune effects, and inducing EGFR endocytosis and degradation. Nimotuzumab as a single agent showed activity in high grade brain tumors, and resulted in high rates of antitumor response in patients with locally advanced squamous cell carcinomas of the head and neck, when combined with radiation therapy. Nimotuzumab is approved in different countries for the treatment of Squamous Cell Carcinoma of Head and Neck (SCCHN), Glioma and Nasopharyngeal carcinoma.

NOTABLE is a prospective, double-blind, Phase III trial in which the efficacy and safety of Nimotuzumab in combination with Gemcitabine was compared with Gemcitabine alone, in patients with KRAS wild-type, locally advanced or metastatic pancreatic cancer. In this study, 92 patients with locally advanced or metastatic pancreatic cancer were randomly assigned to receive either Nimotuzumab 400 mg IV every week followed by Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 of every 28-day cycle or placebo plus Gemcitabine. Treatment was continued until disease progression or unacceptable toxicity. The treatment groups were well balanced. The median age was 56 years and approximately 56% had prior surgical management or treatment of biliary duct obstruction. The Primary endpoint was Overall Survival (OS), and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety. The researchers envisioned that patients who did not need surgical management or treatment of biliary duct obstruction, typically would have better liver function without jaundice, and therefore would better tolerate chemotherapy. A subgroup analyses was therefore conducted based on whether the patients needed surgical management or treatment of bile duct obstructions prior to receiving chemotherapy.

The median Overall Survival was significantly longer in the Nimotuzumab/Gemcitabine group compared to those who received placebo plus Gemcitabine (10.9 months versus 8.5 months; HR=0.50; P=0.025). The one-year survival rate was 43.6% in the Nimotuzumab/Gemcitabine group versus 26.8% in the placebo-Gemcitabine group and the 3-year survival rate was 13.9% and 2.7%, respectively. The median Progression Free Survival was 4.2 months in the Nimotuzumab/Gemcitabine group compared to 3.6 months in the placebo plus Gemcitabine group (HR=0.56; P=0.013).

Among those patients who did not need surgical management or treatment of biliary duct obstruction, subgroup analyses showed significantly more survival benefit in patients without treatment of biliary obstruction (11.9 months versus. 8.5 months; HR=0.54; P=0.037) and among those with no surgical history (15.8 months versus 6.0 months; HR=0.40). Patients without treatment of biliary obstruction also had a significantly longer PFS (5.5 months versus 3.4 months; P=0.008) respectively. There was no statistical difference in the Objective Response Rates between the two treatment groups (P>0.05). Grade 3 adverse events in the Nimotuzumab/Gemcitabine group were neutropenia (11%), leukopenia (9%) and thrombocytopenia (7%). No Grade 4 adverse events were noted.

It was concluded that Nimotuzumab in combination with Gemcitabine, significantly increased Overall Survival and Progression Free Survival, in patients with K-Ras wild-type locally advanced or metastatic pancreatic cancer. This benefit was even more in patients who did not need surgical management or treatment of biliary duct obstruction.

Nimotuzumab combined with gemcitabine versus gemcitabine in K-RAS wild-type locally advanced or metastatic pancreatic cancer: A prospective, randomized-controlled, double-blinded, multicenter, and phase III clinical trial. Qin S, Bai Y, Wang Z, et al. J Clin Oncol. 2022;40(suppl 17):LBA4011. doi:10.1200/JCO.2022.40.17_suppl.LBA4011.

Screening for Pancreatic Cancer Results in Early Detection and Improved Overall Survival

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SUMMARY: The American Cancer Society’s estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 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 10%. 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

Detecting cancer at early stages can significantly increase survival rates and outcomes. Pancreatic ductal adenocarcinoma is one of the deadliest cancers, and is typically detected when the disease is advanced. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is not recommended by the FDA for screening, as it may be elevated in several benign conditions.

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.

Screening for pancreatic cancer has been recommended for individuals considered to be at high risk of developing pancreatic ductal adenocarcinoma (5% or higher estimated lifetime risk). The risk increases with the number of affected first-degree relatives with pancreatic cancer and in those who carry a pathogenic germline variant in a pancreatic cancer susceptibility gene. The goals of screening for pancreatic cancer are to reduce mortality from pancreatic cancer through early detection, at a stage when the disease is most curable (Stage I), or when there is only a noninvasive neoplasm with high-grade dysplasia.

The Cancer of the Pancreas Screening Study (CAPS) is a research program developed at Johns Hopkins in 1998, to evaluate the effectiveness of early detection screening in high risk individuals of pancreatic cancer, and to progress the discovery of new biomarkers to improve early detection. The screening consortium agreed that to be successful, a screening program should detect and treat T1N0M0 margin-negative pancreatic cancer and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). CAPS 1–4 studies were single-institution studies, whereas CAPS 5 is a multicenter, prospective cohort study involving eight academic medical centers in the United States that opened to enrollment in 2014. The goal of CAPS 5 was to report pancreas surveillance outcomes of high-risk individuals within the CAPS 5 study, and to update outcomes of patients enrolled in prior CAPS studies, initiated more than 20 years ago. .

CAPS 5 prospectively enrolled 1,461 high-risk individuals for pancreas surveillance. High Risk Individuals included those with hereditary syndromes or germline variant carriers such as BRCA2, ATM, BRCA1, PALB2 or Lynch syndrome associated genes with a family history of pancreatic ductal adenocarcinoma, FAMMM-Familial Atypical Multiple mole Melanoma (CDKN2A) and Peutz-Jeghers syndrome (STK11). Also included in the high risk group were individuals with a family history of at least one first-degree and one second-degree relative with pancreatic ductal adenocarcinoma. High risk individuals should have met age criteria for surveillance. Surveillance protocol included annual surveillance with endoscopic ultrasound and or MRI/MRCP, often alternating between these two methods. Surveillance interval was modified when suspicious lesions were detected.

The Primary outcome of this study was the early detection of Stage I pancreatic duct adenocarcinoma or a noninvasive neoplasm with high grade dysplasia among high risk individuals undergoing surveillance. The study’s secondary outcome was Overall Survival after a diagnosis of pancreatic ductal adenocarcinoma or high grade dysplasia for high risk individuals enrolled in all CAPS studies (CAPS1-5), estimated using the Kaplan-Meier method.

Among the 1461 high risk individuals undergoing surveillance in the CAPS 5 study, 77.8% of pancreatic cancers were surgical pathology Stage I at diagnosis, 88.9% had resectable disease and the median survival for these patients was 9.8 years. This is in contrast to pancreatic ductal adenocarcinoma diagnosed outside surveillance where more than 50% present with metastatic disease, less than 20% have localized resectable disease and less than 5% have surgical Stage I disease.

In the entire CAPS cohort (CAPS 1-5) to date, the 5-year Overall Survival among screen-detected pancreatic ductal adenocarcinoma was 73.3%. The patients who progressed to pancreatic ductal adenocarcinoma in this study included carriers with germline pathogenic variants and those who met familial-risk criteria only. These results support current CAPS surveillance recommendations and argue against limiting pancreatic surveillance to those high-risk individuals with known pathogenic mutations. The median survival in the entire CAPS cohort for the patients with a screen-detected pancreatic ductal adenocarcinoma was 9.8 years, compared with 1.5 years for patients whose pancreatic ductal adenocarcinoma were diagnosed outside surveillance (HR=0.13; P=0.003).

The researchers concluded that screening for pancreatic cancer in high risk individuals can result in early detection, at a stage when the disease is most curable (Stage I).

The Multicenter Cancer of Pancreas Screening Study: Impact on Stage and Survival. Dbouk M, Katona BW, Brand RE, et al., J Clin Oncol. 2022 Jun 15;JCO2200298. doi: 10.1200/JCO.22.00298. Online ahead of print.

Early-Stage Multi-Cancer Detection Using an Extracellular Vesicle Protein-Based Blood Test

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SUMMARY: The American Cancer Society’s estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 people will die of the disease, 19,880 women will receive a new diagnosis of ovarian cancer and about 12,810 women will die of the disease, and about 81,800 new cases of bladder cancer will be diagnosed in 2022 and about 17,100 patients will die of the disease. These three cancer types are estimated to account for approximately 80,000 deaths in the US in 2022. Detecting cancer at early stages can significantly increase survival rates and outcomes.

Several multi-cancer early detection tests are being developed that involve blood-based circulating cell-free tumor DNA (cfDNA) in the plasma, to track hundreds of patient-specific mutations, to detect Minimal Residual Disease (MRD) , as well as detection of abnormal methylation patterns, followed by machine learning approaches, to differentiate between cancer and non-cancer, for detecting clinically significant, late-stage (III and IV) cancers. Early detection of cancer however is the key to improving survival. This is particularly relevant for certain cancer types. Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the deadliest cancers, and a leading cause of all cancer-related deaths in the United States, and is typically detected when the disease is advanced. However, when detected at Stage I, survival rates can be as high as 80%. Ovarian cancer is often detected when the disease is advanced and the 5-year survival rates are less than 30%, but can be as high as 93% when detected early. The same holds true for metastatic bladder cancer, with 5-year survival rates of only 6%, whereas while detected when the tumor is still localized to the bladder wall inner layer results in a 5-year survival rate of 96%. Even though serum CA19-9 is intended as an aid in the management of patients with confirmed pancreatic cancer for serial monitoring of their response to therapy and disease progression, it is not recommended by the FDA for screening, as it may be elevated in several benign conditions. Similarly, serum CA-125 is FDA approved for use in monitoring patients with ovarian cancer for disease persistence and recurrence, but is not recommended to screen for ovarian cancer. Currently, there are few general screening strategies to detect asymptomatic, early-stage PDAC, ovarian, or bladder cancer and there is therefore a significant unmet need in this patient group.

Exosomes are 30-150 nm-sized Extracellular Vesicles (EVs) secreted by multiple different cell types and ejected by tumors into the bloodstream. They mediate intercellular signaling by transferring mRNAs and microRNAs between distant cells and tissues and therefore carry functional protein biomarkers representing the tumor proteome. Exosomes represent one potential approach for more sensitive detection of cancer-related biomarkers from blood.

The researchers in this study used an Alternating Current Electrokinetic (ACE)-based platform (Verita™ System) to efficiently isolate EVs from soluble contaminants such as cells, small proteins, or other vesicles from patient samples, and then measured the concentrations of associated protein biomarkers (“EV proteins”) present in the purified EV samples from our case-control study subjects. The researchers chose this platform over the current gold standard ultracentrifugation method, which the authors felt was inefficient and not suitable for point-of-care applications. Artificial Intelligence machine-learning algorithm developed by the researchers, enabled detection of early-stage pancreatic, ovarian, and bladder cancers.

In this case-control pilot study, 139 pathologically confirmed Stage I and II cancer cases representing pancreatic, ovarian, or bladder patients were compared with 184 control subjects, using the Verita™ System. The Extracellular Vesicles (EVs) isolated using this technology, were consistent with the presence of Exosomes, in accordance with the International Society for Extracellular Vesicles (ISEV) 2018 guidelines. The researchers selected a panel of 13 Extracellular Vesicle (EV) proteins along with age, a known cofactor in cancer. In order to simulate a real-world screening scenario, all cancer cases were treatment-naïve and to ensure that these were early-stage patients, the histopathologic staging was confirmed using the American Joint Commission on Cancer (AJCC) guidelines. The median age of the cancer cases was 60 years and 63.3% of the overall cancer cases were Stage I, with the remaining 36.7% at Stage II. The median age of the control group was 57 years and had no known history of cancer, autoimmune diseases, neurodegenerative disorders or diabetes mellitus.

When the overall cancer case cohort was compared with the control individuals using the EV protein biomarker test, the average sensitivity was 71.2%, at a specificity of 99.5%. When considered across all the three cancers studied, EV protein biomarker test using this technology demonstrated similar sensitivities of 70.5% and 72.5% for Stage I and II patients, respectively. This new technology detected 95.5% of Stage I pancreatic cancers, 73.1% of pathologic Stage IA lethally aggressive serous ovarian adenocarcinomas and 43.8% in bladder cancer, demonstrating the potential value of this platform for detection of early stage cancers. The lower sensitivity for detecting early stage bladder cancer may be due to high molecular and histologic heterogeneity of bladder tumors.

It was concluded from this study that blood-based EV protein detection test has potential clinical value for early cancer detection and the use of Verita™ platform resulted in the accurate detection of early stage pancreatic, ovarian, or bladder cancer. The authors added that mortality from pancreatic cancer which will soon become the second leading cause of cancer mortality in the U.S., can be greatly reduced if this study results are validated.

Early-stage multi-cancer detection using an extracellular vesicle protein-based blood test. Hinestrosa, J.P., Kurzrock, R., Lewis, J.M. et al. Commun Med 2, 29 (2022). https://doi.org/10.1038/s43856-022-00088-6.

Maintenance RUBRACA® in Patients with Advanced Pancreatic Cancer with a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2

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SUMMARY: The American Cancer Society estimates that for 2021, about 60,430 people will be diagnosed with pancreatic cancer and about 48,220 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 2021.

DNA damage is a common occurrence in daily life by UV light, ionizing radiation, replication errors, chemical agents, etc. This can result in single and double strand breaks in the DNA structure which must be repaired for cell survival. The two vital pathways for DNA repair in a normal cell are BRCA1/BRCA2 and PARP. BRCA1 and BRCA2 genes recognize and repair double strand DNA breaks via Homologous Recombination Repair (HRR) pathway. Homologous Recombination is a type of genetic recombination, and is a DNA repair pathway utilized by cells to accurately repair DNA double-stranded breaks during the S and G2 phases of the cell cycle, and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1, BRCA2, PALB2, CHEK2 and ATM genes. BRCA1 and BRCA2 are tumor suppressor genes located on chromosome 17 and chromosome 13 respectively and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. 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). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates HR pathway, and other pathways then come in to play, which are less precise and error prone, resulting in the accumulation of additional mutations and chromosomal instability in the cell, with subsequent malignant transformation. Homologous Recombination Deficiency therefore indicates an important loss of DNA repair function.

The PARP (Poly ADP Ribose Polymerase), family of enzymes include, PARP1 and PARP2, and is a related enzymatic pathway that repairs single strand breaks in DNA. In a BRCA mutant, the cancer cell relies solely on PARP pathway for DNA repair to survive. PARP inhibitors trap PARP onto DNA at sites of single-strand breaks, preventing their repair and generating double-strand breaks that cannot be repaired accurately in tumors harboring defects in Homologous Recombination Repair pathway genes, such as BRCA1 or BRCA2 mutations, and this leads to cumulative DNA damage and tumor cell death.

LYNPARZA® (Olaparib) is a PARP inhibitor and is presently approved as maintenance therapy for patients with advanced pancreatic cancer demonstrating a germline BRCA1 or BRCA2 pathogenic variant. However, previously published studies have demonstrated the benefit of PARP inhibitors in breast, prostate and ovarian cancer patients, beyond germline BRCA pathogenic variants. Further, there is an unmet need to expand the group of patients with pancreatic cancer who may benefit from therapy with a PARP inhibitor, beyond those with germline BRCA pathogenic variants.

This investigator-initiated, single-arm Phase II study was conducted to assess the role of oral, small molecule PARP inhibitor RUBRACA® (Rucaparib), as maintenance therapy in advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2 genes. This study enrolled 46 patients with advanced pancreatic cancer with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2, and had received at least 16 weeks of platinum-based chemotherapy without evidence of platinum resistance, which was defined as growing tumors, new lesions, or a steadily rising tumor marker during or within 8 weeks of platinum therapy. The median age was 62 years, approximately 17% had germline BRCA1, 64% had germline BRCA2, 14% had germline PALB2 and 5% had somatic BRCA2 pathogenic variants. Majority of patients (95%) had metastatic disease and 5% had locally advanced disease. Ashkenazi Jewish founder mutation was found in 24% of patients. The Primary end point was Progression Free Survival (PFS) at 6 months (PFS). Secondary end points included Safety, Objective Response Rate (ORR), Disease Control Rate, Duration of Response, and Overall Survival.

The PFS at 6 months was 59.5% and the PFS at 12 months was 54.8%. The median PFS was 13.1 months and median Overall Survival was 23.5 months. The ORR in those with measurable disease was 42%, and the Disease Control Rate was 67%. The median Duration of Response was 17.3 months. These responses were noted across all germline and somatic pathogenic variants in BRCA1, BRCA2, and PALB2 genes, and no new safety signals were noted.

It was concluded from this study that maintenance RUBRACA® is a safe and effective therapy for platinum-sensitive, advanced pancreatic cancer patients, with a pathogenic variant in BRCA1, BRCA2, or PALB2. The authors added that the finding of efficacy in patients with germline PALB2 and somatic BRCA2 pathogenic variants, expands the population of patients likely to benefit from PARP inhibitors, beyond those with germline BRCA1 and BRCA2 pathogenic variants.

Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. Reiss KA, Mick R, O’Hara MH, et al. J Clin Oncol. 2021;39:2497-2505.