Category: Hem/Onc Updates

Increased Physical Activity Associated with Lower Risk of 13 Different Cancer Types

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SUMMARY: The American Cancer Society estimates that in 2016, 1,685,210 new cancer cases will be diagnosed in the United States and 595,690 cancer deaths are projected. It is a well established fact that physical activity reduces the risk of heart disease and all-cause mortality. Additionally, previously published studies have shown reduced risks for Colon, Breast and Endometrial cancers with physical activity. However, it has remained unclear whether physical activity reduces risk of other cancers, which together constitute approximately 75% of all cancers in the United States.

It has been hypothesized that the link between physical activity and cancer is mediated through both hormonal as well as non-hormonal pathways. Hormonal systems such as sex steroids, insulin and insulin-like growth factors, and adipokines can initiate cancer cell growth. Intervention with physical activity by partly reducing adiposity, decreases the levels of estrone, estradiol and insulin in postmenopausal women. Non-hormonal mechanisms linking physical activity to cancer risk, include inflammation, immune function, oxidative stress, and for colon cancer, a reduction in transit time for waste to pass through the gastrointestinal tract.

The authors in this study examined pooled data from 12 prospective cohort studies involving 1.44 million participants, to find out whether there was an association of leisure-time physical activity with incidence of 26 different cancer types. They also examined whether these associations were evident regardless of body size or smoking history. Leisure-time physical activities were defined as activities done at an individual’s discretion, to improve or maintain fitness or health. This could include walking, running, swimming or other moderate- to vigorous-intensity activities. The median physical activity in this study was equivalent to 150 minutes of moderate-intensity activity every week and comparable to the current recommended minimum physical activity level for the US population. Leisure-time physical activity was assessed by self-reported surveys. The median age was 59 years and median BMI was 26.

Participants were followed for a median of 11 years during which period 187,000 new cases of cancer occurred. The authors noted that leisure-time physical activity was associated with lower risk of 13 of 26 cancer types which included Esophageal adenocarcinoma, Liver, Lung, Kidney, Gastric cardia, Endometrial, Myeloid Leukemia, Myeloma, Colon, Head and Neck, Rectal, Bladder and Breast. The greatest risk reduction was noted for Esophageal adenocarcinoma. These associations were evident regardless of body size or smoking history in most cases.

The authors concluded that leisure-time physical activity not only reduces risk of heart disease and risk of death from all causes, but also lowers risk of many types of cancer, regardless of body size or smoking history. Physical activity should therefore be promoted for population-wide cancer prevention and control. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. Moore SC, Lee I, Weiderpass E, et al. JAMA Intern Med. 2016;176:816-825.

FDA Approves AXUMIN® to Identify Prostate Cancer Recurrence in Patients with Rising PSA

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SUMMARY: The FDA on May 27, 2016 approved AXUMIN® (Fluciclovine F18), a novel molecular radiopharmaceutical diagnostic agent, for Positron Emission Tomography (PET) imaging in men with suspected prostate cancer recurrence, based on elevated Prostate Specific Antigen (PSA) levels, following prior treatment. Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease.

The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse.

Rising PSA is therefore a sign of recurrent disease and identifying the site of recurrence can be of immense value for the clinician and can help determine the best course of therapy. The diagnostic accuracy of standard imaging tests, for the identification of sites of recurrence in patients with biochemical recurrence, is low. Almost 90% of the standard imaging tests such as CT/MRI and Bone Scan may be negative. More accurate non-invasive imaging techniques for the detection of recurrent tumor is an unmet need. Prostascint, a Single Photon Emission Computerized Tomography (SPECT) radiopharmaceutical agent, was approved in 1999 for the diagnostic imaging of post-prostatectomy patients with a rising PSA. PET scans have largely superseded this study. FluDeoxyGlucose F18 (FDG), a glucose analogue is the most widely used PET radiotracer, but is not generally used as an imaging agent in prostate cancer. This is because good and reliable quality images are not feasible due to indolent growth of prostate cancers and the high urinary excretion of FDG. The other PET radiotracer that is available, Choline C11, has been shown to improve cancer detection in men with biochemical recurrent prostate cancer, but this agent has a short half life of 20 minutes, requires greater patient preparation including 6 hours of fasting prior to administration of Choline C11, delivers higher radiation dose to patients and image quality is poor.

AXUMIN® (Fluciclovine), a diagnostic radiopharmaceutical, is a synthetic amino acid that is preferentially transported into prostate cancer cells by amino acid transporters such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. This agent is neither metabolized nor incorporated into newly synthesized proteins. The visualization of the increased amino acid transport is facilitated by labeling AXUMIN® with F18 for PET imaging. The FDA approval of AXUMIN® was based on two retrospective trials (Trial 1 and Trial 2) which evaluated the safety and efficacy of AXUMIN® for imaging prostate cancer, in patients with recurrent disease. Trial 1 compared 105 (N=105) AXUMIN® scans in men with suspected prostate cancer, to the histopathology (study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. PET/CT imaging generally included both abdomen and pelvic regions. Local radiologist read the scans initially and subsequently, three independent radiologists read the same scans in a blinded study. Trial 2 evaluated the concordance between 96 (N=96) AXUMIN® and Choline C11 scans, in patients with median PSA values of 1.44 ng/mL. Local radiologist read the Choline C11 scans, and the same three independent radiologists from Trial 1 read the scans, in this second blinded study.

The FDA reported that results of the independent scan readings were generally consistent and confirmed the local scan reading results, and both studies supported the safety and efficacy of AXUMIN® for imaging prostate cancer in men with elevated PSA levels, following prior treatment. It should be noted that a negative study does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. The most commonly reported adverse events in patients were injection site pain, redness and a metallic taste in the mouth.

It was concluded that AXUMIN® can determine the location of the recurrent prostate cancer in patients with low PSA levels. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208054Orig1s000TOC.cfm

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer – Part II

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. Developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies and prospective comparative observational studies published from 2006 through 2014, these recommendations are meant to provide guidance to the Health Care Provider, as appropriate treatment is considered for patients with newly diagnosed, early-stage invasive breast cancer.

Two important questions were addressed by these guidelines – The Part I edition last week (www.oncoprescribe.com) addressed the first clinical question. This week’s edition (Part II) addresses the second clinical question.

Clinical Question 2: For women with early-stage invasive breast cancer and with known estrogen receptor/progesterone receptor and HER2 status, which additional biomarkers have demonstrated clinical utility to guide the choice of specific drugs or regimens for adjuvant systemic therapy?

Tamoxifen

CYP2D6 polymorphisms should not be used to guide adjuvant endocrine therapy selection. The expression of p27 by IHC should not be used to guide adjuvant endocrine therapy selection.

Aromatase Inhibitors

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide adjuvant endocrine therapy.

Taxanes

Microtubule-associated protein Tau mRNA expression or mRNA expression by IHC should not be used to guide adjuvant chemotherapy selection. HER1/Epidermal Growth Factor Receptor expression by IHC should not be used to guide adjuvant chemotherapy selection.

Anthracyclines

TOP2A gene amplification or TOP2A protein expression by IHC should not be used to guide adjuvant chemotherapy selection. HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 should not be used to guide adjuvant chemotherapy selection.

Trastuzumab

If a patient has HER2 positive breast cancer, PTEN should not be used to guide adjuvant therapy selection. If a patient has HER2 positive breast cancer, soluble HER2 levels should not be used to guide the selection of the type of adjuvant therapy.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

Interim PET Scan may Define Prognosis and Provide Treatment Guidance for Patients with Advanced Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2016, about 8500 new cases of Hodgkin lymphoma will be diagnosed and over 1100 patients will die of the disease. Hodgkin lymphoma is classified into two main groups – Classical Hodgkin lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

Advanced-stage (stage III to stage IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD regimen). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax. The second most often used regimen in the first-line setting, e-BEACOPP (escalated doses of Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) has been associated with a higher Progression Free Survival as well as higher 5-year Overall Survival (approximately 90%). This regimen however is associated with short and long term toxicities such as prolonged fatigue, permanent fertility, Myelodysplasia and secondary malignancies.

A retrospective study by Gallamini and co-workers in 2007 had shown that a PET scan after two cycles of ABVD chemotherapy was an independent prognostic factor, with a 2-year Progression Free Survival rate of 95%, for those patients with negative interim PET scan, compared to only 12.8% for those with persistently positive PET scan. Based on these observations, the authors in this prospective trial evaluated the benefit of a “response-adapted” approach, by performing a PET scan following 2 cycles of ABVD treatment and modifying therapy based on the interim PET scan findings.

In this randomized controlled trial, 1203 eligible patients with newly diagnosed advanced Classical Hodgkin lymphoma were registered. The median age was 33 years. Following 2 cycles of chemotherapy with ABVD regimen, 1119 patients had an interim PET-CT scan and patients with negative PET findings (83.7%) were randomly assigned in a 1:1 ratio to continue ABVD regimen (ABVD group) or receive ABVD omitting Bleomycin (AVD group), for cycles 3 through 6. Radiotherapy was not recommended for patients with negative findings on interim PET scans. Patients with positive interim PET scan findings following two cycles of ABVD (16%), received 4-6 cycles of BEACOPP regimen. The primary outcome was the difference in the 3-year Progression Free Survival rate between randomized groups.

With a median follow up of 41 months, the 3-year Progression Free Survival was 85.7% with ABVD and 84.4% with AVD and 3 year Overall Survival was 97.2% and 97.6% in these two respective groups. Pulmonary toxicities were more severe in the ABVD group than in the AVD group and deleting Bleomycin following 2 cycles of ABVD, in patients with negative interim PET scan, did not compromise outcomes. Patients who received BEACOPP regimen based on a positive interim PET scan after the first 2 cycles of ABVD (N=172), had a 3-year Progression Free Survival of 67.5% and Overall Survival rate of 87.8%.

The authors concluded that following 2 cycles of ABVD regimen, omitting Bleomycin from the ABVD regimen, based on a negative interim PET scan (response-adapted therapy), resulted in lower incidence of pulmonary toxicities, compared with continued treatment with ABVD, without compromising efficacy. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin’s Lymphoma. Johnson P, Federico M, Kirkwood A, et al. N Engl J Med 2016; 374:2419-2429

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer Part 1

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. A multitude of biomarker assays are presently available for the practicing Health Care Provider. Choosing the appropriate biomarker assay for a given patient can be a daunting task and the ASCO guidelines set forth herein, were developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies, and prospective comparative observational studies, published from 2006 through 2014. These guidelines are only applicable for patients with newly diagnosed, non-metastatic, primary breast cancer, to prognosticate and predict outcomes but they do not however comment on the choice of specific treatment or regimens based on recurrence score. Treatment decisions should take into consideration disease stage, comorbidities and patient preferences. Even though several tests are now recommended in the guidelines, only one test should be used to guide therapy for an individual patient.

Two important questions were addressed by these guidelines – This edition (Part 1) addresses the first Clinical Question

Clinical Question 1: For women with early-stage invasive breast cancer and with known Estrogen receptor/Progesterone receptor and HER2 status, which other biomarkers have demonstrated clinical utility to guide decisions on the need for adjuvant systemic therapy?

Oncotype DX

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, the Oncotype DX 21-gene recurrence score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node positive disease. It should not be used in patients with HER2 positive or triple negative disease.

PAM50 Risk of Recurrence Score

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the PAM50 Risk of Recurrence score may be used in conjunction with other clinicopathologic variables to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive breast cancer and those with triple-negative breast cancer to guide decisions on adjuvant systemic therapy.

EndoPredict

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, EndoPredict 12-gene risk score may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple-negative disease.

Breast Cancer Index

If a patient has ER/PR positive, HER2 negative, node-negative breast cancer, the Breast Cancer Index may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with ER/PR positive, HER2 negative, node-positive disease. It should not be used in patients with HER2 positive or triple negative breast cancer to guide decisions on adjuvant systemic therapy.

Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1

If a patient has ER/PR positive, HER2 negative, node negative breast cancer, Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 may be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

MammaPrint

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the MammaPrint 70-gene assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive disease. It should not be used in patients with triple negative breast cancer.

Mammostrat

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, the Mammostrat 5-protein assay should not be used to guide decisions on adjuvant systemic therapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Immunohistochemistry 4

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Immunohistochemistry 4 (IHC4) should not be used to guide decisions on adjuvant systemic chemotherapy. It should not be used in patients with HER2 positive or triple negative breast cancer.

Circulating Tumor Cells

The clinician should not use circulating tumor cells to guide decisions on adjuvant systemic therapy.

Tumor-Infiltrating Lymphocytes

If a patient has ER/PR positive, HER2 negative (node-positive or node-negative) breast cancer, Tumor-Infiltrating Lymphocytes should not be used for decision making. It should not be used in patients with HER2 positive or triple negative breast cancer.

Protein Encoded by MKI67 Gene

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide choice on adjuvant chemotherapy.

Extended Endocrine Therapy

If a patient has ER/PR positive, HER2 negative (node-negative) breast cancer and has had 5 years of endocrine therapy without evidence of recurrence, multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or IHC4) should not be used to guide decisions on extended endocrine therapy.

The Clinical Question 2 will be addressed in the eNL edition (Part 2) next week.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

Late Breaking Abstract – ASCO 2016 Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

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Late Breaking Abstract – ASCO 2016: Liquid Biopsy Can Rapidly Detect Certain Gene Mutations with High Specificity

SUMMARY: The FDA approved the first “Liquid Biopsy” test on June 1, 2016 for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene. On the heels of this approval, Zill and colleagues reported the results of the largest liquid biopsy study ever conducted thus far. It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful, as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma, also called liquid biopsy, can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The authors in this study utilized Next Generation Sequencing (NGS) of circulating tumor DNA (ctDNA), isolated from plasma specimens (liquid biopsy specimens) of 15,191 patients of whom 37% had advanced lung cancer, 14% had breast cancer, 10% had colorectal cancer and 39% had other malignancies. Seventy genes were targeted and accuracy of ctDNA sequencing was assessed by comparing with matched tissue tests for 386 patients and frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects such as data from The Cancer Genome Atlas (TCGA).

It was noted that the ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% and the accuracy increased to 98% when blood and tumor were collected less than six months apart. Pearson Correlation between sets of data is a measure of how well these sets are related. Between 0.5 and 1.0 is considered high correlation. Pearson correlation for TP53 gene was 0.94, for KRAS was 0.99 and for PIK3CA was 0.99.

The researchers commented on the clinical outcome benefits using liquid biopsy, in four distinct groups:

1) Testing for actionable mutations (ALK fusion, EGFR or BRAF activating mutations in lung; ERBB2 amplification in gastric cancer) in cases with insufficient tissue quantity.

2) Testing for actionable resistance mutations (MET amplification or EGFR T790M in lung cancer), at the time of progression.

3) Genomic evolution upon progression such as ERBB2-amplified metastatic breast cancer in patients with triple negative primary tumor.

4) Tumors with genotypes that need more extensive driver mutation testing such as BRAF V600E in lung.

The authors concluded that there is a high correlation between ctDNA plasma samples and tissue testing with the exception of resistance mutations such as EGFR T790M mutation which evolve while on anti-EGFR inhibitor therapy and consequently may not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation. Patients who received treatment based on ctDNA findings also experienced better clinical outcomes. Zill OA, Mortimer S, Banks KC, et al Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016;34(suppl; abstr LBA11501).

YONDELIS® – A Marine-Derived Drug for Soft Tissue Sarcomas

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SUMMARY: The FDA approved the first “Liquid Biopsy” test on June 1, 2016 for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the Epidermal Growth Factor Receptor (EGFR) gene. On the heels of this approval, Zill and colleagues reported the results of the largest liquid biopsy study ever conducted thus far. It has been well established that treatment with EGFR TKIs results in superior outcomes, for patients with tumors harboring exon 19 deletions and exon 21 mutations. The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tumor specimen, following progression or recurrence. Archived biopsy specimens may not be helpful, as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping cell free DNA in the plasma, also called liquid biopsy, can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The authors in this study utilized Next Generation Sequencing (NGS) of circulating tumor DNA (ctDNA), isolated from plasma specimens (liquid biopsy specimens) of 15,191 patients of whom 37% had advanced lung cancer, 14% had breast cancer, 10% had colorectal cancer and 39% had other malignancies. Seventy genes were targeted and accuracy of ctDNA sequencing was assessed by comparing with matched tissue tests for 386 patients and frequencies of somatic ctDNA alterations per gene were compared to those previously described in tissue sequencing projects such as data from The Cancer Genome Atlas (TCGA).

It was noted that the ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA. The overall accuracy of ctDNA sequencing in comparison with matched tissue tests was 87% and the accuracy increased to 98% when blood and tumor were collected less than six months apart. Pearson Correlation between sets of data is a measure of how well these sets are related. Between 0.5 and 1.0 is considered high correlation. Pearson correlation for TP53 gene was 0.94, for KRAS was 0.99 and for PIK3CA was 0.99.

The researchers commented on the clinical outcome benefits using liquid biopsy, in four distinct groups:

1) Testing for actionable mutations (ALK fusion, EGFR or BRAF activating mutations in lung; ERBB2 amplification in gastric cancer) in cases with insufficient tissue quantity.

2) Testing for actionable resistance mutations (MET amplification or EGFR T790M in lung cancer), at the time of progression.

3) Genomic evolution upon progression such as ERBB2-amplified metastatic breast cancer in patients with triple negative primary tumor.

4) Tumors with genotypes that need more extensive driver mutation testing such as BRAF V600E in lung.

The authors concluded that there is a high correlation between ctDNA plasma samples and tissue testing with the exception of resistance mutations such as EGFR T790M mutation which evolve while on anti-EGFR inhibitor therapy and consequently may not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation. Patients who received treatment based on ctDNA findings also experienced better clinical outcomes. Zill OA, Mortimer S, Banks KC, et al Somatic genomic landscape of over 15,000 patients with advanced-stage cancer from clinical next-generation sequencing analysis of circulating tumor DNA. J Clin Oncol. 2016;34(suppl; abstr LBA11501).

Updated Survival Analysis of ONIVYDE®, 5-FU and Leucovorin Combination in Metastatic Pancreatic Carcinoma

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SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with pancreatic cancer in the United States and close to 42,000 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.

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, ONIVYDE® plus 5-FluoroUracil (5-FU) and Leucovorin or 5-FU with Leucovorin (control group). 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. The primary study endpoint was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR).

The primary survival analysis was previously reported was based on 313 events. The combination of ONIVYDE®, 5-FU and Leucovorin resulted in a median OS of 6.1 months compared with 4.2 months with 5-FU and Leucovorin alone (HR = 0.67; P=0.012). The median PFS was 3.1 months for the ONIVYDE® combination compared with 1.5 months with 5-FU and Leucovorin alone (HR= 0.55; P=0.0001). The ORR was low in both treatment groups (7.7% vs 0.8%), respectively. ONIVYDE® montherapy was not superior, compared with 5-FU and Leucovorin and was associated with more side effects compared to the combination regimen. In an expanded, pre-specified analyses, patients who received at least 80% of the target dose in the first 6 weeks experienced an even greater Overall Survival benefit (43% improvement) with ONIVYDE® combination, compared with 5-FU and Leucovorin alone (8.9 months vs 5.1 months, HR=0.57, P=0.011).

This publication is an updated analysis of OS along with 6 and 12 month survival estimates and safety, based on 378 events, as of 25 May 2015. The authors noted that that 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 (HR = 0.75; P=0.04). Again, there was no OS advantage with ONIVYDE® monotherapy, when compared with 5-FU and Leucovorin. The 6 month survival estimate was 53% with ONIVYDE®, 5-FU and Leucovorin compared with 38% for 5-FU and Leucovorin alone and 12 month survival estimates were 26% for ONIVYDE®, 5-FU and Leucovorin versus 16% for 5-FU and Leucovorin alone. The impact of ONIVYDE® on Overall Survival was more dramatic, with increasing benefit seen with higher levels of CA 19-9. The most common grade 3/4 adverse events with ONIVYDE® plus 5-FU and Leucovorin were neutropenia, fatigue, diarrhea and vomiting.

The authors following this updated analysis concluded that the median Overall Survival benefit for ONIVYDE® plus 5-FU and Leucovorin was maintained, with no new adverse events and this combination may be a new standard of care for patients with metastatic Pancreatic cancer, previously treated with Gemcitabine based therapy. Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Wang-Gillam A, Li C, Bodoky G, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 417)

First Oral Triplet Combination – NINLARO®, REVLIMID® and Dexamethasone for Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,330 new cases will be diagnosed in 2016 and 12,650 patients will die of the disease. Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Myeloma cells depend on the proteasomes to facilitate this metabolic function, to regulate their growth and survival. NINLARO® (Ixazomib) unlike VELCADE® (Bortezomib) is a second generation, oral, proteasome inhibitor, which disrupts protein metabolism in Myeloma cells, by inhibiting proteasomes and has an antiproliferative and pro-apoptotic effect.

The approval of NINLARO® was based a pivotal, multicenter, randomized, double-blind, placebo-controlled, phase III trial (TOURMALINE-MM1 study), in which 722 patients with Multiple Myeloma were randomized in a 1:1 ratio to receive either a combination of NINLARO®, REVLIMID® and Dexamethasone (N=360) or a combination of Placebo, REVLIMID® and Dexamethasone (n=362). NINLARO® was administered at 4 mg PO on days 1, 8, and 15 in combination with REVLIMID® 25 mg PO on days 1 thru 21 and Dexamethasone 40 mg PO on days 1, 8, 15, and 22 of a 28 day treatment cycle. Treatment was continued until disease progression or unacceptable toxicity. Enrolled patients had received 1 to 3 prior lines of therapy, which included VELCADE® (69%), THALOMID® (45%), and REVLIMID® (12%) and 77% of the patients had relapsed Multiple Myeloma. The median age of patients was 66 years. The primary end point of the study was Progression Free survival (PFS) and secondary endpoints included Objective Response Rate (ORR), safety, and Overall Survival.

At a median follow-up of 14.7 months, the PFS with the combination of NINLARO®, REVLIMID® and Dexamethasone was 20.6 months compared with 14.7 months for the combination group of Placebo, REVLIMID® and Dexamethasone (HR= 0.74, P=0.01). This benefit in the NINLARO® group, was noted in all prespecified patient subgroups, including those with high risk cytogenetic abnormalities. The Objective Response Rate was 78% in the NINLARO® group and 72% in the placebo group, and the Complete Response plus Very Good Partial Response in these two treatment groups were 48% and 39% respectively. The median time to response was 1.1 months in the NINLARO® group and 1.9 months in the placebo group and the median duration of response was 20.5 months and 15.0 months respectively. At a median follow up of 23 months, the Overall Survival has not been reached in either study group. Serious adverse events (at least grade 3) were similar in the two study groups (47% in the NINLARO® group and 49% in the placebo group). Patients in the NINLARO® group experienced more adverse events such as thrombocytopenia, vomiting, diarrhea, peripheral neuropathy and skin rash. However, patient-reported Quality of Life was similar in both treatment groups.

The authors concluded that NINLARO® based oral triplet therapy significantly prolonged Progression Free Survival compared with REVLIMID® and Dexamethasone, in patients with relapsed/refractory Multiple Myeloma, with acceptable toxicities. Studies are underway, evaluating NINLARO® in newly diagnosed Myeloma patients as well as maintenance therapy in non-transplant patients. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Moreau P, Masszi T, Grzasko N, et al. N Engl J Med 2016; 374:1621-1634

Recurrent VTE in Cancer Patients Treated with XARELTO®

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000 – 100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Patients with unprovoked DVT and PE are two to four times more likely to be diagnosed with cancer within the following 12 months compared to the general population. In patients with cancer associated thrombosis, COUMADIN® (Warfarin) and XARELTO® (Rivaroxaban) are often prescribed, despite guidelines recommending Low Molecular Weight Heparin (LMWH) in this patient population.

Recently published data suggests that the rates of major bleeding, with use of XARELTO® in a highly selected group of cancer patients with venous thromboembolic disease, compared favorably with those treated with LMWH. (Mantha S, et al. 2015 ASH Annual Meeting). There is however limited data comparing the efficacy of different anticoagulants for VTE treatment in cancer patients.

The authors conducted this study in cancer patients, to compare the VTE recurrence rates, following most frequently prescribed anticoagulants in the United States. Newly diagnosed cancer patients with a first VTE, who initiated LMWH, COUMADIN® or XARELTO®, were selected using healthcare claims from the Humana database. The study population included 2,428 patients (XARELTO®: N=707; LMWH: N=660; COUMADIN® N =1,061). VTE recurrences were defined as hospitalizations with a primary diagnosis of VTE. Outpatients with a primary diagnosis of VTE were added as a sensitivity analysis to the recurrence definition.

The median duration on initial LMWH treatment was 1 month, on COUMADIN® was 3.5 months and on XARELTO® was 3 months. When compared to LMWH, VTE recurrence rates were lower with initial XARELTO® treatment at 6 months (13.2% versus 17.1%; P=0.06) and at 12 months (16.5% versus 22.2%; P=0.03). When initially treated with XARELTO®, recurrent VTE was 28% less likely than with LMWH (HR=0.72; P<0.03).

When compared to COUMADIN®, VTE recurrence rates were again lower with initial XARELTO® treatment at 6 months (13.2% versus 17.5%; P=0.02) and at 12 months (15.7% versus 19.9%; P=0.02). When initially treated with XARELTO®, recurrent VTE was 26% less likely than with COUMADIN® (HR=0.74; P<0.03). This benefit with XARELTO® when compared with LMWH and COUMADIN® users, was also noted in the sensitivity analysis.

The authors concluded that based on this real world healthcare claims data in cancer patients, XARELTO® was associated with a lower risk of recurrent VTE than LMWH or COUMADIN® and this could be a reflection of a shorter duration of treatment with LMWH and difficult therapeutic anticoagulation with COUMADIN®. Recurrent VTE in cancer patients treated with anticoagulation. Streiff MB, Milentijevic D, McCrae K, et al. J Clin Oncol 34, 2016 (suppl; abstr 10024)