Updated Analysis KEYTRUDA® Doubles Overall Survival Compared with Chemotherapy in Advanced NSCLC

September 27th, 2019

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for up to 2 years or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. Patients in the chemotherapy group who experienced disease progression were allowed to cross over to the KEYTRUDA® group. The Primary end point was Progression Free Survival (PFS) and Secondary end points included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

It was previously reported that at a median follow up of 11.2 months, the median PFS was 10.3 months in the KEYTRUDA® group versus 6 months in the chemotherapy group (HR=0.50; P<0.001). However, median OS had not been reached in the KEYTRUDA® group at the time of that analysis. The Independent Data and Safety Monitoring Committee (IDMC) based on these results recommended stopping the trial early, to allow for use of KEYTRUDA® in patients randomly assigned to chemotherapy. Eighty two patients (N=82) assigned to chemotherapy, met criteria to cross over to the KEYTRUDA® group, upon progression.

This publication is an updated analysis of the KEYNOTE-024 study, after a median follow-up of 25.2 months. The median OS was 30 months in the KEYTRUDA® group and 14.2 months in the chemotherapy group (HR=0.63; P=0.002). When adjusted for crossover, the OS benefit was maintained and the Hazard Ratio for OS among KEYTRUDA® group versus chemotherapy group was 0.49. Further, more patients in the KEYTRUDA® group achieved 12-month OS (70.3% versus 54.8%), and an ORR response (45.5% versus 29.8%), compared to the chemotherapy group respectively. The ORR among those who crossed over to KEYTRUDA®, was 20.7%. The median Duration of Response has not yet been reached for patients assigned to KEYTRUDA® and also for those who crossed over to KEYTRUDA®. For those assigned chemotherapy, the median Duration of Response was 7.1 months. Patients in the KEYTRUDA® group had lower rates of Grade 3-5 adverse events, compared to those in the chemotherapy group (31.2% versus 53.3%), as well as a lower rate of any-grade adverse events (76.6% versus 90%).

It was concluded that in this updated analysis of KEYNOTE-024, KEYTRUDA® continued to provide improved Overall Survival benefit, inspite of the high rate of crossover, with lower rates of Adverse Events, when compared to chemotherapy, among patients with metastatic NSCLC and high PD-L1 expression. The authors added that these updated long term results support KEYTRUDA® monotherapy as a standard-of-care regimen for first line treatment of advanced NSCLC with PD-L1 expression of 50% or greater and without EGFR/ALK alterations. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non–Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck M , Rodríguez–Abreu D, Robinson AG, et al. J Clin Oncol 2019;37:537-546

Clinical Utility of NETest®, a Liquid Biopsy Assay for Diagnosis, Monitoring Therapy and Prognosis, in Patients with Neuroendocrine Tumors

September 27th, 2019

SUMMARY: It is estimated that in the United States, more than 12,000 people are diagnosed with a Neuroendocrine tumor each year. NeuroEndocrine Tumors (NETs) arise from cells of the endocrine and nervous systems and produce biogenic amines and polypeptide hormones. NETs can be clinically symptomatic (functioning) or silent (nonfunctioning). The incidence is higher in African-Americans and the most common sites of NETs are the lung, stomach, appendix, cecum, duodenum, pancreas, jejunum/ileum, colon, and rectum. NeuroEndocrine Tumors originating in the gastrointestinal tract and pancreas are also known as GastroEnteroPancreatic NETs (GEP-NETs). They constitute about 2% of all neoplasms and account for about 50-70% of all NETs. They are more frequent in gastric fundus/body, proximal duodenum, Vater’s papilla, pancreas, tip of the appendix, terminal ileum, and lower rectum. Majority of GEP-NETs are not symptomatic (nonfunctioning tumors), difficult to diagnose, and present with advanced disease at initial diagnosis. They often metastasize to the mesentery, peritoneum and liver. The functioning tumors however secrete biologically active substances that can lead to the development of characteristic clinical syndromes. NeuroEndocrine Tumors may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Most NETs are classified based on tumor differentiation into 1) Well-differentiated, Low-grade (G1) 2) Well-differentiated, Intermediate-grade (G2) and 3) Poorly differentiated, High-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. Even though surgery is curative when the tumor is detected early, this is often not the case, as most patients present with metastatic disease at the time of diagnosis.

Chromogranin A is a glycoprotein precursor to several functional peptides and is considered a standard biomarker for NETs. However, serum Chromogranin A levels can be elevated in several non-oncologic conditions such as atrophic gastritis, pancreatitis, chronic hepatitis, liver cirrhosis, irritable bowel, and inflammatory bowel diseases. The use of proton pump inhibitors can also result in elevated Chromogranin A levels. Diagnostic imaging as well as serum biomarkers lack the sensitivity and are unable to detect early changes in disease state. As such, the absence of a clinically useful blood biomarker remains an important unmet need.

The NETest® is a novel blood-based (liquid biopsy) molecular diagnostic test intended to aid in the identification of neuroendocrine tumor disease activity. The assay involves measurement of 51 neuroendocrine tumor gene transcripts, by Polymerase Chain Reaction (PCR). The gene expression signatures, which is the tumor activity score, stratifies patients into three groups: low score (40% or less), moderate/intermediate score (41-79%) and high score (80% or more). A higher score at the time of testing indicates a higher risk of tumor activity. Previously published prospective clinical studies have demonstrated the value of NETest® in predicting the effectiveness of surgery, in its ability to monitor tumor progression during SomatoStatin Analog (SSA) therapy, in its utility for watch‐and‐wait programs, as well as its ability in predicting response to Peptide Receptor RadioTherapy (PRRT) prior to treatment initiation.

The authors in this study examined the clinical utility of NETest® multigene assay in a real‐world setting, utilizing a registry of NETs in the USA. This registry was established to include clinical and biomarker data from patients enrolled by interested physicians who could then use it to answer specific clinical questions. NETest® registry patients were evaluated from large referral practices, and their subsequent clinical data, including decision‐making, were interfaced with NETest® data. This study addressed five important questions: 1) What is the diagnostic accuracy of the NETest®? 2) Does the NETest® score accurately reflect the disease status? 3) Does it have clinical utility in decision‐making? 4) Can it alter the frequency and type of imaging? 5) Does the NETest® have greater clinical utility than Chromogranin A?. The diagnostic accuracy and relationship to clinical disease status were evaluated in two patient cohorts (treated and watch‐and‐wait).

A total of 100 patients with pathological confirmation of a NET were enrolled over a 22 month period and NETest® was performed at enrollment. The primary site of the NET was gastroenteropancreatic (68%), lung 20%, and of unknown origin (12%). Stage IV disease was present in 96% of patients, 70% had undergone surgery before enrollment, 97% had well‐differentiated, low‐grade tumors and 56% were on drug therapy. The median age was 62 years and the median follow up was 6 months.

The diagnostic accuracy of NETest® was more than 96% and the NETest® was concordant with image‐confirmed disease in 96% of patients. Scores were reproducible (97%) and concordant with clinical status (98%). Chromogranin A was ordered for 53 of the 100 patients, but was not elevated in 75% of these patients despite documented clinical evidence of disease. NETest® was positive in 100% of these patients (P=0.0004 for accuracy). NETest® scores were reproducible (97%) and concordant with clinical status (98%). Multivariate analyses identified the NETest® score as the only variable significantly related to Progression Free Survival (PFS). High NETest® score correlated with progressive disease (81%; median PFS, 6 months), and low NETest® score correlated with stable disease (87%; median PFS, Not Reached)-P<0.0001). The NETest® score was the only feature linked to PFS (odds ratio, 6.1; p < .0001). In the watch‐and‐wait group of patients, low NETest® scores were concordant with stable disease in 100% of patients, and high NETest® scores were associated with management changes in 83% of patients. In the treated group, all patients with low NETest® scores (100%) remained stable. A high NETest® score was linked to treatment intervention and disease stabilization (100%). Further, the utilization of NETest® was associated with reduced imaging (biannual to annual) in 36-38% of patients.

It was concluded that real‐time liquid biopsy assessment of Neuroendocrine tumors with NETest® has more than 96% diagnostic accuracy, and has clinical utility in monitoring disease status, as well as patient management. Assessment of NETest Clinical Utility in a U.S. Registry‐Based Study. Liu E, Paulson S, Gulati A, et al. The Oncologist 2019;24:783-790.

ERLEADA® (Apalutamide)

September 25th, 2019

The FDA on September 17, 2019 approved ERLEADA® for patients with metastatic Castration-Sensitive Prostate Cancer (CSPC). ERLEADA® was initially approved in 2018 for patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC). ERLEADA® is a product of Janssen Biotech, Inc.

KEYTRUDA® (Pembrolizumab) and LENVIMA® (Lenvatinib)

September 25th, 2019

The FDA on September 17, 2019 granted accelerated approval to the combination of KEYTRUDA® and LENVIMA® for the treatment of patients with advanced Endometrial carcinoma that is not MicroSatellite Instability High (MSI-H) or MisMatch Repair deficient (dMMR), and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. KEYTRUDA® is a product of Merck & Co and LENVIMA® is a product of Eisai Inc.

Maintenance LYNPARZA® Improves Progression Free Survival in BRCA Mutated Metastatic Pancreatic Cancer

September 20th, 2019

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

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

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

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

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

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

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

Antibiotic Treatment Prior to Immune Checkpoint Inhibitor Therapy has a Detrimental Effect on Response Rates and Overall Survival

September 20th, 2019

SUMMARY: The American Cancer Society estimates that in 2019, there will be an estimated 1,762,450 new cancer cases diagnosed and 606,880 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell death protein-1 (PD-1), Programmed cell death ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host's microbiome and there may be a relationship between gut bacteria and immune response to cancer. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can alter the bacterial composition and bacterial diversity of our gut, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

The authors conducted this study to determine whether there was an association between antibiotic therapy administered prior to or concurrently with ICI therapy and Overall Survival (OS) and Response Rates, in patients with cancer, treated with ICIs in routine clinical practice. In this prospective, multicenter cohort study, 196 patients with cancer who received ICI therapy were recruited at two tertiary care centers between January 2015 and April 2018. Majority of enrolled patients had Non-Small Cell Lung Cancer (N=119), but patients with Melanoma (N=38) as well as Urologic and Head and Neck cancers (N=39) were also included in the analysis. The median age was 68 years, and majority of patients had metastatic disease at the time of treatment initiation with ICIs and 96% of patients received anti-PD-1/PD-L1 therapy alone. Broad spectrum antibiotics up to 30 days prior to commencement of ICI qualified as prior antibiotic exposure whereas concurrent treatment with antibiotics was defined as antibiotic treatment from the first day of ICI treatment until cessation. Beta-lactams were the most commonly prescribed antibiotic class, and were given as a single course for less than 7 days. When antibiotics were administered concurrently with ICIs, patients tended to be treated longer and with multiple courses. The common indication for both prior and concurrent antibiotic treatment was respiratory infections, and 15% of patients received antibiotic therapy prior to ICI therapy, whereas 35% of patients received antibiotics concurrently with ICIs. The Primary endpoint was Overall Survival (OS), calculated from the time of ICI therapy commencement and radiologic response to treatment, with disease refractory to ICI therapy defined as progressive disease 6-8 weeks after the first ICI dose, without evidence of pseudoprogression.

In this analysis, antibiotic treatment prior to ICI therapy had a significant adverse effect on Overall Survival, with a median survival of only 2 months for those who received prior antibiotic treatment versus 26 months for antibiotic-naive patients (HR=7.4; P<0.001). Further, patients who had received prior antibiotic treatment had a higher likelihood of primary refractoriness to ICIs, compared to those who did not receive antibiotics (81% versus 44% (P<0.001). The poor OS outcomes when patients received antibiotic treatment prior to ICI therapy were noted, irrespective of tumor site (OS in NSCLC 26 vs 2.5 months, P<0.001, OS in Melanoma 14 vs 3.9 months, P<0.001, OS in other tumors 11 vs 1.1 months, P <0.001). Multivariate analyses confirmed that prior antibiotic therapy and response to ICI therapy were associated with OS, independent of tumor site, disease burden, and performance status. Antibiotic treatment administered concurrently with ICIs however, was not associated with worse Overall Survival.

It was concluded that treatment with antibiotics prior to therapy with Immune Checkpoint Inhibitors in routine clinical practice, is associated with a worse treatment response and Overall Survival in unselected group of patients. This study suggests that timing of antibiotic exposure may be crucial and the authors recommend that studies are urgently required to investigate antibiotic-mediated alterations of gut microbiota as a determinant of poorer outcomes, following treatment with Immune Checkpoint Inhibitors. Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer. Pinato DJ, Howlett S, Ottaviani D, et al. JAMA Oncol. 2019, Sep 12. doi: 10.1001/jamaoncol.2019.2785. [Epub ahead of print]

Liquid Biopsy DNA Methylation Assay Highly Specific for Cancer Detection and Prognosis

September 13th, 2019

SUMMARY: Screening both healthy and high-risk populations with a peripheral blood sample (liquid biopsy) has the potential to detect cancer at an early stage, with an increased opportunity to offer curative therapies. Screening assays for cancer should be highly specific with a low rate of false-positive results and overdiagnosis. Analysis of cell-free DNA (cfDNA) with a Liquid Biopsy is presently approved to select EGFR targeted therapies (cobas EGFR mutation test), in patients with advanced Non Small Cell Lung Cancer. However, the role of cell-free DNA analysis for early detection of cancer is not well established.

The Cancer Genome Atlas (TCGA), a landmark cancer genomics program, is a joint effort between the National Cancer Institute and the National Human Genome Research Institute. This program began in 2006 and has molecularly characterized over 20,000 primary cancers and matched normal samples, across 33 different cancer types. After 12 years and contributions from over 11,000 patients, TCGA has deepened our understanding of the molecular basis of cancer, changed the way cancer patients are managed in the clinic, established a rich genomics data resource for the research community and helped advance health and science technologies.

The Circulating Cell-Free Genome Atlas (CCGA) is a prospective, multi-center, observational study and is the largest study ever initiated, to develop a noninvasive, liquid biopsy assay for early cancer detection, based on cell-free DNA (cfDNA). This study completed enrollment of approximately 15,000 participants with and without cancer (56% with 20 tumor types and all clinical stages), across 142 sites in the US and Canada. The principal goal is to develop a noninvasive cancer detection assay and the CCGA was designed to characterize the landscape of genomic cancer signals in the blood and to detect and validate GRAIL’s multi-cancer early detection blood test through three pre-planned sub-studies. The authors in 2018 previously reported that it is possible to detect early-stage lung cancer, with a high degree of specificity, from a simple blood test, using targeted sequencing and whole-genome sequencing. In this substudy, liquid biopsy could accurately detect over 40% of early-stage lung cancers (Stage I-IIIA), with 98% specificity. It was determined that whole-genome bisulfite sequencing for DNA methylation was the most effective approach for early cancer detection. Liquid-Biopsy

DNA methylation is a natural epigenetic mechanism used by cells to regulate gene expression with some regions of hypermethylation and some regions of hypomethylation, and is a chemical modification to DNA. In cancer, abnormal methylation patterns and the resulting changes in gene expression can contribute to tumor growth (hypermethylation can cause tumor-suppressor genes to be inactivated). Methylation patterns, are unique to the tumor DNA, enabling tumor detection and localization but are not of value when it comes to precision therapies. This is unlike mutations and copy number changes, which can be detected in white blood cells in individuals without cancer as well, leading to false-positives.

In two separate presentations, the authors in this present sub-study reported the results for patients with more than 20 cancer subtypes across all stages and evaluated the prognostic significance of detecting abnormal patterns of cfDNA methylation by whole-genome bisulfite sequencing (WGBS) assay. The goal of targeted methylation assay was to detect both early and advanced disease cancers, and improve clinical outcomes

Liu, MC, et al. reported outcomes for 2,301 participants (1422 had cancer and 879 did not) with more than 20 cancer types (12 prespecified and high-risk cancers included Lung, HR negative Breast, Colorectal, Anorectal, Esophageal, Gastric, Liver, Pancreatic, Head and Neck, Ovary, Myeloma and Lymphoid neoplasms) across all stages. The 12 prespecified cancers account for two thirds of all cancer deaths in the US. At 99% specificity, the sensitivity for these 12 high-risk cancers ranged from 59-86% at early stages (stages I–III). For all 20 cancer types, the overall detection rate across all stages was 55%. Additionally, a Tissue of Origin result was provided for 94% of all cancers detected and of these, the assay correctly identified the Tissue of Origin in 90% of cases, which the authors commented is critical for guiding efficient downstream workup for a positive signal.

Oxnard GR, et al. performed an exploratory longitudinal analysis and reported the results of the Overall Survival of 1,320 participants with more than 20 cancer types in this substudy, thereby evaluating the prognostic significance of detection by this assay. Across all stages of disease, cancers detected by cfDNA whole-genome bisulfite sequencing for DNA methylation were associated with significantly worse survival than those not detected by the blood test. The 2-year Overall Survival was less than 50% among patients whose cancers were detected by the assay compared with 2-year OS of over 90% for those whose cancers were not detected by this assay. The poor prognostic ability of this assay was seen in both cancers that presented with symptoms and those found via screening suggesting that DNA–based detection with this methylation assay may be an indicator of prognosis. In multivariate analysis, cancers detected by this assay had double the risk of death (HR=2.6; P< 0.001) when accounting for clinical stage, cancer type, histologic grade, age, sex, and method of diagnosis and also had comparable prognostic significance to clinical stage (P <0.001).

It was concluded from these two presentations that cfDNA test based on the presence of DNA methylation is highly specific at detecting high-risk malignancies, with very high accuracy for identifying the tissue of origin, and may also have prognostic value.

Genome-wide Cell-free DNA (cfDNA) Methylation Signatures and Effect on Tissue of Origin (TOO) Performance. Liu MC, Jamshidi A, Venn O, et al. 2019 ASCO Annual Meeting. Abstract 3049. Presented June 1, 2019.

Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis. Oxnard GR, Chen X, Fung ET, et al. 2019 ASCO Annual Meeting. Abstract 1545. Presented June 3, 2019.

SBRT Superior to Standard Radiotherapy in Stage I Non-Small Cell Lung Cancer

September 13th, 2019

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2019, about 228,150 new cases of lung cancer will be diagnosed and 142,670 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. Approximately 15% of patients present with early stage (T1-2 N0) disease, and these numbers are likely to increase with the implementation of Lung Cancer screening programs. Patients with early stage disease unless medically unfit, undergo surgical resection with a curative intent. Those who are not surgical candidates are often treated with conventional Radiation Therapy, over a period of 4 to 6 weeks.

Stereotactic Body Radiation Therapy (SBRT) is a non-surgical procedure that allows delivery of significantly higher doses of precisely focused radiation to the tumor, compared to conventional Radiation Therapy, with less collateral damage to the surrounding normal tissue. The technologies used for SBRT include GAMMA KNIFE® which uses highly focused gamma rays, Proton Beam therapy which uses ionized Hydrogen or Protons, Linear Accelerator (LINAC) and CYBER KNIFE® which use Photons, to target the tumor tissue. Because SBRT is fractionated and delivered over 1-5 days, the short-and long-term side effects of radiation therapy are decreased and may allow higher total dosage to be given. Previously published single-arm trials have shown high local control with SBRT, with no significant difference in Overall Survival, compared with conventional Radiotherapy. This Phase III trial was conducted to prospectively assess the effect of SBRT on local control, Overall Survival, toxicity and Quality of Life.SBRT-Treatment

In this multicentre, randomized, Phase III trial, 101 eligible patients with biopsy proven Stage I (T1-T2aN0M0) NSCLC, diagnosed on the basis of FDG PET, who were medically inoperable or had refused surgery, were enrolled. Patients were randomly assigned in a 2:1 ratio to SBRT (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumor was less than 2 cm from the chest wall)-(N=66) or standard Radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2.5 Gy fractions (N=35), based on institutional preference. The tumor had to be non-central and peripherally located, at least 1 cm in the mediastinum and 2 cm from the bifurcation of the lobar bronchi. Patients were stratified by T stage and operability (medically operable but refused surgery versus inoperable). The Primary endpoint was time to local treatment failure and Secondary endpoints included Overall Survival, treatment related toxicity and Quality of Life. The median follow up for local treatment failure was 2.1 years for standard Radiotherapy group and 2.6 years for those patients assigned to SBRT.

Local treatment failure was noted in 14% of patients in the SBRT group whereas 31% of patients in the standard Radiotherapy group progressed locally. Freedom from local treatment failure was significantly improved the SBRT group compared with a standard radiotherapy group (HR=0.32, P=0.0077). Median time to local treatment failure was not reached in either group. Median Overall Survival was 5 years in the SBRT group and 3 years in the standard Radiotherapy group (HR=0.53; P=0.027). Overall Survival at 2 years was 77% for those receiving SBRT and 59% for those in the standard Radiotherapy group. Treatment related toxicities were low in both groups and there were no significant differences in Quality of Life between the treatment groups.

It was concluded that in patients with inoperable peripherally located Stage 1 NSCLC, compared with standard Radiotherapy, SBRT resulted in superior local control of the primary disease without an increase in major toxicity, and improvement in Overall Survival. The authors added that these findings suggest that SBRT should be the treatment of choice for this patient group. Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial. Ball D, Tao Mai G, Vinod S, et al. Lancet Oncol 2019;20:494-503

KISQALI® Improves Overall Survival in Advanced Breast Cancer

September 6th, 2019

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. About 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the second leading cause of cancer death in the US. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and these patients are often treated with anti-estrogen therapy as first line treatment. The incidence of breast cancer among women under the age of 50 has been increasing by 0.2% per year. Premenopausal breast cancer may be biologically different than post menopausal breast cancer and diagnosis of breast cancer at a young age has been associated with adverse outcomes and less sensitivity to endocrine therapy. Further, premenopausal women are often excluded from hormone therapy trials. The incidence of metastatic disease at the time of diagnosis among patients with Hormone Receptor (HR)- positive breast cancer, has been increasing by about 2% per year.

Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.Cell-Cycle-Inhibition-by-RIBOCICLIB-A-CDK4-and-CDK6-Inhibitor

There are presently three CDK4/6 inhibitors approved by the FDA and they include KISQALI® (Ribociclib), IBRANCE® (Palbociclib) and VERZENIO® (Abemaciclib). All three agents have demonstrated similar, significantly prolonged Progression Free Survival (PFS) when administered in combination with endocrine therapy, as first-line treatment, in women with HR-positive metastatic breast cancer (MONALEESA-2 with KISQALI®, PALOMA-2 with IBRANCE® and MONARCH-3 with VERZENIO®). These trials for the first-line treatment of advanced breast cancer however excluded premenopausal women. The toxicities were slightly different with neutropenia more commonly encountered in the IBRANCE® and KISQALI® studies and diarrhea more often noted with VERZENIO®. KISQALI® (Ribociclib) is an orally bioavailable, selective, small-molecule inhibitor of CDK4/6 that blocks the phosphorylation of RetinoBlastoma protein, thereby preventing cell-cycle progression and inducing G1 phase arrest. It is four times more selective for CDK4 than for CDK6.

The MONALEESA-7 trial is an international, randomized, double-blind, placebo-controlled, Phase III trial in which KISQALI® in combination with endocrine therapy was compared with placebo in combination with endocrine therapy, in premenopausal or perimenopausal women with HR-positive, HER2- negative advanced breast cancer. Patients (N=672) were randomly assigned in a 1:1 ratio, to receive KISQALI® at 600 mg orally once daily for 21 days of each 28 day cycle (N=335), or matching placebo (N=337). Both groups received ZOLADEX® (Goserelin) 3.6 mg administered subcutaneously on day 1 of each 28 day cycle. Patients also received either a nonsteroidal Aromatase Inhibitor (Letrozole 2.5 mg or Anastrozole 1 mg) or Tamoxifen 20 mg, orally once daily continuously. The choice of endocrine therapy was made on the basis of the patient’s previous adjuvant or neoadjuvant therapy or investigator or patient preference. Crossover was not permitted between the two treatment groups. Patients were stratified according to the presence or absence of liver or lung metastases, previous chemotherapy for advanced disease and endocrine therapy. The Primary end point was Progression Free Survival (PFS) and Secondary endpoint included Overall Survival (OS). The superior PFS data with KISQALI® compared to endocrine therapy alone, was previously reported. The authors herein report the results on Overall Survival.

After a median follow up of 34.6 months, the addition of KISQALI® to endocrine therapy resulted in significantly longer Overall Survival, compared to endocrine therapy alone. The estimated OS at 42 months was 70.2% in the KISQALI® group and 46.0% in the placebo group (HR for death=0.71; P=0.00973), suggesting a 29% reduction in the risk of death. No new safety signals were observed and in the KISQALI® group, more instances of QT-interval prolongation were observed in patients who received Tamoxifen than in those who received an Aromatase Inhibitor, but without symptomatic arrhythmias or Torsades de pointes.

It was concluded that KISQALI® along with endocrine therapy significantly prolonged Overall Survival, compared to endocrine therapy alone, among pre and perimenopausal patients with advanced HR-positive, HER2-negative breast cancer and these findings represent a major treatment advance in this patient group. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. Im S-A, Lu Y-S, Bardia A, et al. N Engl J Med 2019; 381:307-316.

IMBRUVICA® and RITUXAN® Combination Superior to FCR in Patients with CLL

September 6th, 2019

SUMMARY: The American Cancer Society estimates that for 2019, about 20,720 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 3,930 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies. Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab (FCR) has long been the gold standard and the most commonly used treatment regimen for younger, fit, treatment naïve patients with CLL.This is based on phase III trial data showing improvement in both Progression Free Survival (PFS) and Overall Survival (OS) compared with chemotherapy alone. FCR regimen however is associated with significant toxicities and cannot be tolerated by all CLL patients. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® in phase III trials showed improved PFS and OS when compared to Chlorambucil in previously untreated, elderly patients with CLL. Nonetheless, the efficacy of IMBRUVICA® as a first-line treatment for younger CLL patients (70 years or younger), compared to the most efficacious regimen such as FCR, is unknown.BCR-Signal-Pathways-and-MOA-of-New-Agents

E1912, led by the ECOG-ACRIN Research Group (ECOG-ACRIN), is a randomized phase III study in which IMBRUVICA® plus RITUXAN® (Rituximab) was compared to Fludarabine, Cyclophosphamide, and RITUXAN® (FCR) chemotherapy regimen, in previously untreated patients aged 70 years or younger with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). In this trial, 529 patients were randomly assigned in a 2:1 ratio to receive IMBRUVICA® 420 mg orally daily until disease progression along with RITUXAN® 50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, 500 mg/m2 on day 1 of cycles 3-7 (N=354) or six courses of Fludarabine 25 mg/m2 IV along with Cyclophosphamide 250 mg/m2 IV days 1-3 and RITUXAN® 50 mg/m2 IV on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, 500 mg/m2 on day 1 of cycles 2-6, given every 28 days (N=175). The median age was 58 years and 40% of the patients were 60 years of age or older. The Primary endpoint was Progression Free Survival (PFS) and the Secondary endpoint was Overall Survival (OS).

With a median follow up of 33.6 months, at the first interim analysis, IMBRUVICA® plus RITUXAN® significantly improved PFS and was 89.4%, compared to 72.9% with FCR, at 3 years (HR=0.35; P<0.0001). This meant a 65% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN® compared with FCR. The combination of IMBRUVICA® plus RITUXAN® also demonstrated improved OS and was 98.8% at 3 years versus 91.5% with FCR (HR=0.17; P=0.0003). This suggested that IMBRUVICA® plus RITUXAN® combination reduced the risk of death by 83% compared with FCR. In a subgroup analysis, the PFS benefit with IMBRUVICA® plus RITUXAN® was seen independent of age, sex, Performance Status (0-2), disease stage, as well as presence or absence of cytogenetic abnormality, deletion 11q23. At the time of this analysis, IMBRUVICA® plus RITUXAN® was also superior to FCR among IGHV unmutated patients (90.7% versus 62.5% at 3 years,HR=0.26; P<0.0001),suggesting a 74% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN®, compared to FCR. A statistically significant benefit however was not observed among those with IGHV mutations, although there was a positive trend noted (HR=0.44; P=0.07). Treatment-related Grade 3 or higher toxicities were similar in both treatment groups. FCR however was more frequently associated with Grade 3 or higher infectious complications than IMBRUVICA® plus RITUXAN® combination (20.3% versus 10.5%; P<0.001).

It was concluded that a combination of IMBRUVICA® and RITUXAN® was superior and significantly improved PFS and OS, when compared to FCR among patients 70 years of age or under, with previously untreated CLL. These findings may have immediate practice changing implications and establish IMBRUVICA®-based therapy as the most effective first-line therapy for untreated patients with CLL. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. Shanafelt TD, Wang XV, Kay NE, et al. N Engl J Med 2019; 381:432-443