Category: Meeting Updates

Primary Breast Tumor Surgery Improves Overall Survival in HER2 Positive Advanced Breast Cancer

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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 268,600 new cases of invasive breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Approximately 50% of HER2-positive breast cancers are Hormone Receptor positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes. HER2-targeted therapies include HERCEPTIN® (Trastuzumab), TYKERB® (Lapatinib), PERJETA® (Pertuzumab) and KADCYLA® (ado-Trastuzumab emtansine). Dual HER2 blockade with HERCEPTIN® and PERJETA®, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival. The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies. Not all HER2-positive, Hormone Receptor positive metastatic breast cancer patients, are candidates for chemotherapy. These patients however may benefit from anti-HER2 targeted therapy given along with endocrine therapy.

Breast surgery is often not a consideration for patients with metastatic breast cancer. However, breast surgery can be offered for palliation of symptoms, taking into consideration the risks and benefits of such intervention, in a patient with an ulcerated, bleeding, or a fungating tumor mass, that cannot be controlled with systemic therapy. A few previously published studies which evaluated the addition of surgical resection of the primary tumor to systemic therapy, among patients with metastatic HER2-positive breast cancer, have provided mixed results, with one study showing improved outcomes. The authors therefore conducted a retrospective study to examine the impact of primary breast tumor resection on survival, in HER2-positive Stage IV breast cancer patients, treated with HER2 targeted therapy.

This retrospective cohort study included records of 3,231 women with HER2 positive Stage IV breast cancer from the National Cancer Database, from 2010 to 2012. Of these women, 89.4% had received chemotherapy/anti-HER2 targeted therapies, 37.7% had received endocrine therapy, 31.8% had received radiation and 25% of the patients had bone only metastasis. Overall, 1,130 women (35%) underwent primary breast tumor resection. The mean age of those who had surgery was 56 years and the Primary endpoints were receipt of surgery and Overall Survival (OS).

At a median follow-up of 21.2 months, the median OS for patients who had surgery was 25 months compared with 18 months for those who did not undergo surgical resection (HR=0.56; P=0.0004). This suggested a 44% reduction in the risk of death with primary breast tumor resection. Patients having Medicare/other government or private insurance, as well as those who received radiation, chemotherapy/anti-HER2 targeted therapies and endocrine therapy were more likely to have surgery. Additionally, Caucasian women were also more likely than non-Hispanic black women, to have surgery. These findings suggested that women with Medicare or private insurance as well as white women were also more likely to have surgery and less likely to die of their disease, than non-Hispanic black women, and those with Medicaid or no insurance.

It was concluded that after controlling for independent variables, surgery of the primary site, in patients with metastatic HER2 positive breast cancer who are managed with present day contemporary treatment, is associated with improved Overall Survival. Breast surgery should therefore be discussed as a part of the treatment strategy, for qualified women, in this patient group. The impact of primary tumor surgery on survival in HER2 positive stage IV breast cancer patients in the current era of targeted therapy. Mudgway R, Chavez de Paz Villaneva C, Lin AC, et al. Presented at AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract 4873.

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

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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.

Late Breaking Abstract – ASCO 2019 Front-Line Keytruda® Monotherapy for Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

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SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Risk factors for gastric cancer include age, gender, ethnicity, geography and infection with Helicobacter pylori. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life.

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. KEYTRUDA® in the Phase II KEYNOTE-059 trial demonstrated promising antitumor activity and durable responses in patients with advanced Gastric/GastroEsophageal Junction cancer, who had progressed on more than 2 lines of therapy, with higher Objective Response Rates noted in patients with PD-L1-positive tumors.

KEYNOTE-062 is a randomized, phase III controlled study in which KEYTRUDA® monotherapy was compared to standard chemotherapy as first line treatment, in select patients with advanced Gastric or GastroEsophageal Junction (GEJ) Adenocarcinoma. This trial enrolled 763 newly diagnosed patients of whom 69% had Gastric Adenocarcinoma cancer and 30% had GEJ Adenocarcinoma. Patients were randomized 1:1:1 to receive KEYTRUDA® 200 mg IV every 3 weeks for up to 2 years (N=256), KEYTRUDA® plus Cisplatin 80 mg/m2 IV every three weeks along with either 5-Fluorouracil 800 mg/m2 daily on Days 1-5 every three weeks or XELODA® (Capecitabine) 1000 mg/m2 twice a day on Days 1-14 every three weeks (N=257 ) or placebo plus Cisplatin and either 5-FU or XELODA® given at a similar dose and schedule as the second group (N=250). The median patient age was 62 years and PD-L1 expression was assessed by Combined Positive Score (CPS). The Primary endpoints were Overall Survival (OS) in patients whose tumors expressed PD-L1 CPS 1 or more and CPS 10 or more in the KEYTRUDA® monotherapy group and in combination with chemotherapy group, as well as Progression Free Survival (PFS) in patients whose tumors expressed PD-L1 CPS 1 or more in the combination arm. Secondary endpoints included Overall Response Rate (ORR) and Duration of Response (DOR) in patients whose tumors express PD-L1 CPS 1 or more. In the current trial, all patients had a PD-L1 CPS of at least 1, and 281 patients (37%) had a PD-L1 CPS score of 10 or more. The median follow-up was 11.3 months.

The trial met its Primary endpoint and among patients with a PD-L1 CPS of 1 or more, Overall Survival was noninferior to chemotherapy. The median Overall Survival was 10.6 months in the KEYTRUDA® monotherapy group compared with 11.1 months in the chemotherapy group (HR=0.91). Among patients with a PD-L1 CPS 10 or more, Overall Survival with KEYTRUDA® was superior to chemotherapy. The median Overall Survival was 17.4 months for those receiving KEYTRUDA® compared with 10.8 months for those receiving chemotherapy. After 2 years, 39% of people taking KEYTRUDA® were alive compared with 22% of those taking chemotherapy (HR=0.69). The OS and PFS rates for the combination of KEYTRUDA® and chemotherapy were comparable with those of chemotherapy alone, regardless of PD-L1 CPS. The efficacy outcomes were not influenced by age, tumor size or location, histological subtype, number of metastatic sites and prior gastrectomy status.

It was concluded that KEYTRUDA® monotherapy is noninferior to chemotherapy for OS among patients with PD-L1 CPS 1 or more. There was however a clinically meaningful improvement in OS among patients with PD-L1 CPS 10 or more. Further, there was a more favorable safety profile for KEYTRUDA® over chemotherapy, making this a more desirable treatment option for elderly patients, for whom platinum based chemotherapy may not be appropriate. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The phase III KEYNOTE-062 study. Tabernero J, Van Cutsem E, Bang Y-J, et al. J Clin Oncol 37, 2019 (suppl; abstr LBA4007)

Late Breaking Abstract – ASCO 2019 XTANDI® Improves Overall Survival in Metastatic Hormone-Sensitive Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 174,650 new cases of Prostate cancer will be diagnosed in 2019 and 31,620 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is a nonsteroidal oral anti-androgen, that is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists. XTANDI® (Enzalutamide) is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens. Previously published studies have shown that XTANDI® improved Overall Survival in Castration-Resistant Prostate Cancer, regardless of whether it was used before or after Docetaxel chemotherapy. The benefits of adding Docetaxel or ZYTIGA® (Abiraterone) to testosterone suppression in men with metastatic, hormone-sensitive Prostate cancer have been established in randomized clinical trials.XTANDI - Mechanism-of-Action

ENZAMET (Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer) is an open-label, international, randomized, Phase III trial, conducted to evaluate the benefits of adding XTANDI® to initial standard treatment of Androgen Deprivation Therapy (ADT) with or without early Docetaxel, among patients with metastatic hormone-sensitive Prostate cancer.

A total of 1125 men with metastatic hormone-sensitive Prostate cancer were randomly assigned 1:1 to receive either ADT plus XTANDI® or NonSteroidal Anti-Androgens (NSAA). ADT consisted of parenteral injection of a testosterone-suppressing agent (such as Goserelin, Leuprolide, or Degarelix) with either a 160 mg dose of XTANDI® daily or one of the standard NSAA’s such as CASODEX®, EULEXIN® or NILANDRON®. Of the 1,125 men enrolled in the trial, 503 men received early doses of Docetaxel, and 602 did not. The decision to initiate early treatment with Docetaxel was at the treating physician’s discretion and was administered at 75 mg/m2 IV without prednisone every 3 weeks for a maximum of six cycles. Randomized patients were stratified according to the volume of disease (High Risk- defined as the presence of visceral metastases or at least four bone lesions with at least one lesion located beyond the vertebral bodies and pelvis or low), planned use of early Docetaxel, planned use of bone antiresorptive therapy, and score on ACE-27 (Adult Comorbidity Evaluation 27), with no coexisting conditions rated as 0, mild rated as 1, moderate rated as 2, and severe or multiple conditions rated as 3. The mean age was 68 years, 45% of patients received early Docetaxel as planned treatment and over 50% of the patients had high volume disease. The Primary end point was Overall Survival (OS) and Secondary end points included Progression Free Survival (PFS) as determined by the PSA level, clinical PFS, and adverse events. The median follow up was 34 months.

At the time of the first interim analysis, there was a 33% reduction in the risk of death in the XTANDI® group compared to the standard treatment group ((HR=0.67; P<0.002) and the estimated Overall Survival at 3 years were 80% in the XTANDI® group and 72% in the standard-of-care group. The addition of XTANDI® also improved PSA Progression Free Survival with a 61% reduction in the risk of PSA progression (HR=0.39; P<0.001) and 60% improvement in clinical PFS (HR=0.40; P<0.001). The effects of XTANDI® on clinical PFS were noted in all predefined subgroups, including those with early Docetaxel treatment. Among the patient group who also received early Docetaxel treatment, there was however no significant improvement in Overall Survival. Adding XTANDI® to standard ADT was associated with a higher frequency of toxic effects, especially peripheral neuropathy, associated with the concomitant use of Docetaxel, fatigue and slightly higher risk of seizures compared to standard therapy, and more patients discontinued treatment due to adverse events in the XTANDI® group.

It was concluded that XTANDI® was associated with significantly longer Progression Free Survival and Overall Survival than standard intervention, in men with metastatic, hormone-sensitive Prostate cancer receiving Androgen Deprivation Therapy. Patients who received early Docetaxel treatment, however did not have significant survival benefit. The authors added that ENZAMET is the first metastatic hormone-sensitive Prostate cancer trial to report Overall Survival data of an androgen receptor inhibitor (XTANDI®), and outcomes among a set of patients who also concurrently received Docetaxel. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. Davis ID, Martin AJ, Stockler MR, et al. for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. June 2, 2019. DOI: 10.1056/NEJMoa1903835

Late Breaking Abstract – ASCO 2019 Five-Year Survival Data for KEYTRUDA® in Advanced NSCLC

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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 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®.Unleashing-T-Cell-Function-with-PD-1-and-PDL1-Antibodies

The FDA approved KEYTRUDA® for the first-line treatment of patients with Stage III Non-Small Cell Lung Cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation, as well as those with metastatic NSCLC whose tumors express PD-L1 (Tumor Proportion Score-TPS of 1% or more), as determined by an FDA-approved test. KEYTRUDA® is also approved for the first-line treatment of advanced NSCLC with high PD-L1 expression (Tumor Proportion Score of 50% or more), based on KEYNOTE-024 trial, as well as in combination with Pemetrexed and Carboplatin, as first-line treatment of patients with metastatic non-squamous NSCLC, based on KEYNOTE-021 study. It is also indicated for previously treated advanced NSCLC with a much lower level of PD-L1 expression such as PD-L1 Tumor Proportion Score of 1% or higher, based on KEYNOTE-010 trial.

The authors in this publication presented the 5-year Overall Survival (OS) for patients enrolled in the Phase 1b KEYNOTE-001 study, which was the first trial evaluating KEYTRUDA® in advanced NSCLC. In this trial, 550 patients were enrolled of whom 101 patients were treatment-naïve (N=101) and 449 patients were previously treated (N=449). Patients received KEYTRUDA® 2 mg/kg IV every 3 weeks or KEYTRUDA® 10 mg/kg IV every 2 or 3 weeks. The protocol in the recent years was changed to a straight dose of KEYTRUDA® 200 mg IV every 3 weeks, which is the typical regimen used in clinical practice. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS) and Duration of Response (DOR). The median follow up was 60.6 months and 18% of participants (N=100) were still alive at that point.

The 5-year OS in the treatment-naïve patients (N=101) was 23.2% and 15.5% in previously treated patients (N=449). In treatment-naive patients, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 29.6%, compared with 15.7% with PD-L1 expression levels below 50%. In patients who had received previous treatment, the 5-year OS rate among patients whose tumors expressed PD-L1 expression of 50% or more was 25% compared with 12.6% with PD-L1 expression levels between 1% and 49%. Only 3.5% of people with PD-L1 expression levels below 1% were alive after 5 years. The investigator-reported ORR was 41.6% in treatment-naïve patients and 22.9% in previously treated patients. Median Duration of Response was 16.8 months and 38.9 months respectively. Immune-mediated adverse events were reported in 17% of patients at 5 years. Hypothyroidism was the most commonly reported immune-mediated adverse event, followed by pneumonitis, hyperthyroidism and skin toxicities.

It was concluded that the 5-year data from the KEYNOTE-001 trial showed that treatment with KEYTRUDA® was safe and effective and substantially increased Overall Survival in patients with advanced NSCLC. These data provide the longest efficacy and safety follow-up for NSCLC patients treated with KEYTRUDA®. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001. Garon EB, Hellmann MD, Costa EC, et al. J Clin Oncol. 2019;37(suppl; abstract LBA9015).

KEYTRUDA® versus Chemotherapy as Second-Line Treatment for Advanced Esophageal Cancer

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SUMMARY: The American Cancer Society estimates that in 2019, about 17,650 new cases of esophageal cancer will be diagnosed in the US and about 16,080 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in caucasians. About 20% of patients survive at least 5 years following diagnosis. Patients with advanced esophageal cancer following progression on first line chemotherapy have limited treatment options and have a poor prognosis.

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. KEYTRUDA® in the Phase II KEYNOTE-180 study demonstrated durable responses among heavily pretreated patients with advanced metastatic Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus as well as tumors with PD-L1 Combined Positive Score (CPS) of 10 or higher.

KEYNOTE-181 is a global, open-label, Phase III study which included 628 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert Type I adenocarcinoma of the esophagogastric junction that had progressed after first-line standard therapy. [Adenocarcinomas arising in the vicinity of the EsophagoGastric Junction are classified (Siewert classification) into adenocarcinoma of the distal esophagus (Type I), true carcinoma of the cardia (Type II) and subcardial carcinoma (Type III)].

Patients were randomized 1:1 to KEYTRUDA® 200 mg Q3W for up to 35 cycles (approximately2 years) or investigator’s choice chemotherapy with Docetaxel 75 mg/m2 IV on day 1 of each 21 day cycle, OR Paclitaxel 80-100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, OR Irinotecan 80 mg/m2 IV on day 1 of each 14-day cycle. Randomization was stratified by histology and region (Asia vs rest of world). The majority of patients (N=401; 64%) had Squamous Cell Carcinoma (SCC), and 222 patients had PD-L1 Combined Positive Score (CPS) of 10 or higher. The three Primary end points were Overall Survival (OS) in patients with SCC, patients with PD-L1 CPS of 10 or higher and Intent-To- Treat populations. The median follow up was 7 months.

It was noted that among the patients with a PD-L1 CPS of 10 or higher (35% of the study population), the median Overall Survival was 9.3 months with KEYTRUDA® versus 6.7 months with chemotherapy (HR=0.69; P=0.0074). The 12-month survival rate in this group was 43% versus 20% respectively. In the Squamous Cell Carcinoma subgroup (N=401), the median Overall Survival was 8.2 months with KEYTRUDA® versus 7.1 months with chemotherapy (HR=0.78; P=0.0095). These differences favoring KEYTRUDA® however, did not meet the study’s prespecified statistical boundary. In the Intent-To- Treat population, the median Overall Survival was 7.1 months in each treatment group (HR=0.89; P=0.0560), and was not statistically significant. The Progression Free Survival at 12 months among patients with a PD-L1 CPS of 10 or higher was 21% versus 7% for KEYTRUDA® and chemotherapy, respectively. Further, in this patient group, KEYTRUDA® more than doubled the Response Rates than those achieved with chemotherapy, with a longer median duration of response (9.3 versus 7.7 months respectively). Fewer patients had any grade drug-related adverse events with KEYTRUDA®, compared with chemotherapy.

The authors concluded that KEYTRUDA® significantly improved Overall Survival compared with chemotherapy, as second line therapy for patients with advanced esophageal cancer, with PD-L1 CPS of 10 or higher and also had a more favorable safety profile. They added that these data support KEYTRUDA® as a new second line standard of care for esophageal cancer with PD-L1 CPS of 10 or higher. A Phase III study of KEYTRUDA® plus chemotherapy as first line therapy for advanced esophageal cancer is underway. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. Kojima T, Muro K, Francois E, et al. J Clin Oncol 37, 2019 (suppl 4; abstr 2)

2019 NCCN Pancreatic Cancer Guideline Update Draw Attention to Germline Testing and Molecular Profiling

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

At the 2019 NCCN Annual Conference, three important pancreatic cancer guideline updates were discussed. They included germline testing, molecular analysis of tumors and a new adjuvant chemotherapy option for pancreatic adenocarcinoma.

Germline Testing

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.

1) Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) is a Autosomal Dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 and most often predisposes to colorectal cancer. Patients with Lynch Syndrome also have a 9-11 fold increase in the risk for pancreatic cancer. Consider testing for MSI and/or MMR for patients with locally advanced or metastatic pancreatic adenocarcinoma.

2) 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.

3) Mutations in Fanconi Anemia/BRCA pathway genes including PALB, FANCC and FANCG have also been identified as increasing pancreatic cancer risk.

4) Germline mutations in ATM gene has been identified in approximately 4% of individuals with familial pancreatic cancer.

5) Germline mutations in STK11 gene resulting in Peutz-Jeghers syndrome (associated with GI polyps) increases the risk of developing pancreatic cancer 132 fold. In approximately 5% of pancreatic cancers, somatic mutations in STK11 has been noted.

6) Similar to non-hereditary forms of pancreatitis, familial pancreatitis is also associated with increased risk of pancreatic cancer. Those with familial pancreatitis have been noted to have mutations in the PRSS1, SPINK1 and CFTR genes, increasing the risk of developing pancreatic cancer by 26-87 fold.

7) Familial malignant melanoma syndrome, also known as melanoma–pancreatic cancer syndrome or Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, is associated with a 20-47 fold increased risk of pancreatic cancer. This has been attributed to germline mutation of CDKN2A gene.

Molecular Profiling

Molecular analysis of tumors should be considered for patients with metastatic disease, for treatment guidance

1) In the phase III POLO trial, patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas, benefited with PARP inhibitor, LYNPARZA® (Olaparib), which when given as frontline maintenance therapy, significantly reduced the risk of disease progression or death, when compared to placebo.

2) Patients with unresectable or metastatic MSI-High or MMR deficient (dMMR) solid tumors who had progressed on prior therapies, have significant responses with KEYTRUDA® (Pembrolizumab), and has been approved by the FDA for this indication.

3) For those patients with PALB2 mutation, Gemcitabine along with Cisplatin is a treatment option.

4) The presence of P16 alterations in resected tumors of patients with pancreatic adenocarcinoma is associated with a worse prognosis and may therefore benefit from adjuvant chemotherapy.

Adjuvant mFOLFIRINOX

In a large phase III multicenter, randomized clinical trial, adjuvant mFOLFIRINOX significantly improved Disease Free Survival, Metastasis Free Survival and Overall Survival, compared to Gemcitabine, after pancreatic cancer resection. The median OS was nearly 20 months longer with a mFOLFIRINOX regimen than with Gemcitabine (54.4 months versus 35 months), representing a 34% reduction in the risk of death with mFOLFIRINOX.

NCCN Guidelines Updates: Tempero MA. Treatment of Pancreatic Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

AACR Late-Breaking Research Predicting Response to Anti-PD1/PDL1 Therapy beyond Tumor Mutational Burden

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SUMMARY: Immunotherapy with checkpoint inhibitors such as anti-PD1/PDL1 antibodies, is rapidly moving to the forefront of cancer treatment. These agents include PD1 targeted therapies such as KEYTRUDA® (Pembrolizumab), OPDIVO® (Nivolumab) and LIBTAYO® (Cemiplimab-rwlc) and PDL1 targeted therapies such as TECENTRIQ® (Atezolizumab), IMFINZI® (Durvalumab) and BAVENCIO® (Avelumab). Treatment with checkpoint inhibitors given as a single agent or in combination with chemotherapy has resulted in significant survival benefit in a variety of solid tumors, as well as hematologic malignancies. The efficacy of checkpoint inhibitors however varies considerably across different cancer types. Understanding tumors and their microenvironment and identifying the underlying variables that predict response to anti-PD1/PDL1 antibodies, has been challenging.

Tumor Mutational Burden (TMB) has recently emerged as a potential biomarker for immunotherapy with anti PD-1/PDL1 antibodies. TMB can be measured using Next-Generation Sequencing (NGS) and is defined as the number of somatic coding base substitutions and short insertions and deletions (indels), per megabase of genome examined. Several studies have incorporated Tumor Mutational Burden (TMB) as a biomarker, using the validated cutoff of TMB of 10 or more mutations/megabase as High, and less than 10 mutations/megabase, as Low. Drawbacks with TMB include sample consumption, higher attrition rate due to sample quality and quantity, and lack of standardization for the different TMB testing assays, with the definition of High TMB varying across studies from 7.4 or more to 20 mutations/megabase.

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 authors in this study systematically analyzed Whole Exome Sequencing (WES) and RNA sequencing (RNAseq) data of 10,000 patients from the Cancer Genome Atlas, and the Overall Response Rate (ORR) to anti-PD1/PDL1 therapy of 21 different cancer types obtained from previous clinical trials. The researchers took into consideration more than 30 different variables belonging to three distinct classes: a) those associated with tumor neoantigen landscape (Tumor Mutational Burden-TMB) b) tumor microenvironment and inflammation, and c) the checkpoint inhibitor targets (PD1/PDL1). The performance of each of these variables and their combinations was then evaluated in predicting the ORR to anti-PD1/PDL1 therapy.

It was noted that the most important predictor of response to anti-PD1/PDL1 therapy across cancer types was CD8+ T-cell abundance in the tumor microenvironment, followed by the Tumor Mutational Burden, and a high PD1 gene expression in each cancer type in a fraction of samples. These three top predictors encompassed the three distinct classes considered in this analysis, and their combination was highly predictive of the ORR to anti-PD1/PDL1 therapy, and was able to explain more than 80% of the variance observed across different tumor types.

The authors concluded that in this first systemic evaluation of the different variables associated with PD1/PDL1 therapy response across different tumor types, the three top predictors mentioned above can explain most of the observed cross-cancer response variability. Combining tumor mutational burden, CD8+ T-cell abundance and PD1 mRNA expression accurately predicts response to anti-PD1/PDL1 therapy across cancers. Lee JS and Ruppin E. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.LB-017/9

Immune Checkpoint Inhibitor Combination Efficacious in High-Grade Neuroendocrine Tumors

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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 is most frequently diagnosed in the small intestine, appendix, rectum, lungs and bronchi. The most common type of malignant gastrointestinal NETs originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. NETs may be sporadic or may be a component of inherited genetic syndromes such as Multiple Endocrine Neoplasia (MEN) types 1 and 2. Majority of the NETs are nonfunctioning and are diagnosed incidentally but are clinically symptomatic following spread to the liver. 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.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Immune checkpoint blockade with monoclonal antibodies such as OPDIVO® and YERVOY® has revolutionized the treatment of multiple cancers. Previously published studies have demonstrated successful patient outcomes across various tumor types, when treated with a combination of CTLA-4 and PD-1 inhibitors. However, it has remained unclear whether these agents can benefit those with rare, metastatic solid tumors. The investigators therefore launched the DART trial to fulfill this unmet need.

SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) is the first NCI-funded prospective, open-label, rare tumor immunotherapy basket study. Basket trials involve single treatment and single biomarker, different histologies, placed in multiple groups or baskets. These trials are an efficient way for screening experimental therapeutics across multiple patient populations.

In this phase II trial which included 37 different types of rare tumors, patients received YERVOY® 1 mg/kg IV every 6 weeks along with OPDIVO® 240 mg IV every 2 weeks. The Primary endpoint was Overall Response Rate (ORR) and Secondary endpoints included Progression Free Survival (PFS), Overall Survival (OS), Stable disease more than 6 months, and toxicity. This publication included a cohort of 33 eligible patients with Neuroendocrine tumors. Pancreatic Neuroendocrine tumors are currently being evaluated in a separate cohort within the trial. More than half of the patients (58%) had high-grade disease, and the most common tumor sites were gastrointestinal-non pancreatic (45%) and lung (18%). Enrolled patients had received a median of 2 prior lines of therapy.

The Overall Response Rate was 24% with 3% Complete Responses and 21% Partial Responses. Patients with high-grade Neuroendocrine cancer had a 42% Response Rate, whereas the Response Rate was 0% in low/intermediate grade tumors (P=0.01), independent of primary site. The authors hypothesized that the high response rate among those with high-grade Neuroendocrine carcinomas may be related to a higher Tumor Mutational Burden, which is an indicator of better response to immunotherapy. The 6-month PFS was 30% and the median OS was 11 months (historically, it has been around 10% and 3 months respectively). The most common toxicities were fatigue (30% of patients) and nausea (27%) and the most common grade 3/4 immune-related Adverse Events were ALT elevation in 9% of patients.

It was concluded that YERVOY® plus OPDIVO® combination was well tolerated with a 42% ORR in patients with high-grade Neuroendocrine cancer, regardless of primary site. The authors based on this study pointed out that, clinical trials are feasible even in rare tumors. A Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) S1609: The neuroendocrine cohort. Patel SP, Othus M, Chae YK, et al. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA.

NCCN Establishes TKI Discontinuation Criteria in Updated CML Guideline

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SUMMARY: Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia. The American Cancer Society estimates that about 8,990 new CML cases will be diagnosed in the United States in 2019 and about 1,140 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.Treatment-of-Chronic-Myeloid-Leukemia

The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients, and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. Further, it has been shown on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, precise criteria for stopping CML therapy have not been clearly defined.Monitoring-Molecular-Response-in-CML

Discontinuing TKI therapy after a Deep Molecular Response among patients with CML can potentially improve quality of life, minimize long term toxicities as well as drug-drug interactions, and reduce financial burden. Two important studies, STIM (Stop Imatinib) and EURO-SKI have set the stage for TKI discontinuation of TKI therapy in CML patients, who are in deep molecular remission, taking into consideration Sokal score at diagnosis, duration on TKI therapy and molecular response based on BCR-ABL transcripts log reduction. Sokal score is calculated using a formula that includes Age, Spleen size, Platelet count and percentage of Myeloblasts and has three risk groups: Low-risk (Sokal score<0.8), Intermediate-risk (Sokal score 0.8-1.2) and High-risk (Sokal score >1.2).

Stopping TKI therapy among CML patients appears to be safe and feasible in over 50% of the patients, although about 20% of these patients experience TKI withdrawal syndrome manifesting as musculoskeletal symptoms. Discontinuation of TKI therapy should only be considered in consenting patients after a thorough discussion of the potential risks and benefits.

Criteria for TKI Discontinuation: Outside of a clinical trial, TKI discontinuation should be considered only if a patient meets ALL the criteria listed below-

1) Age 18 years or older.

2) Chronic phase CML with no prior history of Accelerated or Blast phase.

3) On approved TKI therapy for at least 3 years.

4) Prior evidence of quantifiable BCR-ABL1 transcript.

5) Stable molecular response defined as MR4, (BCR-ABL equal to 0.01% or less IS), for 2 or more years as documented on at least 4 tests, performed at least 3 months apart.

6) Access to qPCR test that can reliably detect at least MR4.5 (BCR-ABL equal to 0.0032% or less IS), with results available within 2 weeks.

7) For patients who remain in Major Molecular Remission or MMR (MR3, BCR-ABL equal to 0.1% or less IS) after discontinuation of TKI therapy, the recommendations are monthly molecular monitoring the first year, every 6 weeks the second year and every 12 weeks thereafter, indefinitely.

8) TKI therapy should be promptly resumed within 4 weeks of a loss of MMR, with molecular monitoring every 4 weeks until MMR is re-established and then every 12 weeks thereafter, indefinitely. If a patient fails to achieve MMR after 3 months of TKI resumption, BCR-ABL kinase domain mutation testing should be performed, and monthly molecular monitoring should be continued for an additional 6 months.

9) Consultation with a CML Specialty Center is recommended regarding the appropriateness for TKI discontinuation, and potential risks and benefits of discontinuing therapy, including TKI withdrawal syndrome.

10) It is strongly encouraged to report the following to an NCCN CML Panel Member-

a) Any significant adverse event thought to be related to therapy discontinuation.

b) Progression to Accelerated or Blast phase at any time.

c) Failure to regain MMR after 3 months following treatment reinitiation.

NCCN guidelines updates: discontinuing TKI therapy in the treatment of chronic myeloid leukemia. Shah NP. Presented at 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.