Category: Meeting Updates

Liquid Biopsy Accurate, Reliable and Rapid in Identifying Biomarker Mutations in Newly Diagnosed Advanced Lung Cancer

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SUMMARY: 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. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Patients with newly diagnosed metastatic NSCLC are often tested for guideline-recommended genomic biomarkers which include both predictive biomarker mutations such as EGFR, ALK, ROS1, BRAF, RET, MET, ERBB2, as well as prognostic biomarker mutation such as KRAS.

The application of precision medicine with targeted therapy requires detection of molecular abnormalities in a tissue biopsy specimen. However, if testing is not done with a comprehensive assay, such as Next-Generation Sequencing and is done in successive steps one test after another, tissue sample can be depleted, with not enough tissue left for testing of all biomarkers. Following progression or recurrence, archived biopsy specimens may not be helpful, as it is important to identify additional mutations in the tumor at the time of recurrence or progression, in order to plan appropriate therapy. Further, recurrent tumors may be inaccessible for a safe biopsy procedure or the clinical condition of the patient may not permit a repeat biopsy. Additionally, the biopsy itself may be subject to sampling error due to tumor heterogeneity. Genotyping circulating cell-free tumor DNA (cfDNA) in the plasma can potentially overcome the shortcomings of repeat biopsies and tissue genotyping, allowing the detection of many more targetable gene mutations, thus resulting in better evaluation of the tumor genome landscape.

The Noninvasive versus Invasive Lung Evaluation (NILE) trial is a prospective, multicenter study conducted to demonstrate the noninferiority of comprehensive cell-free DNA (cfDNA) relative to standard-of-care traditional tissue genotyping tests, to identify guideline-recommended genomic biomarkers, in patients with metastatic NSCLC. The authors in this study enrolled 282 newly diagnosed patients at 28 North American centers, with previously untreated, nonsquamous, metastatic NSCLC undergoing standard-of-care tissue genotyping. Enrolled patients submitted a pretreatment blood sample for cfDNA analysis utilizing a CLIA-certified comprehensive 73-gene next generation sequencing panel (Guardant360®). Over 80% of the enrolled patients were white and over 50% were female.

The liquid biopsy utilizing Guardant360®, detected biomarker mutations at a rate similar to standard-of-care tissue genotyping tests, in the enrolled patients, meeting the Primary study objective. At least one of the guideline-recommended genomic biomarkers was detected in 60 patients (21.3%) using tissue-based tests and in 77 patients (27.3%) by cfDNA utilizing Guardant360® (P<0.0001). The detection rate was increased by 48% when Guardant360® was utilized for cfDNA analysis and this included those with negative, not assessed, or Quantity Not Sufficient (QNS) results in tissue. In addition, the Positive Predictive Value was 100% for cfDNA versus tissue genotyping, for FDA approved targets such as EGFR, ALK, ROS1, and BRAF mutations. There are agents already approved by the FDA to treat this patient population. The median turnaround time was significantly lower for cfDNA, compared to tissue genotyping (9 versus 15 days; P <0.0001).

The authors concluded that in this largest cfDNA study among patients with previously untreated advanced NSCLC, cfDNA successfully detected seven biomarker mutations noninvasively, significantly faster than tissue genotype testing, and was also able to rescue biomarker mutation positive patients who had non-diagnostic tissue results. They added that the findings in this study confirms similar findings from Europe and demonstrates the clinical utility of cfDNA in newly diagnosed metastatic NSCLC. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer (mNSCLC). Leighl N, Page RD, Raymond VM, et al. Presented at: AACR Annual Meeting April 2, 2019; Philadelphia, USA.

Adjuvant KADCYLA® Superior to HERCEPTIN® in High Risk 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 and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. The duration of adjuvant HERCEPTIN® therapy has been 12 months and this length of treatment was empirically adopted from the pivotal registration trials.

KADCYLA® (Ado-Trastuzumab Emtansine, T-DM1) is an Antibody-Drug Conjugate (ADC) comprised of the antibody HERCEPTIN® and the chemotherapy agent Emtansine, linked together. Upon binding to the HER2 receptor, it not only inhibits the HER2 signaling pathways but also delivers a chemotherapy agent Emtansine, a microtubule inhibitor, directly inside the tumor cells. This agent is internalized by lysosomes and destroys the HER2-positive tumor cells upon intracellular release. In the EMILIA trial, KADCYLA® was associated with significant increase in Overall Survival when compared with TYKERB® (Lapatinib) plus XELODA® (Capecitabine), in HER2-positive metastatic breast cancer patients, who had previously received HERCEPTIN® and a Taxane.Mechanism-of-Action-KADCYLA

It is well established that patients with HER2-positive early breast cancer following HERCEPTIN® based neoadjuvant therapies have a pathological Complete Response rate of 40-60%. Those without a pathological Complete Response tend to have significantly less favorable outcomes. These patients irrespective of pathological response status complete their standard adjuvant therapy which includes 12 months of HER2-targeted therapy. KATHERINE trial was conducted to evaluate the benefit of switching from standard HER2-directed therapy to single-agent KADCYLA®, after neoadjuvant chemotherapy along with either single or dual HER2 targeted therapy, in patients with residual invasive cancer at surgery. This study was conducted to address the unmet need of patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus HER2-targeted therapy.

The KATHERINE trial is an open-label, phase III global study, which compared KADCYLA® with HERCEPTIN®, as an adjuvant treatment for patients with HER2-positive early breast cancer, who had residual invasive disease following neoadjuvant chemotherapy and HERCEPTIN®. This study included 1,486 patients with HER2-positive early stage breast cancer, who were found to have residual invasive disease in the breast or axillary lymph nodes at surgery, following at least six cycles (16 weeks) of neoadjuvant chemotherapy with a Taxane (with or without Anthracycline) and HERCEPTIN®. Within 12 weeks of surgery, patients (N=1486) were randomly assigned in a 1:1 ratio to KADCYLA® 3.6 mg/kg IV every 3 weeks or HERCEPTIN® 6 mg/kg IV every 3 weeks, for 14 cycles (743 patients in each group). Both treatment groups were well balanced and hormone receptor positive disease was present in 72% of the patients. The majority of the patients (77%) had received an Anthracycline-containing neoadjuvant chemotherapy regimen, and in 19% of the patients, another HER2-targeted agent in addition to HERCEPTIN® (dual HER2 blockade) had been administered as a component of neoadjuvant therapy. The Primary end point was invasive Disease Free Survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause). The median duration of follow up was 41.4 months in the KADCYLA® group and 40.9 months in the HERCEPTIN® group.

At the prespecified interim analysis, invasive disease occurred in 12.2% of patients who received KADCYLA® and 22.2% of patients who received HERCEPTIN®. The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the KADCYLA® group and 77.0% in the HERCEPTIN® group. Invasive Disease Free Survival, which was the Primary end point of the study, was significantly higher in the KADCYLA® group than in the HERCEPTIN® group (HR=0.50; P<0.001).This suggested that KADCYLA® reduced the risk of developing an invasive breast cancer recurrence or death by 50%. Distant recurrence as the first invasive disease event occurred in 10.5% of patients in the KADCYLA® group and in 15.9% of the HERCEPTIN® group. A consistent benefit was seen across all prespecified subgroups. Adverse events were consistent with the known safety profile of KADCYLA®, with more toxicities associated with KADCYLA® than with HERCEPTIN®. Additional follow-up will be necessary to determine the Overall Survival benefit with adjuvant KADCYLA®.

It was concluded that among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, substituting KADCYLA® for adjuvant HERCEPTIN® reduced the risk of recurrence of invasive breast cancer or death by 50%, with the benefit seen across all patient subgroups. The authors added that even though KATHERINE trial focused on higher-risk patients with residual invasive breast cancer after completion of neoadjuvant chemotherapy, CNS recurrence remains a persistent problem. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. von Minckwitz G, Huang C-S, Mano MS, et al. for the KATHERINE Investigators. (published online December 5, 2018). N Engl J Med 2019;380:617-628

Late Breaking Abstract – ASH 2018 New Simplified Practice-Changing Protocol for Interrupting Direct Oral Anticoagulants for Surgery/Procedure

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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, predictable anticoagulant effects, no laboratory monitoring and fixed dosing schedule. The half-life of these agents can however be prolonged in those with renal insufficiency and may be unsafe and direct oral anticoagulants are ineffective in patients with mechanical heart valves. In several clinical studies, DOACs have been shown to reduce the rate of major bleeding by 28% and the rates of intracranial and fatal hemorrhage by 50%, when compared to COUMADIN® (Warfarin).Anticoagulants

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. There are presently five DOACs approved in the US. They include PRADAXA® (Dabigatran), which is a Direct Thrombin Inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors.

The perioperative management of patients who are taking a Direct Oral AntiCoagulant (DOAC) for Atrial Fibrillation and require an elective surgery/procedure, has remained unclear, as there is no published data on the timing of perioperative DOAC interruption and resumption, and if perioperative Heparin bridging and coagulation function testing before surgery are needed. The purpose of the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study was to establish a simple protocol that did not require perioperative anticoagulant bridging or coagulation function testing.

PAUSE is a prospective study of DOACs, which included 3 parallel cohorts of patients with Atrial Fibrillation taking ELIQUIS® (N=1257), PRADAXA® (N=668) or XARELTO® (N=1082), and requiring anticoagulant interruption for an elective surgery/procedure. This current analysis included patients from Canada, U.S. and Europe. A third of the patients (33.5%) were scheduled to undergo a high-bleeding risk surgery and the adjusted stroke risk among these patients was about 4.5%, based CHADS2 scores. The mean patient age was 72.5 years and 66% of patients were men.

The researchers in this study used a standardized protocol based on pharmacokinetic properties of the DOACs, procedure-associated bleeding risk, Creatinine Clearance, and held DOACs for 1 day before and 1 day after surgery for procedures with low bleeding risk, and for 2 days before and 2 days after for procedures with high bleeding risk. Patients on PRADAXA® with a creatinine clearance of less than 50 mL/min and who were planned for a procedure with a high bleeding risk, stopped the drug four days before and two days after surgery. Blood samples were obtained just before the procedure to measure residual DOAC levels. Bridging with Heparin and preoperative coagulation testing were not used to manage patients. Participants were followed weekly for 30 days post-procedure to measure incidence of major bleeding and Arterial ThromboEmbolism, which was the Primary endpoint.

The 30-day postoperative major bleeding rates were 1.35% in the ELIQUIS® group, 0.9% in the PRADAXA® group and 1.85% in the XARELTO® group. The rate of Arterial ThromboEmbolism was 0.16% in the ELIQUIS® group, 0.6% in the PRADAXA® group and 0.37% in the XARELTO® group. The researchers also measured preoperative DOAC levels in 85% of patients and noted that 99% of these patients having a high bleeding risk procedure had DOAC levels less than 50 ng/mL.

It was concluded that a standardized DOAC-specific perioperative management strategy was safe for patient care among patients with Atrial Fibrillation, who were taking a DOAC and required anticoagulant interruption for an elective surgery/procedure. Utilizing this standardized protocol was associated with low rates of perioperative major bleeding (less than 2%) and Arterial ThromboEmbolism (less than 1%). The authors added that PAUSE is the largest practice-changing study to date, that addresses perioperative DOAC management, and will very likely establish a treatment standard, impacting practice guidelines in perioperative care. Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant. Douketis J, Spyropoulos AC, Duncan JM, et al. Abstract LBA-5. Presented at the 2018 ASH Annual Meeting, December 4, 2018; San Diego, CA.

Maintenance Therapy with NINLARO® Extends Progression Free Survival in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 32,110 new cases will be diagnosed in 2019 and 12,960 patients are expected to die of the disease. Multiple Myeloma (MM) in 2019 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation, can result in significantly longer PFS and OS, compared to those patients who receive therapy for a fixed duration of time. REVLIMID® (Lenalidomide) was approved by the FDA in 2017 as maintenance therapy for patients with multiple myeloma following Autologous Stem Cell Ttransplant (ASCT) and to date is the only drug approved for this indication. REVLIMID® maintenance however is associated with the development of second new primary malignancies and tolerability issues.

Proteasomes are enzymes found in cells and they enable the breakdown of abnormal or mutant proteins. The amino acids from these proteins are recycled to make new proteins. Just like normal cells make proteins, so do cancerous cells. But the proteins made by the cancerous cells are ineffective and in excess. Myeloma cells depend on the Proteasomes to facilitate this metabolic function, to regulate their growth and survival. Proteasome Inhibitors (PIs) inhibit Proteasome function and are a backbone of multiple myeloma treatment. VELCADE® (Bortezomib), a Proteasome Inhibitor has shown promising activity in early clinical trials, as maintenance treatment post-ASCT. The limitations with VELCADE® as maintenance therapy include, parenteral administration and tolerability. There is therefore an unmet need for an effective oral PI maintenance therapy that is convenient for the patients, with acceptable toxicities. NINLARO® (Ixazomib) unlike VELCADE® (Bortezomib) is a second generation, oral, Proteasome Inhibitor, which disrupts protein metabolism in myeloma cells, by inhibiting Proteasomes and has an antiproliferative and pro-apoptotic effect.

TOURMALINE-MM3 study is a multicenter, double-blind, placebo-controlled, phase III trial in which weekly NINLARO® was compared with placebo, as maintenance treatment, in newly diagnosed multiple myeloma patients, who had at least a Partial Response to induction therapy with a Proteasome Inhibitor and/or Immunomodulatory drug, (IMiD) followed by single Autologous Stem Cell Transplantation (ASCT). In this study, 656 patients were randomized in a 3:2 ratio to receive NINLARO® (N=395) at a dose of 3 mg orally during cycles 1-4, increasing to 4 mg from cycle 5 (if tolerated during previous cycles) or matched placebo (N=261), on days 1, 8, and 15 of 28-day cycles, for up to 2 years or until progressive disease or unacceptable toxicity. Both treatment groups were well balanced. The median age was 57 years and 37% had International Staging System (ISS) stage I disease and 63% had ISS stage II or III disease. About 18% of patients had high-risk cytogenetics such as del(17p), t(4;14), or t(14;16) and close to 90% of patients had received induction therapy with a Proteasome Inhibitor prior to ASCT. Patients were ineligible if they had received post-ASCT consolidation or tandem ASCT. The Primary endpoint was Progression Free Survival per Independent Review Committee (IRC), who were blinded to treatment assignment. The key Secondary endpoint was Overall Survival. The authors herein reported the data from the final analysis for Progression Free Survival.

After a median follow up of 31 months, the median PFS was 26.5 months with NINLARO® versus 21.3 months with placebo (HR=0.72; P=0.002). This corresponded to a 39% improvement in PFS and 28% reduction in the risk of progression or death, meeting the Primary endpoint of this study. The PFS benefit was observed broadly across patient subgroups. NINLARO® maintenance led to higher rates of deep response compared with placebo (P=0.004) and there was a higher rate of conversion from documented MRD positivity at study entry to MRD negativity with NINLARO®, compared with placebo (12% versus 7%). Overall Survival has not yet been reached in both treatment groups. Grade 3 or more Adverse Events were more common with NINLARO® (19%) versus placebo (5%), and overall 7% of patients on NINLARO® discontinued treatment compared with 5% on placebo. There was no difference in the rate of new second primary malignancies and was 3% in both arms. Further Quality of Life scores were similar in the two treatment groups.

It was concluded that NINLARO® maintenance in responding patients after ASCT resulted in a significant reduction in the risk of progression and death, and was associated with a favorable safety profile, including an absence of risk of second primary malignancies and low rates of peripheral neuropathy. The authors added that NINLARO® has a different mechanism of action and provides an alternative to REVLIMID®. With its manageable toxicity profile and convenient weekly oral dosing, NINLARO® would be ideal for maintenance treatment. Maintenance Therapy with the Oral Proteasome Inhibitor (PI) Ixazomib Significantly Prolongs Progression-Free Survival (PFS) Following Autologous Stem Cell Transplantation (ASCT) in Patients with Newly Diagnosed Multiple Myeloma (NDMM): Phase 3 Tourmaline-MM3 Trial. Dimopoulos MA, Gay F, Schjesvold FH, et al. Proceedings from the 2018 ASH Annual Meeting and Exposition; December 1 to 4, 2018; San Diego, California. Abstract 301.

ASH 2018 Four Cycles of Chemotherapy Equally Effective as Six Cycles in Diffuse Large B-Cell Lymphoma

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SUMMARY: The American Cancer Society estimates that in 2019, about 74,200 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 19,970 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet. DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. The MInT trial (MabThera International Trial Group) published in The Lancet Oncology in 2006 established that for a subgroup of young DLBCL patients with favorable prognosis (age-adjusted International Prognostic Index (aaIPI) of 0 and no bulky disease, 6 cycles CHOP-like chemotherapy plus RITUXAN® resulted in a 3-year Event Free Survival of 89%, Progression Free Survival of 95% and Overall Survival of 98% (Lancet Oncol 2006;7:379-391).

The International Prognostic Index includes the following risk factors and one point is assigned to each risk factor (Age greater than 60 years, ECOG PS of 2, 3 or 4, elevated serum LDH, more than one Extranodal site and Stages III or IV disease). Age-Adjusted IPI is a simplified version and can be used when comparing patients within an age group (i.e. 60 years or younger, or over 60 years) and includes only 3 of the above factors (Performance Status, LDH and Stage).

Treatment with CHOP-like chemotherapy can result in delayed toxicities including cardiotoxicity and second malignancies. De-escalating chemotherapy can reduce toxicities and cost, while improving patient convenience. The authors conducted the FLYER trial to evaluate whether a shorter chemotherapy course of 4 cycles of R-CHOP plus 2 cycles of RITUXAN® alone was non-inferior to the standard treatment of 6 cycles of R-CHOP.

The FLYER trial is an international, multicenter, randomized phase III study in which 592 treatment naïve patients with favorable risk (age 18-60 years, tumor size less than 7.5 cm), Stage I or II DLBCL, were randomly assigned to receive either 6 cycles of R-CHOP, or 4 cycles of R-CHOP plus 2 cycles of RITUXAN®. For this final analysis, 588 patients were evaluable. Each treatment cycle was 21 days. Radiotherapy was not part of the planned treatment, with the exception of prophylactic radiotherapy of the contralateral testis, in patients with Testicular lymphoma. Both treatment groups were well balanced. The mean age was 48 years, 99% were classified as IPI = 0 and 1% as IPI = 1. The Primary endpoint was Progression Free Survival (PFS).

At a median follow up of 66 months, there was no significant difference in the PFS between the two treatment groups (P=0.76). The 3-year Progression Free Survival (PFS) rate was 94% for patients who received 6 cycles of R-CHOP (N=295) compared with 96% for those who received 4 cycles of R-CHOP followed by 2 cycles of RITUXAN® (N=293). The 3-year Overall Survival (OS) rate was 98% among those who received 6 cycles of R-CHOP versus 99% for those who received 4 cycles of R-CHOP followed by 2 cycles of RITUXAN® (P=0.89). There was also no significant difference in the Relapse Rate between the two treatment groups (4-5%). Grade 3 and 4 nonhematologic as well as hematologic Adverse Events were higher in those patients who received 6 cycles of R-CHOP versus the 4 cycles of R-CHOP.

The authors concluded that in this randomized, noninferiority, phase III study, 2 fewer cycles of R-CHOP greatly reduced toxicity without compromising efficacy, in young treatment naïve patients, with low-risk Diffuse Large B-Cell Lymphoma. Data on outcomes in the Germinal Center B-cell-like (GCB) versus Activated B-Cell-like (ABC) subsets is not available. Excellent outcome of young patients (18-60 years) with favourable-prognosis diffuse large B-cell lymphoma (DLBCL) treated with 4 cycles CHOP plus 6 applications of rituximab: results of the 592 patients of the FLYER trial of the Dshnhl/GLA. Poeschel V, Held G, Ziepert M, et al. Presented at ASH Annual Meeting and Exposition: December 4-8, 2018; San Diego, California. Abstract 781.

Late Breaking Abstract – ASH 2018 IMBRUVICA® and RITUXAN® Combination Superior to FCR in Younger Patients with CLL

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SUMMARY: The American Cancer Society estimates that for 2018, about 20,940 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4,510 patients will die of the disease. CLL accounts for about 25% of the new cases of leukemia and the average age at the time of diagnosis is around 71 years. B-cell CLL is the most common type of leukemia in adults, accounting for about 11% of all hematologic malignancies. Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab (FCR) has long been the gold standard and the most commonly used treatment regimen for younger, fit, treatment naïve patients with chronic lymphocytic leukemia. This is based on phase III trial data showing improvement in both Progression Free Survival (PFS) and Overall Survival (OS) compared with chemotherapy alone. FCR regimen however is associated with significant toxicities and cannot be tolerated by all CLL patients. IMBRUVICA® (Ibrutinib) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® in phase III trials showed improved PFS and OS when compared to Chlorambucil in previously untreated, elderly patients with CLL. Nonetheless, the efficacy of IMBRUVICA® as a first-line treatment for younger CLL patients (70 years or younger), compared to the most efficacious regimen such as FCR, is unknown.BCR-Signal-Pathways

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

With a median follow up of 33.4 months, at the first interim analysis, IMBRUVICA® plus RITUXAN® significantly improved PFS compared to FCR (HR=0.35; P<0.0001), with a 65% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN® compared with FCR. The combination of IMBRUVICA® plus RITUXAN® also demonstrated improved OS (HR=0.17; P=0.0003) and this suggested that IMBRUVICA® plus RITUXAN® combination reduced the risk of death by 83% compared with FCR. In a subgroup analysis, the PFS benefit with IMBRUVICA® plus RITUXAN® was seen independent of age, sex, Performance Status (0-2), disease stage, as well as presence or absence of cytogenetic abnormality, deletion 11q23. At the time of this analysis, IMBRUVICA® plus RITUXAN® was also superior to FCR among IGHV unmutated patients (HR=0.26; P<0.0001), suggesting a 74% reduction in the risk of progression or death with IMBRUVICA® plus RITUXAN®, compared to FCR. A statistically significant benefit however was not observed among those with IGHV mutations, although there was a positive trend noted (HR=0.44; P=0.07). Treatment-related Grade 3 and 4 toxicities were significantly lower with IMBRUVICA® compared with FCR (58% versus 72%, respectively; P=0.004). FCR was more frequently associated with Grade 3 and 4 neutropenia (44% versus 23%) as well as infectious complications (18% versus 7%).

It was concluded that a combination of IMBRUVICA® and RITUXAN®, significantly improved PFS and OS, when compared to FCR, with fewer toxicities, among patients 70 years of age or under, with previously untreated CLL. The authors noted that these findings have immediate practice changing implications and establish IMBRUVICA® – based therapy as the most effective first-line therapy for untreated patients with CLL. Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912. Shanafelt TD, Wang V, Kay NE, et al. Presented at the 2018 ASH Annual Meeting. December 1-4, 2018; San Diego. Abstract LBA-4.

Axillary Radiotherapy is an Alternative to Complete Lymph Node Dissection in Early-Stage 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. Axillary lymph node evaluation is an important part of breast cancer staging and the presence of axillary lymph metastases decreases the 5-year survival rate by 28-40%. Axillary lymph node status remains the most powerful predictor of breast cancer recurrence and survival. Axillary Lymph Node Dissection (ALND) was first advocated in the 18th century as part of the treatment of invasive breast cancer and has been standard practice until 2 decades back. ALND can be associated with significant morbidities such as upper limb lymphedema, pain, and sensitivity disorders and this can have a major psychological impact on breast cancer patients. Sentinel Lymph Node Biopsy (SLNB) which was introduced into clinical practice in the mid 1990’s, however has now become the standard for Stage I and II breast cancer. The sentinel node is the first lymph node(s) to which cancer cells are most likely to metastasize from a primary tumor. With the introduction of intraoperative lymphatic mapping in the 1990s, Sentinel Lymph Node Biopsy (SLNB) has now gained general acceptance and if the sentinel node is negative for metastatic disease or only has minimal disease, then no further axillary surgery is indicated. Unlike Axillary Lymph Node Dissection (ALND), SLNB is associated with a lower incidence of lymphedema/ seroma at the surgery site, paresthesias and restriction of joint movement. Nine randomized clinical trials have not shown any difference in mortality among patients who underwent ALND or SLNB for either lymph node metastases or negative sentinel lymph nodes, validating Sentinel Lymph Node Biopsy (SLNB). The American Society of Clinical Oncology (ASCO) first published guidelines on the use of SLNB for patients with early stage breast cancer in 2005, based on one randomized clinical trial. Since then, ASCO updated Clinical Practice Guideline based on additional information from 9 randomized clinical trials and13 cohort studies pertinent to SLNB and ALND.

Patients with T1-2 tumors with positive Sentinel Lymph Node Biopsy usually undergo complete ALND and there is increasing controversy about whether ALND is always necessary. AMAROS is a multicenter, randomized phase III trial, sponsored by the European Organisation for Research and Treatment of Cancer (EORTC), in which the effectiveness of complete Axillary Lymph Node Dissection (ALND) was compared with axillary Radiation Therapy (RT), in patients with invasive breast cancer. The rationale was that Radiation Therapy uses high-energy x-rays to damage tumor cells and may be a less invasive treatment and causes fewer side effects than complete ALND. This study was conducted to evaluate whether axillary RT could yield comparable outcomes to ALND with fewer adverse side effects, in this patient population. This trial enrolled 4806 patients with early-stage, clinically node-negative breast cancer of whom 1425 patients had a positive sentinel lymph node biopsy. Of these patients, 744 were randomly assigned to undergo complete ALND, whereas 681 patients received axillary RT. Both treatment groups were well balanced. The first 5-year follow up data published in 2013 showed that upper extremity lymphedema occurred significantly less often in those who received Radiotherapy compared with those who underwent complete ALND, and recent Quality of life and morbidity data supported these earlier findings.

The authors herein presented the 10 year follow up data of the AMAROS trial. It was noted that at 10 years, 1.82% of patients assigned to axillary RT had an axillary recurrence compared with 0.93% of those assigned to complete ALND, and this suggested that there was no significant difference (P=0.36). Further, there was no significant difference in the distant metastasis–free survival or Overall Survival between the two treatment groups. The distant metastasis–free survival was 78.2% among those assigned to axillary RT and 81.7% among those assigned to complete ALND and Overall Survival in the two treatment groups was 81.4% and 84.6%, respectively. It was noted that there was a higher 10-year cumulative incidence of second primaries among patients assigned to axillary RT compared with those assigned to complete Axillary Lymph Node Dissection (12% versus 8.3%). It remains unclear whether the addition of the radiation will increase the risk of second primary cancers.

It was concluded that axillary Radiotherapy is noninferior to complete Axillary Lymph Node Dissection in terms of locoregional control and this trial suggests that some patients with a positive sentinel lymph node biopsy may be appropriate candidates for axillary Radiotherapy. Rutgers, E. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: 10-year results of the EORTC AMAROS trial. Presented at the 2018 San Antonio Breast Cancer Symposium; December 4-8; San Antonio, Texas.(Abstract GS4-01)

Luspatercept Reduces Blood Transfusion Requirements in MDS and Beta-Thalassemia

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SUMMARY: Anemia is a common finding in patients with MyeloDysplastic Syndromes (MDS) and Beta-Thalassemia. These patients are in chronic need for transfusions which in turn can result in iron overload. Erythropoiesis Stimulating Agents (ESAs) are first-line therapy for anemia associated with lower-risk non-del(5q) MDS. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. There are however few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients. Beta-Thalassemia is an inherited hemoglobinopathy associated with an erythroid maturation defect and is characterized by ineffective erythropoiesis and impaired RBC maturation.Luspatercept-Restores-Red-Blood-Cell's-Ability-to-Mature

Luspatercept is a soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant Smad2/3 signaling thereby promoting late-stage Red Blood Cell precursor differentiation and maturation. The following two, separate phase III studies have shown reduced blood transfusions requirements in two separate patient populations.

The MEDALIST trial is a randomized, double-blind, placebo-controlled phase III study which evaluated the efficacy and safety of Luspatercept in patients with anemia secondary to MDS, defined as very low-risk, low-risk, or Intermediate-risk with Ring Sideroblasts, according to the Revised International Prognostic Scoring System. Eligible patients were refractory, intolerant, or ineligible to receive ESAs and required RBC transfusions. A total of 229 patients (N=229) were randomized 2:1 to receive either Luspatercept at a starting dose level of 1mg/kg SC with titration up to 1.75 mg/kg if needed (N=153), or placebo SC (N=76), every 3 weeks for 24 weeks or more. The median age was 71 years and median time from diagnosis was 41.8 months. Approximately 95% of patients had previously received ESAs and 90% had an SF3B1 mutation. The Primary endpoint was RBC transfusion independence for 8 weeks or more between week 1 and 24. A key secondary endpoint was RBC transfusion independence for 12 weeks or more between week 1 and 24.

Among those receiving Luspatercept, 38% achieved the Primary endpoint of RBC transfusion independence for 8 weeks or more compared with 13.2% receiving placebo (P<0.0001). Further among those receiving Luspatercept, 28.1% achieved the key secondary endpoint of RBC transfusion independence for 12 weeks or more compared with 7.9% receiving placebo (P=0.0002). Additionally, patients receiving Luspatercept were more likely to achieve an mHI-E (modified hematologic improvement-erythroid) response, defined as a reduction in transfusion of 4 or more RBC units per 8 weeks or a mean hemoglobin increase of 1.5 g/dL or more per 8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9% versus 11.8% during weeks 1-24; P<0.0001).

It was concluded that treatment with Luspatercept significantly decreased transfusion requirements among patients with low or Intermediate-risk MDS with Ring Sideroblasts.

The BELIEVE trial is a randomized, double-blind, placebo-controlled phase III study conducted to determine the efficacy and safety of Luspatercept in adult Beta-Thalassemia patients requiring regular RBC transfusions. In this study, 336 patients with Beta-Thalassemia or Hemoglobin E/ Beta-Thalassemia were randomized in a 2:1 to receive Luspatercept, at a starting dose of 1mg/kg with titration up to 1.25 mg/kg, or placebo, SC every 3 weeks for 48 weeks or more. Patients in both treatment groups continued to receive RBC transfusions and iron chelation therapy to maintain the same baseline Hgb level. Enrolled patients were 18 years or older and required regular RBC transfusions of 6-20 units in the 24 weeks prior to randomization with no transfusion-free period 35 days or more during that time. The median age was 30 years and 58% of patients were female. Patients received a median of 6 RBC units in the 12 weeks prior to treatment and 58% of patients in each treatment group had undergone splenectomy. The Primary endpoint was a 33% or more reduction in transfusion burden (with a reduction of 2 or more RBC units) during weeks 13–24, when compared with a 12-week baseline period.

It was noted that 21.4% of patients in the Luspatercept group achieved the Primary endpoint compared with 4.5% patients in the placebo group (P<0.0001). Towards the end of the trial, 20% of patients overall had decreased their transfusion units by one third or more, and 10% of patients had decreased their transfusions units by half or more. Overall, 70.5% of patients receiving Luspatercept achieved a 33% or more RBC transfusion reduction over any consecutive 12 weeks compared with 29.5% patients receiving placebo (P<0.0001).

It was concluded that treatment with Luspatercept resulted in significant reductions in RBC transfusion requirement, in adults with transfusion-dependent Beta-Thalassemia.

The most common adverse events included fatigue and muscle pain. It remains to be seen if Luspatercept would have similar efficacy in patients with high-risk MDS and patients with lower-risk MDS without ring sideroblasts.

The Medalist Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of luspatercept to treat anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) with ring sideroblasts (RS) who require red blood cell (RBC) transfusion. Fenaux P, Platzbecker U, Mufti GJ, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 1. https://ash.confex.com/ash/2018/webprogram/Paper110805.html

The Believe Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept in Adult Beta-Thalassemia Patients Who Require Regular Red Blood Cell (RBC) Transfusions. Cappellini MD, Viprakasit V, Taher A, et al. Presented at: 2018 ASH Annual Meeting; Dec. 1-4, 2018; San Diego. Abstract 163. https://ash.confex.com/ash/2018/webprogram/Paper112435.html

Testing for BRCA1 and BRCA2 Mutations May Not Be Adequate in Breast Cancer Patients

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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. It is estimated that 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and 40,920 women are expected to die from the disease. DNA can be damaged due to errors during its replication or as a result of environmental exposure to ultraviolet radiation from the sun or other toxins. The tumor suppressor genes such as BRCA1 (Breast Cancer 1) and BRCA2 help repair damaged DNA and thus play an important role in maintaining cellular genetic integrity, failing which these genetic aberrations can result in malignancies. The BRCA1 gene is located on the long (q) arm of chromosome 17 whereas BRCA2 is located on the long arm of chromosome 13. Mutations in BRCA1 and BRCA2 account for about 20 to 25 percent of hereditary breast cancers and about 5 to 10 percent of all breast cancers.These mutations can be inherited from either of the parents and a child has a 50 percent chance of inheriting this mutation and the deleterious effects of the mutations are seen even when an individual’s second copy of the gene is normal.

Breast cancer patients have a 5-12% lifetime risk of a second primary cancer. It remains unclear however whether patients with breast cancer and another primary cancer have mutations in genes other than BRCA1 and BRCA2, compared to those with a single breast cancer. There are well established data on the cancer risks, associated with different gene mutations. The authors hypothesized that among these patients, a number of factors including environmental exposures and genetic predisposition, may play a role in the development of more than one primary cancer in their lifetime. Recently published study suggested that there was a 85% cumulative breast cancer risk by age 60 years, among those with mutations in the TP53 gene (Cancer2016;122(23):3673-3681). Further with the increasing recognition that germline mutations in genes may have clinical and treatment implications, majority of patients are feeling comfortable opting for upfront multiple genetic mutation testing.

The researchers in this study looked at a panel of 15 actionable mutations beyond BRCA and the gene panel included TP53, PALB2, CDH1, PTEN, STK11, CHEK2, ATM, NBN, MSH6, PMS2, MSH2, MLH1, CDKN2A, MUTYH monoallelic, and CHEK2 Low Risk. Two cohorts of BRCA1 and BRCA2 negative patients were studied. The first cohort included high-risk breast cancer patients with either a single breast cancer (N=464) or breast cancer and an additional primary cancer (N=551). The second cohort comprised of patients with familial breast cancer (inherited risk) with either a single breast cancer (N=1464) or breast cancer and another primary cancer (N=340).

In a total of 891 patients in both cohorts who had breast cancer and an additional primary cancer, there was twice the risk of inheriting mutations in genes other than BRCA1 and BRCA2. In cohort 1, the mutation rate among patients who had breast cancer and an additional primary cancer was 8.7% compared to 4.1% among those with single breast cancer (P=0.003) and in cohort 2, the mutation rate was 8.2% versus 4.2%, respectively (P=0.003).

There was however a differences in individual gene mutation rates between the two cohorts. Among patients with breast cancer and an additional primary cancer in cohort 1, mutations in TP53 and MSH6 were significantly higher, whereas among the patients in cohort 2 with familial breast cancer, mutations in ATM, CHEK2 and PALB2 were significantly higher both in those with breast cancer and another primary cancer and those with a single breast cancer.

The authors concluded that patients with multiple primary cancers should be offered multiplex panel testing to identify patients at risk. Identifying mutations, especially mutations in the TP53 gene may have a bearing on appropriate recommendations such as risk-reducing bilateral mastectomy or mastectomy instead of a lumpectomy in this patient group. Thus, risk assessment using multiple genetic testing panels can be beneficial for clinical care and surveillance. Inherited mutations in breast cancer patients with and without multiple primary cancers. Maxwell KN, Vijai V, Lilyquist J, et al. DOI: 10.1200/JCO.2018.36.15_suppl.1503 Journal of Clinical Oncology 36, no. 15_suppl (May 2018) 1503-1503.

Survival Benefit Significantly More in North America with Frontline ADCETRIS® Chemotherapy Combination in Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2018, about 8,500 new cases of Hodgkin Lymphoma will be diagnosed and about 1,050 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin Lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).WHO-Classification-of-Hodgkin-Lymphoma

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin Lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin Lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. ADCETRIS® is presently approved by the FDA for previously untreated Stage III or IV Classical Hodgkin Lymphoma (cHL), in combination with chemotherapy, for treatment of Classical Hodgkin lymphoma at high risk of relapse or progression, as post-autologous Hematopoietic Stem Cell Transplantation (auto-HSCT) consolidation, and for treatment of Classical Hodgkin Lymphoma after failure of auto-HSCT or after failure of at least two prior multi-agent chemotherapy regimens, in patients who are not auto-HSCT candidates.

ECHELON-1 study, which is an international, open-label, randomized, multicenter, phase III trial, compared A+AVD with ABVD, as frontline therapy in patients with Stage III or IV Classical Hodgkin Lymphoma. This study included 1334 previously untreated patients with Stage III or IV Classical Hodgkin Lymphoma, who were randomly assigned in a 1:1 ratio to receive A+AVD (N=664), which consisted of ADCETRIS® 1.2 mg/kg , Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2 or ABVD (N=670), which consisted of Doxorubicin 25 mg/m2, Bleomycin 10 units/m2, Vinblastine 6 mg/m2 and Dacarbazine 375 mg/m2, given intravenously on days 1 and 15 of each 28-day cycle, for up to 6 cycles. The Primary end point was “modified” Progression Free Survival (mPFS), defined as progression, death, or the receipt of additional treatment, for patients not achieving CR at the completion of frontline therapy. It was previously reported that at a median follow up of 24.6 months, the 2 year modified PFS in the A+AVD and ABVD groups were 82.1% and 77.2% respectively (HR=0.77; P=0.04), suggesting an approximately 5% benefit with A+AVD.

The North American subgroup analysis of the ECHELON-1 study was conducted because of potential regional differences in the outcomes in the primary study and mPFS benefit was not equally distributed globally. The authors in this prespecified analysis examined the efficacy and safety of A+AVD vs ABVD in North America, as these patients accounted for approximately 40% of the over 1300 patients included in the ECHELON-1 study. This population group included 497 North American patients with advanced Classical Hodgkin Lymphoma, randomized 1:1 to receive up to six cycles of A+AVD or ABVD.

This subgroup analysis revealed an absolute difference of 10.6% in the mPFS per IRF-Independent Review Facility (A+AVD and ABVD groups were 84.3% and 73.7% respectively, HR=0.60; P=0.012) and an 11.7% difference in PFS per investigator review (A+AVD and ABVD groups were 88.1% and 76.4% respectively, HR=0.50; P=0.002), at 2 years. This analysis suggested that a larger proportion of patients in North America benefitted with the A+AVD regimen (10%-12% in North America as opposed to 5% globally). It is postulated that there may be biologic differences in the disease, regional differences in drug metabolism and differences in practice patterns, between countries. Toxicity profile was similar globally. There was a higher incidence of neutropenia in the A+AVD group and G-CSF prophylaxis should be a part of the regimen when A+AVD is used, in contrast to ABVD. Use of G-CSF primary prophylaxis was associated with a lower rate of ADCETRIS® dose delays and dose reductions compared to those without. There was a higher incidence of peripheral neuropathy in the A+AVD group as well, with majority of these events being grade 1 and 2, and this improved or resolved over time. Pulmonary toxicity was lower in patients receiving A+AVD compared to those receiving ABVD.

It was concluded that for patients treated in North America on the ECHELON-1 trial, the absolute difference between A+AVD and ABVD at 2 years for mPFS by IRF was 10.6% and for PFS per Investigator review was 11.7% (10%-12% benefit in North America as opposed to 5% globally). A prospective clinical trial is planned in advanced stage Hodgkin Lymphoma patients treated with A+AVD, to confirm these safety and efficacy findings, in the North American community setting. Brentuximab vedotin (BV) plus chemotherapy in patients with newly diagnosed advanced stage Hodgkin lymphoma (HL): North American results. Ramchandren R, Advani RH, Ansell SM, et al. J Clin Oncol.2018;36(suppl; abstr 7541). doi: 10.1200/JCO.2018.36.15.