Author: RR

Late Breaking Abstract – ESMO 2019 Ripretinib Shows Dramatic Improvement in PFS in Heavily Pretreated GIST Patients

RR

SUMMARY: The American Cancer Society estimates that in the US, about 4000-5000 cases of Gastro Intestinal Stromal Tumors (GISTs) are diagnosed each year. GI Stromal Tumor (GIST) is one of the most common types of Soft Tissue Sarcoma and can develop anywhere along the GI tract, but are primarily found in the stomach (60%) and small intestine (30%). GISTs originate from the interstitial cells of Cajal or related stem cells and are associated with activating mutations in KIT-CD117 (80%) or PDGFRA- Platelet-Derived Growth Factor Receptor-A (5-10%). These two mutations are mutually exclusive and are important in the molecular pathogenesis of these tumors. Approximately two thirds of the patients with GISTs are cured with surgery but recurrences are frequent and this risk of relapse is dependent on the tumor size, mitotic rate and primary tumor site. The risk stratification of GISTs by Joensuu, unlike the NIH criteria, takes into account primary tumor site and tumor rupture as well, which can influence outcomes.

Treatment of patients with advanced or metastatic GIST with Tyrosine Kinase Inhibitor GLEEVEC® (Imatinib) achieves high Objective Response and diseases stabilization rates. Patients with KIT exon 9 mutation have a poor prognosis compared to those with KIT exon 11 mutation (most common) and benefit from a higher dose of GLEEVEC® (800 mg daily). The majority of PDGFRA mutations affect exon 18. It should also be noted that patients with PDGFRA D842V mutation are GLEEVEC® resistant. Following progression on GLEEVEC®, FDA approved therapies include SUTENT® (Sunitinib) and STIVARGA® (Regorafenib).

Ripretinib is an orally administered kinase switch-control inhibitor of KIT and PDGFRA at the JuxtaMembrane Domain (JMD), and the main activation loop switch. The agent restores the inhibitory JMD switch, which is often deactivated in GIST, and helps to stabilize the kinase in an inactive state. Ripretinib is a KIT and PDGFRA inhibitor that blocks initiating KIT mutations in exons 9, 11, 13, 14, 17, and 18, known to be present in GIST patients, and the D816V exon 17 mutation known to be present in patients with Advanced Systemic Mastocytosis. Ripretinib inhibits PDGFRA mutations in exon 18, including the D842V mutation that drives a subset of GIST. Ripretinib was specifically designed to improve the outcomes in GIST patients by inhibiting the full spectrum of known mutations in KIT and PDGFRA.

The INVICTUS trial is an international, multicenter, randomized, double-blind, placebo-controlled Phase III trial, in which the safety, efficacy and tolerability of Ripretinib was compared to placebo, among heavily pretreated patients with advanced GIST. In this study, 129 patients were randomized in a 2:1 ratio to receive Ripretinib at 150 mg orally daily (N=85) or placebo (N=44). Previous therapies for enrolled patients included at least GLEEVEC®, SUTENT® and STIVARGA®. Two-thirds of patients had received 3 prior therapies, and a third had received more than 4 lines of therapy. The median patient age was 60 years and the most common mutation was at KIT exon 11 (58%) followed by KIT exon 9 (16%). Patients with disease progression on placebo were allowed to cross over to receive Ripretinib. The Primary endpoint was Progression Free Survival.

It was noted that Ripretinib significantly reduced the risk of disease progression or death by 85% compared to placebo, with a median PFS of 6.3 months compared to 1.0 month in the placebo group (HR=0.15, P<0.0001). This PFS benefit was consistent across all assessed patient subgroups. Additionally, Ripretinib reduced the risk of death by 64% compared to placebo, with a median OS of 15.1 months compared to 6.6 months in the placebo group (HR=0.36; P=0.0004). According to the pre-specified hierarchical testing procedure of the endpoints for the study, statistical significance for OS could not be established. The most common Adverse Events with Ripretinib included alopecia, nausea, abdominal pain, constipation and myalgias.

It was concluded that Ripretinib significantly improves Progression Free Survival and very likely also improves Overall Survival in heavily pretreated patient population with Gastrointestinal Stromal Tumors. INVICTUS: A Phase 3, International, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Ripretinib as 4th Line Therapy or more in Patients with Advanced Gastrointestinal Stromal Tumors (GIST) Who Have Received Treatment with Prior Anticancer Therapies (NCT03353753). van Mehren M, Attia S, Bauer S, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA87.

Late breaking Abstract – ESMO 2019 Chemotherapy-Free First Line Immunotherapy Combination Improves Overall Survival in Advanced NSCLC

RR

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. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system.

Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. OPDIVO® is presently approved for treatment of patients with metastatic NSCLC and progression on or after Platinum-based chemotherapy. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4).

CheckMate-227 is an open-label, multi-part, global, Phase III trial in which OPDIVO® based regimens were compared with Platinum-doublet chemotherapy in patients with first line advanced NSCLC, across non-squamous and squamous tumor histologies. In Part 1 of this trial, there were 2 cohorts- Part 1a in which OPDIVO® plus low dose YERVOY® (N=396) or OPDIVO® monotherapy (N=396) was compared with chemotherapy alone (N=397), in patients whose tumors expressed PD-L1 expression of 1% or more and Part 1b in which OPDIVO® plus low dose YERVOY® (N=187) or OPDIVO® plus chemotherapy (N=177) was compared with chemotherapy alone (N=186), in patients whose tumors did not express PD-L1 (less than 1%). (In Part 2 of this trial, OPDIVO® plus chemotherapy was compared with chemotherapy alone, regardless of PD-L1 expression. Part 2 did not meet its Primary endpoint for Overall Survival for OPDIVO® plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC, and is published elsewhere). It should be noted that when this trial was launched, chemotherapy along with immunotherapy or immunotherapy alone was not approved for the front-line treatment of NSCLC. Therefore, dual immunotherapy combination was not compared with current standards of care such as chemotherapy plus immunotherapy.Unleashing-T-Cell-Function-with-Combination-Immunotherapy

OPDIVO® was administered at 3 mg/kg every 2 weeks, and in the combination arm, YERVOY® was administered at 1 mg/kg every 6 weeks. When administered with chemotherapy, OPDIVO® was administered at 360 mg every 3 weeks. Patients were stratified by histology, and treatment was administered until disease progression, unacceptable toxicity, or for 2 years, for immunotherapy. There were two Co-primary endpoints in Part 1 for OPDIVO® plus YERVOY® versus chemotherapy: Overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and Progression Free Survival (PFS) in patients with TMB of 10 mut/Mb or more, across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). The minimum follow up for the Primary endpoint was 29 months.

Both Part 1a and Part 1b groups met their Primary endpoints. In the Part 1a cohort with PD-L1 expression of 1% or more, the Overall Survival was significantly longer with OPDIVO® plus YERVOY®, compared to chemotherapy. The median Overall Survival was 17.1 months in the Immunotherapy combination group compared to 14.9 months in the chemotherapy group (HR=0.79; P=0.007). Progression Free Survival, Objective Response Rates and Duration of Response were all greater with OPDIVO® plus YERVOY® combination, compared to chemotherapy. In the Part 1b cohort with PD-L1 expression of less than 1%, Overall Survival benefit was again observed with the OPDIVO® plus YERVOY® combination, compared with chemotherapy. Grade 3 and 4 treatment-related Adverse Events across all patients was 33% in those treated with OPDIVO® plus YERVOY® combination, 19% with single agent OPDIVO® and 36% with chemotherapy.

It was concluded that first-line treatment of patients with advanced NSCLC with a combination of two immunotherapy drugs improves Overall Survival, compared to chemotherapy, and offers a chemotherapy-free first line treatment option for a subset of NSCLC patients, leaving chemotherapy for later lines of therapy. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non–small cell lung cancer: CheckMate-227 part 1 final analysis. Peters S, Ramalingam SS, Paz-Ares L, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA4.

Late breaking Abstract – ESMO 2019 TIBSOVO® Improves Survival in IDH1 Mutated Advanced Cholangiocarcinoma

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SUMMARY: Bile Duct cancer (Cholangiocarcinoma), comprise about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.MOA-of-Ivosidenib

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia (AML) and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic CholangioCarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

TIBSOVO® (Ivosidenib) is an oral, targeted, small-molecule inhibitor of mutant IDH1. The FDA in July, 2018, approved TIBSOVO® for adult patients with relapsed or refractory AML with a susceptible IDH1 mutation. A previously published Phase I study demonstrated the safety and activity of TIBSOVO® in patients with IDH1 mutated advanced CholangioCarcinoma.

ClarIDHy is an international, randomized, double-blind, Phase III study, in which 185 patients with advanced CholangioCarcinoma with an IDH1 mutation were randomly assigned 2:1 to receive TIBSOVO® 500 mg orally once daily (N=124) or matched placebo (N=61). All patients had advanced unresectable CholangioCarcinoma. The median age was 62 years, 91% had intrahepatic CholangioCarcinoma, 92% of patients had metastatic disease and 43% had received two prior therapies. The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Safety, Objective Response Rate (ORR) and Overall Survival (OS). Crossover from placebo to TIBSOVO® was permitted upon radiographic disease progression.

This study met its Primary endpoint and the median PFS was 2.7 months for patients treated with TIBSOVO® compared to 1.4 months with placebo (HR=0.37; P<0.001). More importantly, the median PFS at 6 and 12 months were 32% and 22% in the TIBSOVO® group, whereas no patients randomized to the placebo group were progression-free for 6 or more months, at the time of data cutoff. There was a favorable trend in Overall Survival with TIBSOVO® and the median OS was 10.8 months for TIBSOVO® and 9.7 months for placebo (HR=0.69, one-sided P=0.06). However, the adjusted OS among the placebo group patients was 6 months, after taking into account that 57% of these patients crossed over to TIBSOVO®, and this was significantly shorter, when compared to the TIBSOVO® group (HR=0.46; P=0.0008). Most common Adverse Events were nausea, diarrhea, fatigue, cough, abdominal discomfort, ascites, anemia and vomiting.

It was concluded that treatment with TIBSOVO® among patients with advanced CholangioCarcinoma with an IDH1 mutation, resulted in significant improvement in Progression Free Survival as well as favorable Overall Survival trend, when compared to Placebo. The authors added that this is the first pivotal study demonstrating the clinical benefit of targeting IDH1 mutation in this patient group. Studies are also underway targeting another molecular alteration, FGFR2, which is detected in approximately 15% of patients with CholangioCarcinoma. ClarIDHy: A global, phase 3, randomized, double-blind study of ivosidenib (IVO) vs placebo in patients with advanced cholangiocarcinoma (CC) with an isocitrate dehydrogenase 1 (IDH1) mutation. Abou-Alfa GK, Maraculla TM, Javle M, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA10_PR.

Late breaking Abstract – ESMO 2019 Targeted Therapy with LYNPARZA® Delays Progression of Advanced Prostate Cancer

RR

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. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation, anti-androgen agents, which include, ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). ZYTIGA® inhibits CYP17A1 enzyme and depletes adrenal and intratumoral androgens, thereby impairing AR signaling. XTANDI® and ERLEADA® compete with Testosterone and Dihydrotestosterone and avidly binds to the Androgen Receptor, thereby inhibiting AR signaling, and in addition inhibits translocation of the AR into the nucleus and thus inhibits the transcriptional activities of the AR.

Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. Among those patients without metastases at CRPC diagnosis, 33% are likely to develop metastases within two years. The estimated mean survival of patients with CRPC is 9-36 months and there is therefore an unmet need for new effective therapies.

The malignant transformation of prostatic epithelial cell as well as the development of CRPC has been attributed to deleterious alterations in a variety of genes including loss-of-function alterations in Homologous Recombination repair genes such as BRCA1, BRCA2 and ATM. Homologous Recombination (HR) is a type of genetic recombination, and this DNA repair pathway is used by cells to accurately repair DNA double-stranded breaks (DSBs) and thereby maintain genomic integrity. Homologous Recombination Deficiency (HRD) is noted following mutation of genes involved in HR repair pathway. At least 15 genes are involved in the Homologous Recombination Repair (HRR) pathway including BRCA1 and BRCA2 genes. BRCA1 and BRCA2 are tumor suppressor genes and functional BRCA proteins repair damaged DNA, and play an important role in maintaining cellular genetic integrity. They regulate cell growth and prevent abnormal cell division and development of malignancy. Mutations in BRCA1 and BRCA2 account for about 20-25% of hereditary breast cancers and about 5-10% of all breast cancers. They also account for 15% of ovarian cancers, in addition to other cancers such as Colon and Prostate. BRCA mutations can either be inherited (Germline) and present in all individual cells or can be acquired and occur exclusively in the tumor cells (Somatic). Somatic mutations account for a significant portion of overall BRCA1 and BRCA2 aberrations. Loss of BRCA function due to frequent somatic aberrations likely deregulates Homologous Recombination (HR) pathway and increases sensitivity to platinum drugs. Majority of the individuals with Germline BRCA mutations (gBRCA) are positive for HR deficiency.MOA-of_LYNPARZA

The PARP (Poly ADP Ribose Polymerase) family of enzymes which include PARP1 and PARP2 repair damaged DNA. PARP inhibitors inhibit the PARP protein in cancer cells and kill tumors defective in the BRCA1 or BRCA2 genes through the concept of synthetic lethality. LYNPARZA® (Olaparib) is a first-in-class PARP inhibitor and blocks DNA damage response in tumors harboring a deficiency in Homologous Recombination Repair, as is noted in those with mutations such as BRCA1 and/or BRCA2. LYNPARZA® showed promising results in a Phase II trial (TOPARP), when given as monotherapy, in patients with BRCA1/2 or ATM gene-mutated mCRPC, who had received a prior Taxane-based chemotherapy, and at least one newer hormonal agent (ZYTIGA® or XTANDI®).

PROfound is a prospective, multicentre, randomized, open-label, Phase III trial in which the efficacy and safety of LYNPARZA® was compared with physician’s choice of either XTANDI® or ZYTIGA® in two groups of patients with mCRPC, who had progressed on prior treatment with new hormonal anticancer treatments, and had a qualifying tumor mutation in one of 15 genes involved in the Homologous Recombination Repair (HRR) pathway. Those in Cohort A (N=245) had alterations in BRCA1, BRCA2 or ATM genes while those in Cohort B (N=142) had alterations in any one of 12 other genes known to be involved in DNA repair which included BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L. Patients were randomized 2:1 within each cohort to receive LYNPARZA® 300 mg orally BID or physician’s choice of XTANDI® 160 mg orally QD or ZYTIGA® 1000 mg orally QD along with Prednisone 5 mg orally BID. Patient characteristics were well-balanced between arms in each treatment group, median patient age was 68 years, approximately 25% of patients had de novo metastatic disease, about 65% of patients received prior Taxane therapy and more than 20% had received two lines of chemotherapy. Patients were allowed to cross over to LYNPARZA® upon progression. The Primary endpoint was radiographic Progression-Free Survival (rPFS) in Cohort A, assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Objective Response Rate (ORR), Time to pain progression and Overall Survival (OS) in Cohort A.

It was noted that in Cohort A, the median PFS was 7.4 months with LYNPARZA®, compared to 3.5 months with hormonal treatment (HR=0.34, P<0.0001). This represented a 66% greater delay in disease progression compared to hormonal therapy. In the overall population (Cohort A+B), median PFS was 5.8 months versus 3.5 months respectively (HR=0.49, P<0.0001). The interim Overall Survival analysis in Cohort A showed that median OS was 18.5 months with LYNPARZA® compared to 15 months with hormonal treatment (HR=0.64, P=0.0173). Median OS in the overall population (Cohort A+B) was 17.5 months versus 14.2 months with LYNPARZA® versus hormonal treatment, respectively (HR 0.67, P=0.0063). In Cohort A, the Objective Response Rate (ORR) was 33.3% with LYNPARZA® compared with 2.3% with the hormonal therapies (P<0.0001). The median Time to pain progression was not yet reached with LYNPARZA® compared with 9.9 months for the hormonal agents. This suggested a 56% reduction in the risk of pain progression (HR=0.44; P=0.019). The most common Adverse Events associated with LYNPARZA® were nausea, decreased appetite, anemia and fatigue.

It was concluded that in this landmark, molecularly targeted, Phase III trial, LYNPARZA® improved Progression Free Survival and Objective Response Rates, with a trend for Overall Survival, among patients with heavily pretreated metastatic CRPC, and alterations in the Homologous Recombination Repair genes. PROFOUND: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Hussain M, Mateo J, Fizazi K, et al. Presented at ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA12_PR.

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.

Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer ASCO Clinical Practice Guideline

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SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 145,600 new cases of CRC will be diagnosed in the United States in 2019 and about 51,020 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) Colon Cancer, has been the standard of care since the 1990s. Adjuvant treatment with an ELOXATIN® (Oxaliplatin) based chemotherapy regimen has been considered standard intervention since 2004, for patients with Stage III colon cancer, following surgical resection, and has been proven to decrease the chance of recurrent disease. Chemotherapy regimens have included (FOLFOX – Leucovorin, 5-FluoroUracil, ELOXATIN®) or CAPOX/XELOX (XELODA®/Capecitabine and ELOXATIN®), given over a period of 6 months. ELOXATIN® can however be associated with neuropathy which can be long lasting or permanent, depending on the duration of therapy. Additional toxicities with longer duration of chemotherapy include diarrhea, fatigue as well as more office visits.

This ASCO Clinical Practice Guideline was based on the IDEA Collaboration, which is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. The goal of this study was to determine if 3 months of adjuvant chemotherapy would be as effective as 6 months of therapy and would be non-inferior. Approximately, 40% of patients received CAPOX regimen and 60% received FOLFOX regimen. The Primary endpoint was Disease Free Survival (DFS).

In an exploratory subgroup analyses by risk of recurrence within the high-risk group defined in the IDEA Collaboration (T4 – tumor invades through the visceral peritoneum including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum or tumor directly invades or adheres to other adjacent organs or structures and/or N2 – metastasis in 4 or more regional lymph nodes), superior DFS was found with 6 months versus 3 months duration of ELOXATIN® based adjuvant chemotherapy. In the low-risk group however, (T1-tumor invades submucosa, T2-tumor invades muscularis propria, or T3-tumor invades through the muscularis propria into the pericolorectal tissues and N1-metastasis in 1-3 regional lymph nodes), DFS was noninferior with 3 months versus 6 months duration of adjuvant chemotherapy.

In prespecified subgroup analysis by type of ELOXATIN®-based chemotherapy, 3 months of treatment was non-inferior to 6 months for patients treated with CAPOX regimen. However, 3 months of treatment was inferior to 6 months, for patients treated with FOLFOX regimen. It has been hypothesized that the protracted delivery of a Fluoropyrimidine with CAPOX might have been more effective than the twice-monthly 5-FUinfusions with FOLFOX as an adjuvant therapy. Grade 2 or more neurotoxicity was significantly lower for patients who received 3 months of adjuvant therapy versus 6 months (P <0.0001), regardless of the treatment regimen (17% vs 48% for FOLFOX and 15% vs 45% for CAPOX/XELOX, respectively).

It was concluded from this study that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with Stage III Colon Cancer, taking into consideration choice of treatment regimen and duration of therapy. In patients treated with adjuvant CAPOX/XELOX regimen, 3 months of therapy was as effective as 6 months, particularly in the low risk subgroup. In patients treated with FOLFOX, 6 months of adjuvant therapy compared to 3 months, resulted in a higher rate of Disease Free Survival, particularly in the high-risk subgroup.

Guideline Question: What is the optimal duration (3 months vs 6 months) of ELOXATIN®-based chemotherapy for patients with completely resected Stage III Colon Cancer?

Target Population: Patients with completely resected Stage III Colon Cancer. Target Audience: Medical oncologists, general surgeons, colorectal surgeons, surgical oncologists, and oncology Advanced Practice Providers who treat patients with Colon Cancer.

Methods: A multidisciplinary Expert Panel which included clinicians with expertise in colorectal surgery and medical oncology as well as a patient representative and an ASCO guidelines health research expert, was convened to develop clinical practice guideline recommendations, based on a systematic review of the medical literature from April 2004 to August 2018, for Phase III randomized clinical trials (RCTs) that included a comparison of two or more durations of treatment with FOLFOX or CAPOX chemotherapy.

Recommendations for patients with Stage III resected Colon Cancer who are being offered treatment with ELOXATIN®-based chemotherapy.

Recommendation 1: For patients with High-risk (T4 and/or N2) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy should be offered for a duration of 6 months.

Recommendation 2: For patients with Low-risk (T1, T2, or T3 and N1) Stage III resected Colon Cancer, adjuvant ELOXATIN®-based chemotherapy may be offered for a duration of 3 months or 6 months, after a discussion with the patient of the potential benefits and risks of harm associated with the options for treatment duration.

Recommendation 3: A shared decision-making approach should be used for duration of ELOXATIN®-based chemotherapy for patients with Stage III resected Colon Cancer, taking into account a patient’s tumor characteristics, completeness of surgical resection, number of lymph nodes examined, comorbidities, functional status, performance status, values and preferences, age at diagnosis, life expectancy, potential years at risk for long-term sequelae of treatment, and including a discussion of the potential for benefit and risks of harm associated with treatment duration.

Duration of Oxaliplatin-Containing Adjuvant Therapy for Stage III Colon Cancer: ASCO Clinical Practice Guideline.Lieu C, Kennedy EB, Bergsland E, J Clin Oncol. 2019;37:1436-1447.

Updated Analysis KEYTRUDA® Doubles Overall Survival Compared with Chemotherapy 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 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

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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 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)

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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)

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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.