Category: Hem/Onc Updates

FDA Approves ERLEADA® for Non-Metastatic Castrate Resistant Prostate Cancer

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SUMMARY: The FDA on February 14, 2018 approved ERLEADA® (Apalutamide) for patients with Non-Metastatic Castration Resistant Prostate Cancer (NM-CRPC). 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 164,690 new cases of Prostate cancer will be diagnosed in 2018 and 29,430 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention for Castration Sensitive Prostate Cancer (CSPC). Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide). The median duration of response is approximately 1 year and majority of these patients progress to Castration Resistant Prostate Cancer (CRPC). The mechanism of resistance to Androgen Deprivation Therapy (ADT) include reactivation of Androgen Receptor signaling through persistent adrenal androgen production, modification of the biologic characteristics of Androgen Receptors, intratumoral testosterone production and parallel steroidogenic pathways. Progression to Castration Resistant Prostate Cancer (CRPC) often manifests itself with a rising PSA (Prostate Specific Antigen), and watchful waiting is recommended in men with non-metastatic CRPC. However, those with a rapidly rising PSA on ADT (doubling time of less than 8-10 months), are at significantly greater risk of developing metastases and death.

ERLEADA® is a next-generation, nonsteroidal, competitive inhibitor of the Androgen Receptor. ERLEADA® prevents binding of androgens to the Androgen Receptor by competitively binding directly to the ligand-binding domain of the Androgen Receptor, and prevents the translocation of the Androgen Receptor to the nucleus and thereby impedes Androgen Receptor mediated DNA transcription. ERLEADA® resulted in durable PSA responses in a phase II study, among men with non-metastatic CRPC, who were at high risk for disease progression (with a PSA level of 8 ng/ml or more or a PSA doubling time of 10 months or less). Based on this preliminary data, the authors evaluated the efficacy of ERLEADA® in men with non-metastatic CRPC, who were at a high risk for the development of metastasis.

SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial is an international, randomized, placebo-controlled, phase III study in which 1207 men were randomly assigned in a 2:1 ratio, to receive ERLEADA® 240 mg orally daily (N=806) or placebo (N=401). Eligible patients had non-metastatic CRPC and were at high risk for the development of metastasis, with a PSA doubling time of 10 months or less during continuous Androgen Deprivation Therapy (bilateral orchiectomy or treatment with Gonadotropin Releasing Hormone analogue agonists or antagonists).

All the patients at the time of screening for eligibility, underwent a technetium-99m bone scan and Computed Tomography (CT) of the head, chest, abdomen and pelvis, abdomen, and were excluded from the study if distant metastasis was detected. Androgen Deprivation Therapy was continued throughout the study period. Patients were eligible to receive treatment with sponsor-provided ZYTIGA® (Abiraterone acetate) plus Prednisone, after the first detection of distant metastasis. The Primary end point was Metastasis-Free Survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. Secondary end points included time to metastasis, Progression Free Survival, time to symptomatic progression, Overall Survival, and time to the initiation of cytotoxic chemotherapy. For those patients who developed metastases, the time between randomization to the first treatment for metastatic CRPC and subsequent progression (second Progression Free Survival-PFS2), was also evaluated.

At the time of the planned primary analysis, the median Metastasis-Free Survival was 40.5 months in the ERLEADA® group as compared with 16.2 months in the placebo group (HR for metastasis or death =0.28; P<0.001). This meant a 72% reduction in the risk of metastasis and death in the ERLEADA® group and significantly prolonged median Metastasis-Free Survival by 2 years, compared with placebo. Further, ERLEADA® significantly improved the time to metastasis, Progression Free Survival and symptom progression, compared with placebo. The time to symptomatic progression was significantly longer with ERLEADA® than with placebo (HR=0.45; P<0.001), which meant a 55% risk reduction in the time to symptomatic disease progression. All prespecified subgroups consistently benefited from ERLEADA®.

In spite of subsequent approved treatment for metastatic CRPC in 78% of placebo recipients (most common subsequent treatment being ZYTIGA® plus Prednisone), the second Progression Free Survival was significantly longer in the ERLEADA® group, compared to the placebo group (Hazard Ratio for progression or death=0.49). A trend toward improved survival was observed in the ERLEADA® group. At a median follow up of 20.3 months, 61% in the ERLEADA® group and 30% in the placebo group were still on therapy. Treatment discontinuation due to adverse events was 10.6% in the ERLEADA® group and 7.0% in the placebo group, and patients in the ERLEADA® group had a higher incidence of rash, hypothyroidism and fractures.

It was concluded that among patients with non-metastatic Castration Resistant Prostate Cancer, ERLEADA® significantly prolonged Metastasis-Free Survival and time to symptomatic progression, when compared to placebo. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. Smith MR, Saad F, Chowdhury S, et al. for the SPARTAN Investigators. N Engl J Med. February 8, 2018. DOI: 10.1056/NEJMoa1715546

Larotrectinib – A Novel Age and Tumor Agnostic Therapy for TRK Fusion-Positive Cancers

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Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. Next-Generation Sequencing (NGS) platforms or second-generation sequencing perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.
Larotrectinib is a potent and highly selective small molecule inhibitor of three TRK proteins, Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3. In a phase I-II study involving children, adolescents and adults with 17 unique cancer diagnoses, the Overall Response Rate was 75% and at 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. It was concluded from this study that TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults and Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or tumor type.

Adjuvant Chemotherapy May Improve Overall Survival Following Preoperative Chemoradiotherapy and Surgery in GastroEsophageal Cancer

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SUMMARY: The American Cancer Society estimates that in the US, about 17,290 new Esophageal cancer cases will be diagnosed in 2018 and about 15,850 patients will die of the disease. Squamous Cell Carcinoma is the most common type of cancer of the Esophagus among African Americans, while Adenocarcinoma is more common in caucasians. Esophageal cancer is more common among men than among women. It is estimated that about 20% of patients survive at least 5 years after diagnosis.

Patients with resectable, locally advanced, Esophageal or GastricEsophageal junctional cancer are often treated with multimodality therapy. The CROSS trial (ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study) compared neoadjuvant chemoradiotherapy with weekly Carboplatin and Paclitaxel plus Radiotherapy followed by surgery, to surgery alone, in patients with Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus or GastricEsophageal junction. Neoadjuvant chemoradiotherapy when added to surgery in this study, conferred Overall Survival benefit, for both Squamous Cell Carcinoma and Adenocarcinoma histological subtypes and is now regarded as the standard of care, for this patient population. Nonetheless, it should be noted that the survival benefit was most pronounced in patients with squamous cell histology but was less definitive for those with adenocarcinoma histology, with approximately a third of patients developing distant failure. It has been postulated that the reduced dose and duration systemic chemotherapy given concurrently with radiation therapy, in preoperative setting, may have limited the efficacy of chemotherapy to prevent distant failure.

There is limited data on the role of adjuvant chemotherapy added to preoperative chemoradiotherapy and surgery, for patients with GastricEsophageal (GE) junctional adenocarcinoma. To address this question, the authors in this publication compared Overall Survival among patients with GE adenocarcinoma, receiving adjuvant chemotherapy versus postoperative observation, following preoperative chemoradiotherapy and surgical resection.

Using the National Cancer Database, the authors identified 10,086 patients, 9272 in the postoperative observation group and 814 who had received adjuvant chemotherapy. They then used propensity score matching to compare Overall Survival between the adjuvant chemotherapy and postoperative observation groups. Patients included in the study were diagnosed to have clinical stage T1,N1-3,M0 or T2-4,N0-3,M0 adenocarcinoma of the distal esophagus or gastric cardia, between 2006 and 2013, and were treated with preoperative chemoradiotherapy and surgical resection with a curative intent. Patients receiving adjuvant chemotherapy were younger and were more likely to have advanced disease and shorter postoperative hospitalization. A total of 732 patients in the adjuvant chemotherapy group were matched by propensity score to 3660 patients in the postoperative observation group.

It was noted that adjuvant chemotherapy was associated with improved Overall Survival compared with postoperative observation without adjuvant chemotherapy (median survival 40 months versus 34 months; HR=0.79, P <0.001). The Overall Survival at 1, 3, and 5 years was 94%, 54%, and 38% in the adjuvant chemotherapy group and 88%, 47%, and 34% in the observation group, respectively. The survival benefit with adjuvant chemotherapy was noted in most patient subgroups.

Based on this analysis it was concluded that for patients with locally advanced GastroEsophageal adenocarcinoma treated with preoperative chemoradiotherapy and surgical resection, adjuvant chemotherapy was associated with improved Overall Survival. Adjuvant Chemotherapy vs Postoperative Observation Following Preoperative Chemoradiotherapy and Resection in Gastroesophageal Cancer. A Propensity Score–Matched Analysis. Mokdad AA, Yopp AC, Polanco PM, et al. JAMA Oncol. 2018;4:31-38

Long Term Survival Outcomes with OPDIVO® 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. The American Cancer Society estimates that for 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of Non Small Cell Lung Cancer (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. Under normal circumstances, Immune checkpoints or gate keepers inhibit intense immune responses by switching off the T cells of the immune system. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.Unleashing-T Cell-Function-with-OPDIVO-for-Advanced-Non-Small-Cell-Lung-Cancer

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® significantly prolonged Overall Survival (OS) and had a favorable toxicity profile, when compared to TAXOTERE® (Docetaxel), in two open-label, randomized, phase III trials, among patients with advanced squamous (CheckMate 017) or non-squamous (CheckMate 057) NSCLC, who had disease progression during or after platinum-based chemotherapy. This data led to the approval of OPDIVO® in previously treated advanced NSCLC.

There is however limited data on long term efficacy and safety for immune checkpoint inhibitors in patients with NSCLC when compared with chemotherapy. The authors in this publication reported updated efficacy and safety data for OPDIVO® in patients with advanced NSCLC from the CheckMate 017 and CheckMate 057 trials, with a minimum follow up of 2 years in all patients. Patients in both trials had stage IIIB or IV disease and had disease progression during or after platinum-based chemotherapy. In CheckMate 017 study, 272 patients with metastatic squamous NSCLC were randomized to receive OPDIVO® (Nivolumab) 3 mg/kg IV every 2 weeks (N=135) or TAXOTERE® (Docetaxel) 75 mg/m2 IV every 3 weeks (N=137). In CheckMate 057 trial, 582 patients were randomized to receive OPDIVO® 3 mg/kg IV every 2 weeks (N=292) or TAXOTERE® 75 mg/m2 IV every 3 weeks (N=290). Treatment was continued until disease progression or unacceptable toxicity. The minimum follow up for survival was 24.2 months.

The Overall Survival rate at 2 years with OPDIVO® versus TAXOTERE® were 23% vs 8% among squamous NSCLC patients and 29% vs 16% among non-squamous NSCLC patients. The relative reductions in the risk of death with OPDIVO® versus TAXOTERE® was similar to what was reported in the primary analyses. As was reported at the time of the primary analysis of these two trials, the superiority of OPDIVO® over TAXOTERE® was independent of Programmed cell Death Ligand 1 (PD-L1) expression in squamous NSCLC, whereas among patients with non-squamous histology, the benefit with OPDIVO® was greater in those with higher levels of PD-L1 expression, but patients with PD-L1 expression of less than 1% benefited as well.

In the pooled analysis of both trials, the median OS was 11.1 months with OPDIVO® versus 8.1 months with TAXOTERE® (HR=0.72). The relative reduction in the risk of death with OPDIVO® was 28%. Higher PD-L1 expression levels was associated with greater OS benefit with OPDIVO® (HR=0.42 in patients with 50% or more PD-L1 expression). Survival benefit however was still observed in patients with 1% or less PD-L1 expression (HR=0.78). Durable responses were noted with OPDIVO® among 37% of the confirmed responders with squamous NSCLC and 34% of confirmed responders with non-squamous NSCLC. These patients had ongoing responses after a minimum follow up of 2 years whereas no patient in the TAXOTERE® treated group had an ongoing response. The rates of treatment-related adverse events of any grade were lower with OPDIVO® compared to TAXOTERE® (any grade: 68% vs 88%; grade 3-4: 10% vs 55%, respectively).

The authors concluded that OPDIVO® provides long term clinical benefit and has a favorable tolerability profile compared with TAXOTERE®, in previously treated patients with advanced NSCLC. Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non–Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057). Horn L, Spigel DR, Vokes EE, et al. J Clin Oncol 2017;35:3924-3933

Germline Testing with NGS Multigene Cancer Panels Recommended for All Young Patients with Colorectal Cancer

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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 140,250 new cases of CRC will be diagnosed in the United States in 2018 and about 50,630 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 21 (4.7%).

Even though the incidence of Colorectal cancer (CRC) in the United States has been rapidly declining overall, primarily driven by screening, the incidence however has been increasing among adults younger than age 50 years. Currently, genetic testing is recommended in patients with polyposis phenotypes, strong family histories, and those whose tumors demonstrate MicroSatellite Instability (MSI) or fail to stain for MisMatch Repair (MMR) gene proteins by immunohistochemistry. Whether patients younger than 50 years of age with CRC, should be tested with a broad multigene panel to detect additional genetic abnormalities, has remained unclear.

The authors conducted this study to ascertain the proportion of young CRC cases associated with genetic predisposition. In this retrospective study, 430 individuals diagnosed with CRC at an age younger than 50 years were evaluated by the clinical genetics service at a single tertiary care cancer center from 1998 through 2015. Data collection included patient histories, tumor phenotypes, and results of germline DNA sequencing. If information was uninformative, germline DNA samples were resequenced using a research-based Next-Generation Sequencing multigene panel. The primary outcome was identification of a pathogenic germline mutation associated with cancer predisposition.

The researchers noted that 26% of young CRC cases had a first-degree relative with CRC and 10% had tumors with histologic evidence for MisMatch Repair (MMR) deficiency and 6% had polyposis phenotype. Germline mutations associated with a hereditary cancer syndrome were identified in 79 patients (18%) following clinically driven germline sequencing, and Next-Generation Sequence analysis using a multigene panel detected actionable germline variants in 6 patients (5%) with uninformative clinical evaluations. Lynch syndrome was identified in 56 patients (14%) of the entire cohort, Familial Adenomatous Polyposis in 2%, MUTYH in 2%, and SMAD4 was mutated in 2 patients, BRCA1 in one, TP53 in one, and CHEK2 in one. Only 51% of the patients with germline mutations associated with a hereditary cancer syndrome gave a family history of CRC diagnosis in a first-degree relative.

The authors concluded that 20% of patients diagnosed with CRC at age younger than 50 years carry a germline mutation associated with cancer, and half of these patients do not have clinical histories typically associated with the identified syndrome. Germline testing with Next-Generation Sequencing multigene cancer panels should therefore be considered for all young patients with CRC. Germline Genetic Features of Young Individuals with Colorectal Cancer. Stoffel EM, Koeppe E, Everett J, et al. Gastroenterology 2017 Nov 13; [e-pub]. (http://dx.doi.org/10.1053/j.gastro.2017.11.004)

Circulating Tumor Cells Predict Late Recurrence in Early Stage HR-Positive 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. Circulating Tumor Cells (CTCs) are epithelial cells that are shed into the circulation from a primary or metastatic tumor. After being shed, CTCs can remain in the circulation or undergo apoptosis. Evaluation of CTCs during the course of disease has prognostic value. Because of the very low concentrations of CTCs (1 CTC in the background of millions of normal hematopoietic cells) in the peripheral blood, different technologies have been developed that will allow enrichment and detection of these CTCs. One such technology is the CELLSEARCH® system which is the first FDA-approved test for CTC assessment, in the peripheral blood of patients with breast cancer. This automated system is able to enrich the peripheral blood sample with CTCs and the cells then are fluorescently stained for CytoKeratins (CK8,18 and 19), Common Leukocyte Antigen (CD45) and a nuclear dye (DAPI). CTCs are identified when they are CK positive, CD45 negative and DAPI positive. In essence, CTC assessment is a real time, peripheral blood evaluation (“Liquid Biopsy”) in breast cancer patients.Differentiating-Circulating-Tumor-Cells-from-Leukocytes

In women with Hormone Receptor (HR)-positive breast cancer, late recurrences occurring 5 or more years after diagnosis, account for approximately 50% of recurrences. In a meta-analysis from the EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) group, the 10-year risk of recurrence after 5 years of endocrine therapy was found to be 5% in patients with node negative breast cancer, 10% in patients with 1-3 positive lymph nodes, and 22% in patients with 4-9 positive lymph nodes. Late recurrence in patients with HR-positive breast cancer has therefore become a major concern, as this risk for recurrence and death from breast cancer can be ongoing for at least 20 years after the original diagnosis..

The blood and tumor samples of patients are valuable for research and allow the exploration of possible tumor and host-related factors contributing to recurrence. The Coalition of Cancer Cooperative Groups, a non-profit member organization of the National Cancer Institute-sponsored Cooperative Groups, in 2013, created the North American Breast Cancer Groups (NABCG) Biospecimen Bank for Determinants of Late Relapse in Operable Breast Cancer. The purpose for the collection and analysis of samples is, to improve our understanding of breast cancer, and identify which patients are most likely to benefit from specific therapies. The NABCG Biospecimen Bank remains a unique resource of archived primary and metastatic tumor tissue, blood, and DNA, collected from more than 15,000 women, who participated in two large cooperative group cancer treatment trials, TAILORx and E5103.

The authors in this analysis included 546 patients with HER-2-negative, stage II to stage III breast cancer from the E5103 clinical trial, with no clinical evidence of recurrence between 4.5 to 7.5 years following their initial diagnosis. ECOG-ACRIN clinical trial E5103 is a randomized phase III trial, which evaluated the addition of Bevacizumab (AVASTIN®), a Vascular Endothelial Growth Factor (VEGF) inhibitor, to adjuvant chemotherapy following surgery, in patients with lymph node-positive or high-risk, lymph node-negative breast cancer. All patients had undergone surgery and adjuvant chemotherapy as well as endocrine therapy for at least 5 years, if hormone receptor positive. The CTCs from the blood samples of these patients were measured using the CELLSEARCH® CTC assay. None of the patients had clinical evidence of recurrence at the time of this analysis. More than half of the patients (56%) were 50 years or older, 59% of the patients had a tumor 2 cm or larger, 73% had positive lymph nodes and 65% had Hormone Receptor (HR) positive disease. This Primary endpoint of this study was time to recurrence and the primary focus in this analysis was on the group with Hormone Receptor positive disease.

After a median follow up of 1.6 years, 4.8% of patients had a positive CTC assay result overall (1 or more cells/7.5 mL in the blood). Among those with Hormone Receptor positive breast cancer, 5.1% had a positive CTC assay result whereas positive CTC assay result was noted in 4.1% of patients with hormone receptor negative disease. Of the 353 patients with HR-positive disease in this analysis, 4% had a recurrence whereas only 0.5% with HR-negative disease had a local recurrence. The Hazard Ratio for patients with CTC negative results compared with CTC positive results was 21.7 (P<0.001). A positive CTC assay result was associated with a nearly 21.7 fold increased risk of breast cancer recurrence in patients with HR-positive disease. A positive CTC assay was not associated with recurrence in the HR-negative group. The Positive Predictive Value of a positive CTC assay for recurrence at 2 years, in patients with HR-positive disease was 35%, and the Negative Predictive Value for patients in this cohort was 98%.

It was concluded that detection of positive Circulating Tumor Cells in the blood, 5 years after breast cancer diagnosis, was associated with an increased risk for late recurrence, in women with HR-positive, HER2-negative breast cancer. Sparano JA, O’Neill A, Alpaugh K, et al. Circulating tumor cells and late recurrence of breast cancer. Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS6-03.

Monoclonal Gammopathy of Undetermined Significance Associated with Shorter Survival

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SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. MGUS is defined as the presence of a serum monoclonal protein (M protein) at a concentration of 3 g/dl or less, urine with none or only modest amounts of monoclonal light chains, absence of CRAB features that are related to the M protein (Hypercalcemia, Renal insufficiency, Anemia, and Bone lesions) and 10% or fewer monoclonal plasma cells in the bone marrow. MGUS occurs in approximately 3% of individuals 50 years of age or older and in 5.3% of those 70 years of age or older.

MGUS is classified into two major subtypes, IgM and non-IgM. This is because the clonal cell that is involved and the nature of progression, differ between these two types. The origin of IgM MGUS is typically from a CD20 positive Lymphoplasmacytic cell that has not undergone Switch Recombination (Class-Switch Recombination or CSR, is a biological mechanism that changes a B cell production of immunoglobulin from one type to another, such as from the isotype IgM to the isotype IgG.), and this disease type is associated with a risk of progression to Lymphoma or Waldenström’s macroglobulinemia. In contrast, non-IgM MGUS typically arises from mature plasma cells that have undergone Switch Recombination and is associated with a risk of progression to Multiple Myeloma. Both disease types can progress to AL Amyloidosis.

There is limited information regarding malignant transformation of MGUS to Multiple Myeloma as well as Overall Survival, after diagnosis is made. Further, the risk of progression to Multiple Myeloma among the two major biologic subtypes of MGUS, IgM and non-IgM, is different, and data regarding the prognosis and risk stratification associated with these entities have not been well characterized. The authors in this publication, which is a longer follow up of previously reported findings, studied 1384 patients with MGUS, who were identified in a well-defined geographic area, from 1960-1994. The median follow up was 34.1 years. The Primary end point was progression to Multiple Myeloma or another Plasma-cell or Lymphoid disorder.

During 14,130 person-years of follow up, the rate of progression of MGUS to Multiple Myeloma was 6.5 times as high as the rate in the control population. The risk of progression to Multiple Myeloma was 10% at 10 years, 18% at 20 years, 28% at 30 years, 36% at 35 years, and 36% at 40 years. The risk of progression varied depending on the biologic subtypes of MGUS and other adverse risk factors. Among patients with IgM MGUS, the presence of two adverse risk factors – an abnormal serum free light chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein level (1.5 g/dl or greater), was associated with a risk of progression at 20 years of 55%, as compared with 41% among patients who had one adverse risk factor and 19% among patients who had neither risk factor. Among patients with non-IgM MGUS, the risk of progression to Multiple Myeloma at 20 years was 30% among those who had the two risk factors, 20% among those who had one risk factor, and 7% among those who had neither risk factor. More importantly, patients with MGUS had shorter survival compared to age and sex matched control population (median 8.1 versus 12.4 years, P<0.001).

It was concluded that there were significant differences noted in the risk of progression between patients with IgM MGUS and those with non-IgM MGUS and Overall Survival was shorter among patients with MGUS than was expected in a matched control population. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. Kyle RA, Larson DR, Therneau TM, et al. N Engl J Med 2018; 378:241-249

Larotrectinib – A Novel Age and Tumor Agnostic Therapy for TRK Fusion-Positive Cancers

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SUMMARY: Tumor genomic profiling enables the identification of specific genomic alterations and thereby can provide personalized treatment options with targeted therapies that are specific for those molecular targets. The FDA in May 2017, granted accelerated approval to KEYTRUDA® (Pembrolizumab), for adult and pediatric patients with unresectable or metastatic, MicroSatellite Instability-High (MSI-H) or MisMatch Repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This is the first FDA approval of a systemic cancer treatment, based on a specific genetic biomarker, independent of tumor origin (first tissue/site-agnostic approval).

A genomic test can be performed on a tumor specimen or on cell-free DNA in plasma (“liquid biopsy”) or an ImmunoHistoChemistry (IHC) test can be performed on tumor tissue for protein expression that demonstrates a genomic variant known to be a drug target, or to predict sensitivity to a chemotherapeutic drug. Next-generation sequencing (NGS) platforms or second-generation sequencing unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. Recently reported genomic profiling studies performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.Tropomyosin-Receptor-Kinase-Signaling-Pathway

The molecules of interest are Neurotrophic Tropomyosin Receptor Kinase (NTRK) gene rearrangements. The three TRK family of Tropomyosin Receptor Kinase (TRK) transmembrane proteins TRKA, TRKB, and TRKC are encoded by Neurotrophic Tropomyosin Receptor Kinase genes NTRK1, NTRK2, and NTRK3, respectively. These receptor tyrosine kinases are expressed in human neuronal tissue and are involved in a variety of signaling events such as cell differentiation, cell survival and apoptosis of peripheral and central neurons. They therefore play an essential role in the physiology of development and function of the nervous system. Chromosomal fusion involving NTRK genes represent the main molecular alterations with known oncogenic and transforming potential and have been identified in a variety of cancers both in children and adults. Gene fusions involving NTRK genes lead to transcription of chimeric TRK proteins which can confer oncogenic potential by increasing cell proliferation and survival. These genetic abnormalities have generated a lot of interest and have emerged as targets for cancer therapy. NGS has allowed the discovery of these gene fusions. Early clinical evidence suggests that these gene fusions lead to oncogene addiction regardless of tissue of origin. (Oncogene addiction is the dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype).

Larotrectinib is a potent and highly selective small molecule inhibitor of all three TRK proteins. The authors in this development program included patients of any age and with any tumor type who had chromosomal fusion involving NTRK genes (Age and Tumor agnostic therapy). This program enrolled 55 patients, ranging in age from 4 months to 76 years, with consecutively and prospectively identified TRK fusion-positive cancers, detected by molecular profiling. They were assigned to three clinical studies – a phase I study involving adults, a phase I-II study involving children and a phase II study involving adolescents and adults.

This population of patients encompassed 17 unique cancer diagnoses and enrolled patients had locally advanced or metastatic solid tumors, and had received prior standard therapy (if available). The Primary end point for the combined analysis was the Overall Response Rate according to Independent review. Secondary end points included Duration of Response, Progression Free Survival, and safety. The researchers in this publication reported the safety and efficacy analysis of the first 55 consecutively enrolled patients, identified with TRK fusion-positive cancers, treated across these studies.

The Overall Response Rate was 75%. A total of 13% of the patients had a Complete Response, 62% had a Partial Response and 13% had stable disease. The median Duration of Response and Progression Free Survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response continued treatment or had undergone curative surgery. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The most common adverse events of any grade were fatigue, vomiting and abnormal liver function studies. None of the patients on Larotrectinib discontinued therapy due to a drug-related adverse event.

It was concluded that TRK fusions defined a unique molecular subgroup of advanced solid tumors in children and adults and Larotrectinib had marked and durable antitumor activity in patients with TRK fusion-positive cancer, regardless of the age of the patient or tumor type. Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children. Drilon A, Laetsch TW, Kummar S, et al. N Engl J Med 2018; 378:731-739

Long Term Disease Free Survival Benefit with Adjuvant NERLYNX® in HER2-positive 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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 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. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2 and adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early breast cancer. Nonetheless, approximately 25% of patients will develop recurrent disease within 10 years following this adjuvant intervention. Extending the duration of adjuvant HERCEPTIN® therapy or adding TYKERB® (Lapatinib), a Tyrosine Kinase Inhibitor that targets HER1 and HER2, has not improved outcomes.HER2-Directed-Therapy

NERLYNX® is a potent, irreversible, oral Tyrosine Kinase Inhibitor, of HER1, HER2 and HER4 (pan-HER inhibitor).NERLYNX® interacts with the catalytic domain of HER1, HER2, and HER4 and blocks their downstream signaling pathways, resulting in decreased cell proliferation and increased cell death. Clinical data has suggested that NERLYNX® has significant activity in suppressing HER-mediated tumor growth and is able to overcome tumor escape mechanisms experienced with current HER2-targeted and chemotherapeutic agents. It has been well known that hormone receptor positive breast cancer patients, who are also HER2-positive, have relative resistance to hormone therapy. Preclinical models had suggested that the addition of NERLYNX® could improve responses in ER positive, HER2-positive breast cancer patients. Further, NERLYNX® has clinical activity in patients with HER2-positive metastatic breast cancer.

ExteNET trial is a multicentre, randomized, double-blind, placebo-controlled, phase III study, in which the efficacy and safety of 12 months of NERLYNX® after HERCEPTIN®-based adjuvant therapy was evaluated, in patients with early stage HER2-positive breast cancer. Patients with early stage HER2-positive breast cancer (N=2,840), and within two years of completing adjuvant HERCEPTIN®, were randomized in a 1:1 ratio to receive either oral NERLYNX® 240 mg per day (N=1420) or placebo (N=1420), for one year. Patients were stratified by hormone receptor status, nodal status (0, 1-3, or 4 or more), and HERCEPTIN® adjuvant regimen (sequentially versus concurrently with chemotherapy). The authors had previously reported that NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly improved 2-year invasive Disease Free Survival.

They now reported updated efficacy outcomes, from a protocol-defined 5-year follow-up sensitivity analysis, and long-term toxicity findings. The predefined endpoint of the 5-year analysis was invasive Disease Free Survival (iDFS), defined as the time between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause. The median follow up was 5.2 years.

It was noted that patients in the NERLYNX® group had significantly fewer invasive Disease Free Survival events, than those in the placebo group (HR=0.73; P=0.0083). The 5-year invasive Disease Free Survival was 90.2% in the NERLYNX® group and 87.7% in the placebo group. The most common grade 3-4 adverse events associated with NERLYNX® were diarrhea, vomiting and nausea. Patients can experience diarrhea early, in the first 2 or 3 days and this can be alleviated using antidiarrheal prophylaxis with Loperamide, initiated with the first dose of NERLYNX® and continued for the first 2 months of treatment and as needed thereafter. There was no evidence of long-term toxicities associated with NERLYNX®, when compared to placebo.

It was concluded that at a median follow up of 5 years, NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly reduced the proportion of clinically relevant breast cancer relapses that might lead to death, such as distant and locoregional recurrences outside the preserved breast. This benefit was seen without increase in the risk of long term toxicity. Overall Survival data will be available at a later date. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Martin M, Holmes FA, Ejlertsen B, et al. for the ExteNET Study Group. Lancet Oncol 2017;18:1688-1700

Perioperative Interruption of Direct Oral Anticoagulants in Patients with Venous Thromboembolic Disease

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Perioperative Interruption of Direct Oral Anticoagulants in Patients with Venous Thromboembolic Disease

SUMMARY: Direct Oral AntiCoagulants (DOACs) are often prescribed for thromboembolic events. This class of anticoagulants, have a rapid onset and offset of action, short half-life and predictable anticoagulant effects, without the need for routine monitoring. Further, several studies have demonstrated non-inferiority or superiority of this class of drugs compared with Vitamin K Aantagonists (VKAs), with regards to prevention and treatment of thromboembolic events. It is estimated that each year 10-15% of patients on DOACs will undergo an invasive procedure or surgery and will require temporary interruption of anticoagulation prior to standard-risk procedures and procedures with increased risk for bleeding. Several studies have evaluated the perioperative interruption of DOACs based on half-life of the anticoagulant and the underlying procedural bleeding risk in patient with Atrial Fibrillation. Whether these findings can be extrapolated to patients with VTE, has remained unclear.Anticoagulants-Classification

The authors in this study evaluated the thrombotic and bleeding outcomes following the perioperative interruption of Direct Oral AntiCoagulants, in patients with prior VTE (Venous ThromboEmbolism). This retrospective study included 190 patients who were on Direct Oral AntiCoagulants, such as PRADAXA® (Dabigatran), XARELTO® (Rivaroxaban), SAVAYSA® (Edoxaban) or ELIQUIS® (Apixaban), for previous VTE, and were scheduled to undergo an invasive procedure or surgery. They required temporary interruption of anticoagulation prior to standard-risk procedures and procedures with increased risk for bleeding. About 80% of the patients had unprovoked VTE, as the most recent thrombotic event, and 25% of the patients had recurrent VTE. The mean age was 59 years.Bleeding-Risk-for-Invasive-Procedures

The timing to interrupt and reinitiate Direct Oral Anticoagulant therapy was at the discretion of the treating physician, and typically DOACs were held for three half-lives prior to and restarted 2 days following standard-bleeding risk procedures, and for five half-lives prior to and restarted 4 days following high-bleeding risk procedures. The mean time from last dose of DOAC to surgery was 56.9 hours for standard-bleeding risk procedures and 69.9 hours for high-bleeding risk procedures. The mean time to therapeutic dosing of DOACs was 47 hours in the standard-bleeding risk group and 80.2 hours in the high-bleeding risk group. Approximately 41% of patients also received prophylactic doses of Low Molecular Weight Heparin or DOACs in the immediate postoperative period before re-initiation of therapeutic anticoagulation. Also taken into consideration was the elimination half-life of DOACs which can be increased by decreased renal function (PRADAXA® > SAVAYSA® > XARELTO® and ELIQUIS®), severe hepatic insufficiency (XARELTO® and ELIQUIS® > SAVAYSA® > PRADAXA®) and drug interactions. The Primary efficacy outcome was the 30-day symptomatic VTE rate, and the Primary safety outcome was the 30-day major bleeding rate. Secondary outcomes included overall mortality and the rate of clinically relevant non-major bleeding.

The 30-day VTE rate was 1.05% and the 30-day major bleeding rate was 0.53%. There were no deaths during the 30-day follow-up period. The rate of clinically relevant non-major bleeding was 3.16%.

It was concluded that perioperative interruption of Direct Oral AntiCoagulants, using a strategy that considered the half-life of the DOAC and the underlying procedural bleeding risk, appeared to be both safe and effective among patients with prior Venous ThromboEmbolism. Thrombotic and bleeding outcomes following perioperative interruption of direct oral anticoagulants in patients with venous thromboembolic disease. Shaw J, de Wit C, Le Gal G, et al. J Thromb Haemost. 2017;doi:10.1111/jth.13670