Increased Risk of Breast Cancer after Recent Childbirth

In a large International Premenopausal Breast Cancer study which included close to 900,000 women, compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth.The increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women.

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

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.

Increased Risk of Breast Cancer after Recent Childbirth

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 268,600 new cases of female breast cancer will be diagnosed in 2019 and about 41,760 women will die of the disease. Breast cancer is the most common cancer type in reproductive-aged women. Women with biological children (parous women) are at a lower risk for developing breast cancer compared to nulliparous women. However, parity as a protective factor largely applies to breast cancer developing after age 60 years and may not apply for younger premenopausal women. Evidence from national registry linkage studies in Scandinavian countries suggested that recent childbirth confers a short-term increase in breast cancer risk which may last for 10 years or more, and this risk may be further increased in women who are older at first childbirth. Studies published thus far have not shown consistent findings and have had limited ability to account for factors influencing breast cancer risk such as breastfeeding and family history of breast cancer.

One biological explanation for an increase in breast cancer risk after childbirth may be due to proliferation of breast cells during pregnancy which could promote accelerated development of latent initiated tumor cells. This may also explain the higher breast cancer risk, conferred by older age at first childbirth, as a result of higher proportion of latent initiated tumor cells at older ages. Further, the postpartum breast microenvironment, characterized by lactational involution may also facilitate cancer cell migration and metastasis. Childbirth also brings about maternal changes beyond breast tissue including altered immune function and microbiota, increased stress, and accelerated aging processes.

The authors in this study used data from the International Premenopausal Breast Cancer Collaborative Group and conducted a pooled analysis of individual-level data from 15 prospective cohort studies. In this analysis, the researchers included women younger than 55 years and evaluated the risk of breast cancer in relation to recent childbirth, while taking into account other factors that relate to breast cancer risk such as breastfeeding, numbers of pregnancies and births and family history of breast cancer. It is felt that understanding these risk patterns may have implications for identifying risk-reducing strategies among vulnerable subgroups. A total of 889, 944 women, were available for analysis after excluding women who reported a first birth before age 13 years, women who were 50 years or older at study entry and at most recent birth, or reached parity greater than 10 births before enrollment. All these events were considered to have greater potential for data errors. The mean age at study entry was 42 years.

The researchers noted that compared with nulliparous women, parous women had an increased risk for breast cancer that peaked about 5 years after childbirth and then gradually decreased about 24 years after childbirth. These findings however were not noted among women who had only 1 child, or had their first child before age 25 years. The risk was highest in women who were older at the time of first childbirth, multiparous women and those who had a family history of breast cancer. Among those women with a family history of breast cancer, the risk was the greatest for Estrogen Receptor negative breast cancer. Breast feeding did not influence breast cancer risk patterns.

It was concluded that compared with nulliparous women, parous women have an increased risk for breast cancer after childbirth that is highest the first 5 years but decreases over the following 20 years. Health Care Professionals should take these factors into account when considering individual risk profiles for breast cancer in premenopausal women. Breast Cancer Risk After Recent Childbirth: A Pooled Analysis of 15 Prospective Studies. Nichols HB, Schoemaker MJ, Cai J, et al. Ann Intern Med. 2019;170:22-30

Late Breaking Abstract – ESMO 2018 Radiation Therapy to the Primary Tumor Improves Overall Survival in a Subgroup of Metastatic Prostate Cancer Patients

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

The ASCO clinical practice guideline published in 2018, recommended the addition of either TAXOTERE® (Docetaxel) or ZYTIGA® (Abiraterone acetate) to ADT, based on CHAARTED trial and STAMPEDE/LATITUDE trials respectively, for men with newly diagnosed metastatic Prostate cancer, based on the Overall Survival benefit with these combinations, when compared with the use of ADT alone. It is also well established that the addition of Radiation Therapy (RT) to Androgen Deprivation Therapy (ADT) improves Overall Survival compared to ADT alone, in patients with locally advanced Prostate cancer. Patients with metastatic Prostate cancer however are often treated with systemic therapy alone without any local intervention such as Radiation Therapy to the Prostate gland.

The Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trial is an ongoing phase III study and uses a novel multi-arm, multi-stage (MAMS) platform design, to test whether the addition of further treatments to ADT improves Overall Survival, when used in first-line setting, for patients with hormone sensitive, locally advanced or metastatic Prostate cancer. This group previously reported that there was a significantly improved Overall Survival with the addition of TAXOTERE® to initial ADT and also concluded that ZYTIGA® and prednisolone along with ADT results in significantly higher rates of Overall Survival as well as Failure-Free Survival, compared with ADT alone, among men with hormone sensitive, locally advanced or metastatic Prostate cancer.

The authors in this study had hypothesized based on studies in animal models that local treatment of the Prostate might not only improve local control but also slow progression of metastatic disease and improve Overall Survival in men presenting with metastatic Prostate cancer, and that survival benefit would be greater in men with lower metastatic burden. The accompanying results are from a preplanned analysis of one group in the multi-arm, multi-stage STAMPEDE study.

The study included 2,061 patients with newly diagnosed metastatic Prostate cancer who were randomized 1:1 to Standard of Care treatment consisting of lifelong Androgen Deprivation Therapy with or without early TAXOTERE® or the same Standard of Care plus Radiation Therapy to the Prostate. Radiotherapy was administered in two different schedules – either daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in 6 fractions for 6 weeks) based on investigator’s choice. The median age was 68 years, the median PSA level was 97 ng/mL and 18% received early TAXOTERE® treatment at the investigator’s discretion. Metastatic disease burden was characterized as Low in 40% and High in 54% and 6% was unknown. A High Prostate cancer disease burden was defined as 4 or more bone metastases, with at least 1 metastasis outside the axial skeleton and/or visceral metastases. The rest of the patients were characterized as having Low disease burden. The Primary outcome measure was Overall Survival and Secondary outcomes included Failure-Free Survival (FFS), and toxicity.

It was noted that Radiation Therapy to the Prostate improved FFS (HR=0.76; P<0.001) but not Overall Survival. However subgroup analysis showed that Radiation Therapy to the Prostate improved Overall Survival by 32% in the 819 men with lower metastatic disease burden (HR=0.68) and the 3 year Overall Survival rates were 81% in the Radiation Therapy arm versus 73% for Standard of Care, suggesting an absolute benefit of 8% and this was statistically significant (P =0 .007). By contrast, the 1120 men with higher metastatic disease burden did not benefit from Radiation Therapy. The Radiation Therapy schedule did not have any impact on outcomes. Radiation Therapy to the Prostate was well tolerated, with 5% of patients experiencing grade 3 or 4 adverse events during treatment and 4%, after treatment.

It was concluded that Prostate Radiotherapy in addition to systemic drug therapy improves the Overall Survival of men with newly diagnosed metastatic Prostate cancer who have a low metastatic disease burden, and should now be a standard treatment option. The authors added that this study did not include patients with pelvic node-positive nonmetastatic disease (N1, M0), where the addition of Radiotherapy to systemic drug therapy could be curative. Radiotherapy (RT) to the primary tumour for men with newly diagnosed metastatic prostate cancer (PCa): survival results from STAMPEDE (NCT00268476). Parker CC, James ND, Brawley C, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA5.

FDA Approves CABLIVI® for Thrombotic Thrombocytopenic Purpura

SUMMARY: The FDA on February 6, 2019, approved CABLIVI® (Caplacizumab-yhdp) for adult patients with acquired Thrombotic Thrombocytopenic Purpura (aTTP), in combination with Plasma Exchange and immunosuppressive therapy. Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS) and Atypical Hemolytic Uremic Syndrome (aHUS) are life-threatening Thrombotic MicroAngiopathies (TMAs) associated with systemic microvascular thrombosis, MicroAngiopathic Hemolytic Anemia (MAHA), thrombocytopenia and organ failure. Even though their clinical presentation has some similarities, they are distinct entities with different pathophysiology and hence managed differently.Microangiopathic-Hemolytic-Anemia-Thrombocytopenia

Patients with TTP have either severe deficiency of ADAMTS13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) secondary to anti-ADAMTS13 autoantibodies or rarely due to ADAMTS13 gene mutations. A diagnosis of TTP is therefore based on clinical presentation and laboratory results and is confirmed by documentation of severe ADAMTS13 deficiency, with ADAMTS13 activity levels of less than 10%. The physiological role of ADAMTS13 is to prevent intravascular platelet thrombosis. ADAMTS13 accomplishes this by cleaving ultralarge von Willebrand Factor multimers (which bind to platelets and induce aggregation), thereby mitigating the tendency of von Willebrand Factor (vWF) and platelets to form aggregates in normal microcirculation. Deficiency of ADAMTS13 causes vWF-platelet aggregation in the arterioles and capillaries, characteristic of TTP, resulting in tissue ischemia from microthrombi and end organ damage. Thus the microthrombi in TTP are platelets bound to vWF and not to fibrinogen. Rapid initiation of Plasma Exchange, the frontline therapy in patients with TTP, removes the anti-ADAMTS13 autoantibodies and ultra large vWF multimers and replenishes ADAMTS13. Immunosuppressive therapy with Glucocorticoids and RITUXAN® (Rituximab) inhibits anti-ADAMTS13 autoantibody formation, by targeting the B lymphocytes. These interventions have significantly improved the survival rate among patients with TTP. Despite these advances with the use of Plasma Exchange, approximately 20% of the patients with TTP will succumb to their disease. There is a persistent risk of life-threatening recurrences, which can occur as late as 10 or 20 years after an initial episode of TTP. Persistent or recurrent ADAMTS13 deficiency is a strong risk factor for recurrence.

CABLIVI® is an anti-von Willebrand Factor, humanized, bivalent, variable-domain-only immunoglobulin fragment (Nanobody), directed against the A1 domain of von Willebrand Factor and prevents the interaction of vWF with the platelet glycoprotein Ib-IX-V receptor and thus prevents microvascular thrombosis.

In a phase II study (TITAN trial), CABLIVI® given as an adjunct to Plasma Exchange significantly reduced the median time to a response, with more rapid normalization of platelet count, LDH and creatinine, and also reduced the incidence of major thromboembolic events as well as mean number of Plasma Exchange days, compared with placebo. However, patients who had persistent ADAMTS13 deficiency had a relapse soon after treatment with CABLIVI® was stopped, suggesting that monitoring of ADAMTS13 could be useful, to guide the continuation of therapy.

HERCULES trial is a multicenter, randomized, double blind, placebo controlled, phase III trial which evaluated the efficacy and safety of CABLIVI® in patients with acquired Thrombotic Thrombocytopenic Purpura. The trial also evaluated the benefit of CABLIVI® in reducing the risk of recurrence, by allowing for treatment to continue until immunosuppressive therapy resolved the underlying autoimmune disease. TTP was diagnosed based on clinical presentation (the presence of both thrombocytopenia and MicroAngiopathic Hemolytic Anemia with schistocytes seen on blood smear) and if they had received exactly one Plasma Exchange treatment. Severe ADAMTS13 deficiency was not an eligibility requirement and patients were excluded if they had suspected thrombotic microangiopathies that were not associated with TTP, such as Hemolytic Uremic Syndrome, or if they had congenital TTP.

This study randomly assigned 145 patients with TTP to receive CABLIVI® (N=72) or placebo (N=73). Patients in both groups received daily Plasma Exchange at 1 to 1.5 times the estimated plasma volume, until at least 2 days after normalization of the platelet count and Glucocorticoids (Prednisone or Prednisolone at a dose of 1 mg/kg or more of body weight per day during the daily Plasma Exchange period and continuing for the first week after the end of the daily Plasma Exchange period. Patients received CABLIVI® 10 mg IV loading bolus or placebo before the start of the first Plasma Exchange after randomization followed by 10 mg daily subcutaneously until 30 days after the last daily Plasma Exchange. Treatment was extended at 7-day intervals for a maximum of 28 days, if signs of persistent underlying disease such as suppressed ADAMTS13 activity levels were still present. The Primary outcome was the time to normalization of the platelet count, with discontinuation of daily Plasma Exchange within 5 days thereafter. Key Secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period, refractory TTP and normalization of organ-damage markers.

It was noted that the median time to normalization of the platelet count was shorter with CABLIVI® than with placebo and patients who received CABLIVI® were 1.55 times as likely to have a normalization of the platelet count as those who received placebo (P=0.01). The composite outcome event was 74% lower with CABLIVI® than with placebo (12% versus 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with CABLIVI® than with placebo (12% versus 38%, P<0.001). None of the patients in the CABLIVI® group developed refractory disease whereas 3 three patients in the placebo group did. Patients who received CABLIVI® required fewer Plasma Exchanges and had a shorter hospital stay, than those who received placebo. The most common adverse reactions in at least 15% of patients receiving CABLIVI® were epistaxis, headache, and gingival bleeding.

It was concluded that among patients with TTP, treatment with CABLIVI® resulted in a more rapid normalization of the platelet count, a lower incidence of a composite of TTP-related death, a lower incidence of recurrence of TTP or a thromboembolic event during the treatment period, and a lower rate of recurrence of TTP during the trial period, compared to placebo. Caplacizumab Treatment for Acquired Thrombotic Thrombocytopenic Purpura. Scully M, Cataland SR, Peyvandi F, et al., for the HERCULES Investigators. N Engl J Med 2019; 380:335-346.

Antimicrobial Prophylaxis for Adult Patients with Cancer-Related Immunosuppression ASCO and IDSA Clinical Practice Guideline Update

SUMMARY: Patients undergoing cytotoxic chemotherapy and Hematopoietic Stem Cell Transplantation (HSCT), when neutropenic, are at risk for infection. The risk of infection increases with the depth and duration of neutropenia. The greatest infection risk is among those who experience profound, prolonged neutropenia after chemotherapy. Neutropenia is defined as an absolute neutrophil count of less than 1,000/µL, severe neutropenia as absolute neutrophil count less than 500/µL and profound neutropenia as less than 100/µL. Neutropenia is considered protracted if it lasts for 7 days or more. Fever in neutropenic patients is defined as a single oral temperature of 38.3°C (101°F) or more or a sustained temperature of 38.0°C (100.4°F) or more over a period of 1 hour.

The ASCO in partnership with Infectious Diseases Society of America (IDSA) convened an Expert Panel and updated the 2013 ASCO guideline on antimicrobial prophylaxis for immunosuppressed adult patients undergoing treatment of malignancy. The expert panel conducted a systematic review of relevant studies which included six new or updated meta-analyses and six new primary studies, from May 2011 to November 2016. The guideline recommendations were based on the review of evidence by the Expert Panel.


CLINICAL QUESTION 1 Antibacterial Prophylaxis: Does antibacterial prophylaxis with a Fluoroquinolone, compared with placebo, no intervention, or another class of antibiotic, reduce the incidence of and mortality as a result of febrile episodes in patients with cancer?

Recommendation: Antibiotic prophylaxis with a Fluoroquinolone is recommended for patients who are at high risk for Febrile Neutropenia or profound, protracted neutropenia, such as those patients with Acute Myeloid Leukemia/Myelodysplastic syndromes (AML/MDS) or Hematopoietic Stem Cell Transplantation (HSCT) treated with myeloablative conditioning regimens. Antibiotic prophylaxis is not routinely recommended for patients with solid tumors, for patients who are at low risk of profound, protracted neutropenia and when CSF prophylaxis effectively reduces the severity and duration of neutropenia.

CLINICAL QUESTION 2 Antifungal Prophylaxis: Does antifungal prophylaxis with an oral triazole or parenteral Echinocandin, compared with no prophylaxis, or another treatment option, reduce the incidence of and mortality, as a result of febrile episodes in patients with cancer?

Recommendation 2.1: Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients who are at risk for profound, protracted neutropenia and mucositis, such as most patients with AML/MDS or HSCT. Antifungal prophylaxis is not routinely recommended for patients with solid tumors. Clinicians should be able to differentiate the risks for invasive candidiasis from the risks for invasive mold infection. This is because Fluconazole is active against yeast but not mold whereas Echinocandins and other azole antifungals, such as Posaconozole, Voriconozole, or Isavuconazole are mold-active agents. A mold-active triazole is recommended where the risk of invasive Aspergillosis is more than 6%, such as in patients with AML/MDS during the neutropenic period associated with chemotherapy, in the late stage postallogeneic SCT and/or in the context of GVHD. Antifungal prophylaxis is not routinely recommended for patients who are at low risk of profound, protracted neutropenia and when CSF prophylaxis effectively reduces the severity and duration of neutropenia.

Recommendation 2.2: Prophylaxis is recommended with Trimethoprim-Sulfamethoxazole (TMP-SMX), for patients receiving chemotherapy regimens associated with more than 3.5% risk for pneumonia from Pneumocystis jirovecii (eg, for those on 20 mg or more of prednisone daily for more than 4 weeks). For those hypersensitive to Sulfonamides or unable to tolerate TMP-SMX, alternative options include Dapsone, aerosolized Pentamidine, or Atovaquone.

CLINICAL QUESTION 3 Antiviral Prophylaxis: Does antiviral prophylaxis reduce the incidence of immunosuppression-related viral infections in patients with cancer compared with no prophylaxis or another treatment option?

Recommendation 3.1: Herpes Simplex Virus-seropositive patients undergoing allogeneic HSCT or leukemia induction therapy should receive prophylaxis with a nucleoside analog such as Acyclovir.

Recommendation 3.2: For patients who are at high risk of Hepatitis B Virus reactivation, treatment with a nucleoside reverse transcription inhibitor (eg, Entecavir or Tenofovir) is recommended.

Recommendation 3.3: Yearly influenza vaccination with inactivated quadrivalent vaccine is recommended for all patients receiving chemotherapy for malignancy and all family and household contacts and health care providers. It is best administered more than 1 week after the last treatment or more than 2 weeks before chemotherapy administration. Individuals older than 65 years should receive the high-dose vaccine.

Recommendation 3.4: The Expert Panel also supports other vaccination recommendations for immunosuppressed adult oncology patients that are contained within the IDSA guideline for vaccination of the immunosuppressed patients.

CLINICAL QUESTION 4 – Do additional precautions, such as hand hygiene, air filtration, or a neutropenic diet, reduce the risk of infection in neutropenic patients with cancer compared with no or other additional precautions?

Recommendation 4.1: All health care workers should comply with hand hygiene and respiratory hygiene/cough etiquette guidelines to reduce the risk for aerosol- and direct or indirect contact-based transmission of pathogenic microorganisms in the health care setting.

Recommendation 4.2: Outpatients with neutropenia from cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores (eg, construction and demolition sites, intensive exposure to soil through gardening or digging, or household renovation).

Antimicrobial Prophylaxis for Adult Patients With Cancer-Related Immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. Taplitz RA, Kennedy EB, Bow EJ, et al. J Clin Oncol 2018;36:3043-3054

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

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.

Late Breaking Abstract – ESMO 2018 LONSURF® Improves Overall Survival in Heavily Pretreated Gastric and GE Junction Cancers

SUMMARY: The American Cancer Society estimates that in the US, about 27,510 cases of Gastric Cancer will be diagnosed in 2019 and about 11,140 people will die of the disease. The average age at diagnosis is 68 years and Gastric Cancer is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal (GE) Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. Following progression after first line treatment for metastatic disease, the median survival is approximately 3 months.

LONSURF® (TAS-102) is a combination of two agentsa novel oral nucleoside Trifluridine and a thymidine phosphorylase inhibitor, Tipiracil hydrochloride. This combination has a unique mechanism of action. Trifluridine, the active ingredient of LONSURF® incorporates into DNA resulting in DNA damage. Degradation of Trifluridine which occurs when taken orally is prevented by Tipiracil hydrochloride. In a previously published Phase II study, LONSURF® demonstrated promising efficacy and was well tolerated among pretreated patients with advanced Gastric cancer. TAGS study was conducted to confirm these findings.

The TAGS (TAS-102 Gastric Study) trial is a pivotal Phase III multinational, randomized, double-blind study evaluating LONSURF® (Trifluridine and Tipiracil) plus Best Supportive Care (BSC) versus placebo plus BSC, in patients with metastatic Gastric Cancer, refractory to standard treatments. Enrolled patients (N=507) with histologically confirmed, non-resectable metastatic Gastric cancer including GastroEesophageal junction cancer, who had received 2 or more prior chemotherapy regimens, were randomly assigned in a 2:1 ratio to receive LONSURF® 35 mg/m2 BID on days 1-5 and 8-12 of each 28-day cycle (N=337) or placebo plus Best Supportive Care (N=170). Prior treatments included Fluoropyrimidine, Platinum, Taxane, Irinotecan, or a HER2 inhibitor. Both treatment groups were well balanced and 63% of patients had received 3 or more lines of prior systemic therapy. The Primary endpoint was Overall Survival.

At a median follow-up was 10.7 months, the Primary endpoint was met with a median OS of 5.7 months with LONSURF&rg; versus 3.6 months for those in the placebo group (HR=0.69; P=0.0003). This suggested a 31% reduction in the risk of death when treated with LONSURF®. This benefit was noted across all prespecified subgroups. Treatment with LONSURF® was also associated with 43% lower risk of disease progression or death compared with placebo (HR=0.57; P<0.0001). This Progression Free Survival benefit was again noted in all subgroups. Further, patients in the LONSURF® group had a higher Disease Control Rate (44% versus 14%; P<0.0001) and lower risk of deterioration in Performance Status (HR=0.69; P=0.0005), compared to placebo.

The authors concluded that LONSURF® provided clinically meaningful and statistically significant prolongation in Overall Survival and was well tolerated in patients with heavily pretreated metastatic Gastric Carcinoma. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Arkenau H-T, Tabernero J, Shitara K, et al. Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA25.