Category: Hem/Onc Updates

FDA Approves DARZALEX® in Combination with POMALYST® and Dexamethasone for Relapsed or Refractory Multiple Myeloma

RR

SUMMARY: The FDA on June 16, 2017 approved the use of DARZALEX® (Daratumumab) in combination with POMALYST® (Pomalidomide) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least two prior therapies including REVLIMID® (Lenalidomide) and a Proteasome Inhibitor. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, about 30,280 new cases will be diagnosed in 2017 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. With a record number of regulatory approvals for Myeloma treatment over the past 12 years, the median survival for patients with Myeloma is over 10 years.

DARZALEX® is a human IgG1 antibody that targets CD38, a transmembrane glycoprotein abundantly expressed on malignant plasma cells and with low levels of expression on normal lymphoid and myeloid cells. DARZALEX® exerts its cytotoxic effect on myeloma cells by multiple mechanisms, including Antibody Dependent Cellular Cytotoxicity (ADCC), Complement Mediated Cytotoxicity and direct apoptosis. Additionally, DARZALEX® may have a role in immunomodulation by depleting CD38-positive regulator Immune suppressor cells, and thereby expanding T cells, in patients responding to therapy. The FDA approved DARZALEX® in November 2015 as monotherapy for Myeloma patients who had received at least three prior lines of therapy including a Proteasome Inhibitor (PI) and an Immunomodulatory agent or who are double refractory to a PI and an Immunomodulatory agent. In November 2016, DARZALEX® was approved in combination with REVLIMID® and Dexamethasone, or VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with Multiple Myeloma who have received at least one prior therapy. POMALYST® (Pomalidomide) is a novel, oral, immunomodulatory drug which is far more potent than THALOMID® (Thalidomide) and REVLIMID®, and has been shown to be active in REVLIMID® and VELCADE® refractory patients.

This new FDA approval was based on data from the phase Ib (MMY1001, EQUULEUS) study of DARZALEX® in combination with POMALYST® and Dexamethasone in relapsed or refractory Multiple Myeloma. This open-label study included 103 patients with Multiple Myeloma who had received prior treatment with a Proteasome Inhibitor and an Immunomodulatory agent. Treatment consisted of DARZALEX® 16 mg/kg IV on days 1, 8, 15, and 22 of a 28 day cycle for 8 weeks during cycles 1 and 2, every 2 weeks (on days 1 and 15) for 16 weeks (cycles 3 thru 6), and every 4 weeks thereafter until disease progression. POMALYST® 4 mg PO was administered daily for 21 days along with Dexamethasone 40 mg weekly (20 mg for patients over 75 years of age). The median patient age was 64 years and patients had received a median of 4 prior lines of therapy. About 75% of the patients had prior Autologous Stem Cell Transplant, 90% of patients were refractory to REVLIMID®, 70% were refractory to VELCADE®, and 64% were refractory to both agents.

The Overall Response Rate in this study was 59% with Very Good Partial Response (VGPR) noted in 28% of patients. Complete Response was achieved in 6% of patients and stringent Complete Response was achieved in 8% of patients. The median time to response was 1 month and the median duration of response was 13.6 months. The most common toxicities were infusion reactions, nausea, vomiting, diarrhea, fatigue, fever, upper respiratory tract infection, muscle spasms, cough and dyspnea. The most common grade 3/4 toxicities were cytopenias including lymphopenia.

It was concluded that DARZALEX® in combination with POMALYST® and Dexamethasone is a new combination therapy, with significant clinical benefit, for patients who relapse or become resistant to Proteasome Inhibitors and Immunomodulatory agents. This combination may be a viable option for patients who progress on a combination of REVLIMID®, VELCADE® and Dexamethasone (RVD) regimen, which is often given as first line therapy. A Study of JNJ-54767414 (HuMax CD38) (Anti-CD38 Monoclonal Antibody) in Combination With Backbone Treatments for the Treatment of Patients With Multiple Myeloma. ClinicalTrials.gov Identifier: NCT01998971 https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761036orig1s005ltr.pdf.

Antiemetics American Society of Clinical Oncology Clinical Practice Guideline Update (Part II)

RR

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is quite common and occurs in about 80% of patients receiving chemotherapy. The following (Part II) is a continuation of the ASCO Antiemetics Clinical Practice Guideline Update.

KEY RECOMMENDATIONS (ctd) – PART II

Adult Patients

Breakthrough nausea and vomiting

• (No change) For patients with breakthrough nausea or vomiting, clinicians should re-evaluate emetic risk, disease status, concurrent illnesses, and medications, and ascertain that the best regimen is being administered for the emetic risk.

• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who did not receive Olanzapine prophylactically, should be offered Olanzapine in addition to continuing the standard antiemetic regimen.

• (Updated) Adult patients who experience nausea or vomiting despite optimal prophylaxis, and who have already received Olanzapine, may be offered a drug of a different class—for example, an NK1 receptor antagonist, Lorazepam or Alprazolam, a dopamine receptor antagonist, Dronabinol, or Nabilone—in addition to continuing the standard antiemetic regimen.

Anticipatory nausea and vomiting

• (Reworded for clarity) All patients should receive the most active antiemetic regimen that is appropriate for the antineoplastic agents being administered. Clinicians should use such regimens with initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behavioral therapy with systematic desensitization.

KEY RECOMMENDATIONS

High emetic risk Radiation Therapy

• (Updated) Adult patients who are treated with high-emetic-risk radiation therapy should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone before each fraction and on the day after each fraction if Radiation Therapy is not planned for that day.

Moderate-emetic-risk radiation therapy

• (Reworded for clarity) Adult patients who are treated with moderate-emetic-risk Radiation Therapy should be offered a 5-HT3 receptor antagonist before each fraction, with or without Dexamethasone before the first five fractions. Low-emetic-risk radiation therapy

• (Updated) Adult patients who are treated with Radiation Therapy to the brain should be offered rescue Dexamethasone therapy. Patients who are treated with Radiation Therapy to the head and neck, thorax, or pelvis should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.

Minimal-emetic-risk radiation therapy

• (Updated) Adult patients who are treated with minimal-emetic-risk radiation therapy should be offered rescue therapy with a 5-HT3 receptor antagonist, Dexamethasone, or a Dopamine receptor antagonist.

Concurrent radiation and antineoplastic agent therapy

• (Updated) Adult patients who are treated with concurrent radiation and antineoplastic agents should receive antiemetic therapy that is appropriate for the emetic risk level of antineoplastic agents, unless the risk level of the radiation therapy is higher. During periods when prophylactic antiemetic therapy for antineoplastic agents has ended and ongoing radiation therapy would normally be managed with its own prophylactic therapy, patients should receive prophylactic therapy that is appropriate for the emetic risk of the radiation therapy until the next period of antineoplastic therapy, rather than receiving rescue therapy for antineoplastic agents as needed.

Pediatric Patients

High-emetic-risk antineoplastic agents

• (Updated) Pediatric patients who are treated with high-emetic-risk antineoplastic agents should be offered a three-drug combination of a 5-HT3receptor antagonist, Dexamethasone, and Aprepitant.

• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Aprepitant should be offered a two-drug combination of a 5-HT3 receptor antagonist and Dexamethasone.

• (New) Pediatric patients who are treated with high-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of Palonosetron and Aprepitant.

Moderate-emetic-risk antineoplastic agents

• (Reworded for clarity) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents should be offered a two-drug combination of a 5-HT3receptor antagonist and Dexamethasone.

• (New) Pediatric patients who are treated with moderate-emetic-risk antineoplastic agents who are unable to receive Dexamethasone should be offered a two-drug combination of a 5-HT3 receptor antagonist and Aprepitant.

Low-emetic-risk antineoplastic agents

• (New) Pediatric patients who are treated with low-emetic-risk antineoplastic agents should be offered Ondansetron or Granisetron.

Minimal emetic risk antineoplastic agents

• (New) Pediatric patients who are treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis.

Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Hesketh PJ, Kris MG, Basch E, et al. DOI: 10.1200/JCO.2017.74.4789 Journal of Clinical Oncology – published online before print July 31, 2017

Antiemetics American Society of Clinical Oncology Clinical Practice Guideline Update

RR

SUMMARY: The ASCO guideline for Antiemetics in oncology was updated by the ASCO Expert Panel following a systematic review of 41publications from November 2009 thru June 2016. The recommendations in this guideline are most definitive for adults who are treated with single-day IV chemotherapy. This topic has been divided into Part I and Part II for easy reading. Part II is continued in the second article of this e NewsLetter.

Guideline Question: What are the most effective strategies for preventing or managing nausea and vomiting due to antineoplastic agents or radiation therapy?

Target Population: Adults and children who receive antineoplastic agents and adults who undergo radiation therapy for cancer.

Target Audience: Medical and Radiation Oncologists, Oncology Nurses, Nurse Practitioners, Physician Assistants, Oncology Pharmacists, and Patients with cancer

KEY RECOMMENDATIONS – PART I

Adult Patients

High-emetic-risk antineoplastic agents

• (Updated) Adult patients who are treated with Cisplatin and other high-emetic-risk single agents should be offered a four-drug combination of a Neurokinin 1 (NK1) receptor antagonist, a Serotonin (5-HT3) receptor antagonist, Dexamethasone, and Olanzapine. Dexamethasone and Olanzapine should be continued on days 2 to 4.

• (Updated) Adult patients who are treated with an Anthracycline combined with Cyclophosphamide should be offered a four-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, Dexamethasone, and Olanzapine. Olanzapine should be continued on days 2 to 4.

Moderate-emetic-risk antineoplastic agents

• (Updated) Adult patients who are treated with Carboplatin AUC 4 or more should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.

• (Updated) Adult patients who are treated with moderate-emetic-risk antineoplastic agents, excluding Carboplatin AUC 4 or more, should be offered a two-drug combination of a 5-HT3 receptor antagonist (day 1) and Dexamethasone (day 1).

• (Updated) Adult patients who are treated with Cyclophosphamide, Doxorubicin, Oxaliplatin, and other moderate-emetic-risk antineoplastic agents that are known to cause delayed nausea and vomiting may be offered Dexamethasone on days 2 to 3.

Low-emetic-risk antineoplastic agents

• (Updated) Adult patients who are treated with low-emetic-risk antineoplastic agents should be offered a single dose of a 5-HT3 receptor antagonist or a single 8-mg dose of Dexamethasone before antineoplastic treatment.

Minimal-emetic-risk antineoplastic agents

• (Reworded for clarity) Adult patients who are treated with minimal-emetic-risk antineoplastic agents should not be offered routine antiemetic prophylaxis.

Antineoplastic combinations

• (Reworded for clarity) Adult patients who are treated with antineoplastic combinations should be offered antiemetics that are appropriate for the component antineoplastic agent of greatest emetic risk.

Adjunctive drugs

• (Updated) Lorazepam is a useful adjunct to antiemetic drugs, but is not recommended as a single-agent antiemetic.

Cannabinoids

• (New) Evidence remains insufficient for a recommendation regarding treatment with medical marijuana for the prevention of nausea and vomiting in patients with cancer who receive chemotherapy or radiation therapy. Evidence is also insufficient for a recommendation regarding the use of medical marijuana in place of the tested and US FDA-approved cannabinoids, Dronabinol and Nabilone, for the treatment of nausea and vomiting caused by chemotherapy or radiation therapy.

Complementary and alternative therapies

• (Reworded for clarity) Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies for the prevention of nausea and vomiting in patients with cancer.

High-dose chemotherapy with stem cell or bone marrow transplantation

• (Updated) Adult patients who are treated with high-dose chemotherapy and stem cell or bone marrow transplantation should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.

Multiday antineoplastic therapy

• (Reworded for clarity) Adult patients who are treated with multiday antineoplastic agents should be offered antiemetics before treatment that are appropriate for the emetic risk of the antineoplastic agent administered on each day of the antineoplastic treatment and for 2 days after the completion of the antineoplastic regimen.

• (Strengthened) Adult patients who are treated with 4- or 5-day Cisplatin regimens should be offered a three-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, and Dexamethasone.

Continued….. in Article 2 of this e NewsLetter

Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. Hesketh PJ, Kris MG, Basch E, et al. DOI: 10.1200/JCO.2017.74.4789 Journal of Clinical Oncology – published online before print July 31, 2017

FDA Approves NERLYNX® for Adjuvant Treatment of HER2 Positive Breast Cancer

RR

SUMMARY: The FDA on July 17, 2017 approved NERLYNX® (Neratinib) for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant Trastuzumab (HERCEPTIN®)-based therapy. 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, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 women will die of the disease. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15%-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2 and adjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early breast cancer. Nonetheless, approximately 25% of patients will develop recurrent disease within 10 years following this adjuvant intervention. Extending the duration of adjuvant HERCEPTIN® therapy or adding TYKERB® (Lapatinib), a Tyrosine Kinase Inhibitor that targets HER1 and HER2, has not improved outcomes.

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

The approval of NERLYNX® was based on ExteNET trial, which is a multicentre, randomized, double-blind, placebo-controlled, phase III study, in which the efficacy and safety of 12 months of NERLYNX® after HERCEPTIN®-based adjuvant therapy was evaluated, in patients with early stage HER2-positive breast cancer. Patients with early stage HER2-positive breast cancer (N=2,840), and within two years of completing adjuvant HERCEPTIN®, were randomized in a 1:1 ratio to receive either oral NERLYNX® 240 mg per day (N=1420) or placebo (N=1420), for one year. Patients were stratified by hormone receptor status, nodal status (0, 1-3, or 4 or more), and HERCEPTIN® adjuvant regimen (sequentially versus concurrently with chemotherapy). The Primary endpoint was invasive Disease Free Survival (iDFS), defined as the time between the randomization date to the first occurrence of invasive recurrence (local/regional, ipsilateral or contralateral breast cancer), distant recurrence, or death from any cause, within two years of follow up. The median follow up was 2 years.

In the updated analysis, the two year iDFS was 94.2% in patients treated with NERLYNX® compared with 91.9% in those receiving placebo (HR 0.66; P=0.008). Patients with ER positive breast cancer were noted to have greater benefit. The most common grade 3-4 adverse events associated with NERLYNX® were diarrhea, vomiting and nausea. Patients can experience diarrhea early, in the first 2 or 3 days and this can be alleviated using antidiarrheal prophylaxis with Loperamide, initiated with the first dose of NERLYNX® and continued for the first 2 months of treatment and as needed thereafter.

It was concluded that NERLYNX® when given for 12 months after chemotherapy and HERCEPTIN®-based adjuvant therapy, to women with HER2-positive breast cancer, significantly improved 2-year invasive Disease Free Survival. Longer follow up will hopefully address if there is an Overall Survival benefit with this treatment intervention. NERLYNX® is the first TKI approved by the FDA, shown to reduce the risk for disease recurrence, in patients with early stage HER2-positive breast cancer. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial Chan A, Delaloge S, Holmes FA, et al. The Lancet Oncology 2016; 17:367- 377

Maintenance Treatment with REVLIMID® Improves Progression Free Survival in Diffuse Large B-Cell Lymphoma

RR

SUMMARY: The American Cancer Society estimates that in 2017, about 72,240 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,140 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 to 4% each year. 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 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. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. None of these interventions have been successful.

REVLIMID® (Lenalidomide) is an oral immunomodulatory agent (IMiD) with activity in lymphoid malignancies, primarily through immune modulation (repair T-cell immune synapse dysfunction and Natural Killer cell/T-cell effector augmentation). It additionally has antiproliferative effects. REVLIMID® was shown to have significant activity in relapsed DLBCL when given alone or along with RITUXAN®.

The REMARC study is an international, multicenter, double-blind, randomized, placebo-controlled phase III trial which compared REVLIMID® as maintenance therapy with placebo, in elderly patients with DLBCL, who achieved a Complete Response (CR) or Partial Response (PR) to R-CHOP induction treatment. A total of 650 patients who had CR or PR after 6-8 cycles of R-CHOP were randomly assigned in a 1:1 ratio to receive oral REVLIMID® maintenance 25 mg daily or placebo, for 21 days of every 28-day cycle, for 24 months. The median age was 68 years and approximately 90% of the patients had stage III-IV disease. The Primary end point was Progression Free Survival (PFS) and Secondary end points included safety, the percentage of patients who converted from PR to CR, Event Free Survival and Overall Survival (OS).

With a median follow up of 39 months, median PFS was not reached in the REVLIMID® group compared to 58.9 months in the placebo group (HR=0.70; P=0.013) favoring REVLIMID®. This PFS benefit with REVLIMID® maintenance was seen in all predefined subgroups (all age groups, all IPI scores, molecular subtypes, CR versus PR after R-CHOP, Positive versus Negative PET status at the time of randomization). The Overall Survival however was similar between the treatment groups after a longer median follow up of 52 months (P=0.26). The most common grade 3 or 4 toxcities associated with REVLIMID® maintenance were neutropenia and cutaneous reactions.

It was concluded that maintenance treatment with REVLIMID® for 24 months, after obtaining a CR or PR to R-CHOP, significantly prolonged Progression Free Survival in elderly patients with Diffuse Large B-Cell Lymphoma. This is the first randomized study showing a PFS benefit with an immunomodulatory agent as maintenance therapy, in this patient population. Lenalidomide Maintenance Compared With Placebo in Responding Elderly Patients With Diffuse Large B-Cell Lymphoma Treated With First-Line Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. Thieblemont C, Tilly H, Gomes da Silva M, et al. DOI: 10.1200/JCO.2017.72.6984 Journal of Clinical Oncology – published online before print April 20, 2017

BAVENCIO® – First FDA Approved Agent for Merkel Cell Carcinoma

RR

SUMMARY: The FDA on March 23, 2017, granted accelerated approval to BAVENCIO® (Avelumab) for the treatment of patients 12 years and older with metastatic Merkel Cell Carcinoma (MCC). It is estimated that about 1500 cases of MCC are diagnosed in the United States each year and the life expectancy for metastatic Merkel Cell Carcinoma is less than 1 year and is associated mortality three times that of Malignant Melanoma (46% vs. 15% respectively). Merkel Cell Carcinoma, also described as Trabecular tumor of the skin, is rare but aggressive form neuroendocrine skin cancer and is much more common in elderly Caucasians. The rapid rise in the incidence of MCC over the past several years has been attributed to increased life expectancy, more sun exposure and weakened immune systems. Approximately 80% of Merkel Cell Carcinoma tumors have been found to be infected with Merkel Cell PolyomaVirus (MCPyV) and the natural history of the MCC has been linked to virus-specific humoral and cellular immune responses. MCC tumors are able to evade the immune system in spite of persistent expression of immunogenic viral proteins. It has been postulated that a high mutation burden associated with Merkel Cell Carcinomas leads to many new antigens being presented to the immune system. Tumor cells as well as tumor-infiltrating immune cells express PD-L1 (Programmed cell Death Ligands), which can contribute to inhibition of antitumor immune response in the tumor microenvironment. The immune system is harnessed and Cytotoxic T-cell activity is suppressed by the binding of PD-L1 to PD-1(Programmed cell Death 1) and B7.1 receptors found on T cells. Merkel Cell Carcinoma is associated with increased PD-L1 expression.

BAVENCIO® is a human, immunoglobulin G1 lambda, PD-L1 targeted monoclonal antibody that binds to PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1. This in turn negates the inhibitory effects of PD-L1 on the immune response by unleashing the immune system and restoring antitumor immune responses. In addition, BAVENCIO® induces Antibody Dependent Cell-mediated Cytotoxicity (ADCC). The approval of BAVENCIO® for Merkel Cell Carcinoma was based on the phase II, prospective, open-label, international JAVELIN trial in which 88 patients with Stage IV Merkel Cell Carcinoma received BAVENCIO® 10 mg/kg IV infusion over 60 minutes, every 2 weeks, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior chemotherapy regimen for metastatic disease. Over 50% of the patients had visceral metastases, two thirds of the patients had tumors with PD-L1 expression of 1% or more, by ImmunoHistoChemistry assay and 52% of the evaluable patients tested positive for Merkel cell Polyomavirus. However, patient selection in this study was not based on the level of PD-L1 expression or Polyomavirus status. The median age was 73 years. The Primary endpoint was Objective Response Rate (ORR). Secondary endpoints included Duration of Response and Progression Free Survival (PFS).

At a median follow up of 16 months, the Objective Response Rate at 1 year was 33% with a Complete Response Rate of 11%. The median time to response was 6 weeks. The 6-month durable response rate was 30.6% and the median Duration of Response had not yet been reached. These responses were noted irrespective of PD-L1 tumor cell expression or presence of Merkel cell Polyomavirus. The estimated one year PFS was 30% and one year Overall Survival was 52%. The most common adverse reactions were rash, fatigue, nausea, diarrhea, decreased appetite, musculoskeletal pain, infusion-related reaction and peripheral edema.

The authors concluded that BAVENCIO® showed durable antitumor activity with a manageable safety profile, in patients with metastatic Merkel Cell Carcinoma who had progressed on chemotherapy and is an important new treatment option for this patient population. BAVENCIO® is the very first drug approved by the FDA for Merkel Cell Carcinoma. Studies are also underway with KEYTRUDA® (Pembrolizumab), a PD-1 inhibitor, in this patient group, with promising outcomes thus far. Durable responses to avelumab (anti-PD-L1) in patients with Merkel cell carcinoma progressed after chemotherapy: 1-year efficacy update. Kaufman HL, Russell JS, Hamid O, et al. 2017 AACR Annual Meeting. Abstract CT079. Presented April 3, 2017.

Brachytherapy for Patients With Prostate Cancer American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update Summary

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer and 1 in 7 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 161,360 new cases of Prostate cancer will be diagnosed in 2017 and 26,730 men will die of the disease. Brachytherapy for prostate cancer is a type of Internal radiation treatment in which radioactive material sealed inside a seed, pellet, wire, or capsule is implanted in the prostate gland using a needle or catheter. Brachytherapy allows the delivery of higher doses of radiation to the intended site, compared with the conventional form of radiation therapy (External Beam Radiation Therapy).

Types of Brachytherapy

1) Low-dose rate (LDR) implants that stay in the prostate gland for 1 to 7 days and then are taken out.

2) High-dose rate (HDR) implants that stay in the prostate gland for a few minutes at a time and are then taken out.

3) Permanent implants that stay in the prostate gland and are not removed.

Prostate Cancer Risk Categories

Very Low Risk: T1c, Gleason score 6 or less, PSA less than 10 ng/ml, Fewer than 3 prostate biopsy cores positive with 50% or less cancer in each core

Low Risk: T1-T2a, Gleason score 6 or less, PSA less than 10 ng/ml

Intermediate Risk: T2b-T2c and/or Gleason score =7 and/or PSA 10-20 ng/ml

High Risk: T3a or Gleason score 8-10 or PSA more than 20 ng/ml

Very High Risk: T3b-T4

With the gathering of new evidence from randomized trials since the original publication in 2013, a guidelines update became necessary. The scope of this guideline covers Brachytherapy boost and monotherapy. The relevant evidence was evaluated for inclusion in this updated clinical practice guideline after a systematic review of the literature and five randomized controlled trials provided the evidence for this update. 

Guideline Questions

1) In patients with newly diagnosed Prostate cancer, what is the efficacy of Brachytherapy alone for clinical outcomes compared with External Beam Radiation Therapy (EBRT) alone, or Radical Prostatectomy (RP) alone?

2) In patients with newly diagnosed Prostate cancer, what is the efficacy of Brachytherapy combined with EBRT for clinical outcomes compared with Brachytherapy alone, EBRT alone, or RP alone?

3) Among the isotopes used for low-dose-rate (LDR) Brachytherapy (eg, Iodine-125 [125I], Palladium-103 [103Pd], and Cesium-131 [131Cs]), which isotope maximizes clinical outcomes when used in patients with newly diagnosed Prostate cancer?

Updated recommendations

1) For patients with low-risk Prostate cancer who require or choose active treatment, LDR brachytherapy alone, EBRT alone, or RP should be offered to those who are eligible.

2) For patients with intermediate-risk Prostate cancer choosing EBRT with or without Androgen Deprivation Therapy (ADT), Brachytherapy boost (LDR or high–dose rate [HDR]) should be offered to eligible patients.

3) For low-intermediate risk Prostate cancer (Gleason 7, PSA 10 ng/mL or Gleason 6, PSA 10 to 20 ng/mL) LDR Brachytherapy alone may be offered as monotherapy.

4) For patients with high-risk Prostate cancer receiving EBRT and ADT, Brachytherapy boost (LDR or HDR) should be offered to eligible patients.

5)125I and 103Pd are each reasonable isotope options for patients receiving LDR Brachytherapy; no recommendation can be made for or against using 131Cs or HDR monotherapy.

6) Patients should be encouraged to participate in clinical trials

Qualifying Statements

1) Patients should be counseled about all of their management options (surgery, EBRT, Brachytherapy, or active surveillance, as applicable) in a balanced, objective manner, preferably by practitioners from multiple disciplines.

2) Recommendations for patients with low-risk disease are unchanged from the initial guideline because no new data from randomized studies informing this question have been presented or published since 2013.

3) Patients ineligible for Brachytherapy may include those with moderate to severe baseline urinary symptoms, large prostate volume, or prior transurethral resection of the prostate, those who are medically unfit, and those with contraindications to radiation treatment.

4) ADT may be given in neoadjuvant, concurrent, and/or adjuvant settings at the physician’s discretion. Note that neoadjuvant ADT may cytoreduce the prostate volume sufficiently to allow Brachytherapy.

5) There may be increased genitourinary toxicity with Brachytherapy compared with use of EBRT alone.

6) Brachytherapy should be performed at a center that has strict quality assurance standards.

7) It cannot be determined whether there is an overall or cause-specific survival advantage for Brachytherapy compared with EBRT alone because none of the trials were designed or powered to detect a meaningful difference in survival outcomes.

Brachytherapy for Patients With Prostate Cancer: American Society of Clinical Oncology/Cancer Care Ontario Joint Guideline Update. Chin J, Rumble RB, Kollmeier M, et al. Journal of Clinical Oncology 2017;35:1737-1743.

Weight Gain Increases the Risk for Postmenopausal Breast cancer

RR

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, 255,180 new cases of invasive breast cancer will be diagnosed in 2017 and over 41,070 women will die of the disease. Obesity is an important contributing factor to postmenopausal breast cancer incidence and mortality. Based on recently published meta-analysis, in women diagnosed with breast cancer, there is an approximately 30% increased risk of disease recurrence or death in those who are obese compared to those with ideal body weight. Increasing physical activity may lower the risk of breast cancer recurrence. According to the consensus from the St Gallen Consensus Conference in 2015, obesity has been associated with poor breast cancer outcomes. Obesity is associated with alterations in insulin/glucose homeostasis, adipokines, and sex hormones, which may play a role in breast cancer outcomes. Weight loss can lead to reductions in C-reactive protein, insulin, glucose, and leptin. These mediators have all been implicated to have prognostic significance in breast cancer.

The Nurses’ Health Studies (NHS) are the largest and longest running investigations focused on women’s health. This was established in 1976 and the information provided by its 238,000 dedicated nurse-participants has allowed NHS to produce key advances impacting women’s health. These studies are conducted by researchers at Harvard School of Public Health and Brigham and Women's Hospital in Boston, Massachusetts. The authors conducted a clinical trial in this NHS cohort and studied the effects of weight and weight changes in early adulthood and risk of breast cancer later in life. A prospective observational study was conducted among 74,177 women from the Nurses' Health Study from 1980-2012. These women provided information on breast cancer risk factors such as reproductive factors, hormone therapy, anthropometric variable, benign breast disease, and family history of breast cancer. This information was updated every 2 years up to the time of data analysis. Each individual’s weight at age 18 was collected in 1980.

During the observation period, 4965 cases of invasive breast cancer were reported for the 74,177 women followed from 1980 to 2012. Weight gain over a long period of time from age 18, both during premenopause and postmenopause, were positively associated with postmenopausal breast cancer risk. However, premenopausal weight gain was not related to premenopausal breast cancer risk. Further, weight gain from age 18 yrs onwards was positively associated with ER+/PR+ postmenopausal breast cancer and there was a 50% increased risk for breast cancer with a weight gain of 30 kg. This direct association was not seen for ER+/PR- or ER-/PR- breast cancer. The authors noted that overall, 17% of ER+/PR+ postmenopausal breast cancer and 14% of total postmenopausal breast cancer are attributable to weight gain of more than  5 kg after age 18.

It was concluded that 14% of postmenopausal breast cancer could be prevented if women avoided excessive weight gain of more than 5 kg after age 18. This study adds new insights on weight gain during premenopausal years and risk for postmenopausal breast cancer. Weight and weight changes in early adulthood and later breast cancer risk. Rosner B, Eliassen AH, Toriola AT, et al. Int J Cancer. 2017 Jan 30. doi: 10.1002/ijc.30627 [Epub ahead of print]

FDA Approves ENDARI®, A New Treatment for Sickle Cell Disease

RR

SUMMARY: The FDA on July 7, 2017 approved ENDARI® (L-Glutamine oral powder) for patients age five years and older with Sickle Cell disease to reduce severe complications associated with the blood disorder. Sickle cell disease or Sickle Cell anemia is an Autosomal Recessive disorder and affects approximately 100,000 Americans. It is estimated that it affects 1 out of every 365 African-American births and 1 out of every 16,300 Hispanic-American births. The average life expectancy for patients with Sickle Cell disease in the United States is approximately 40 to 60 years.

HbSS disease or Sickle Cell anemia is the most common Sickle Cell disease genotype and is associated with the most severe manifestations. HbSS disease is caused by a mutation substituting thymine for adenine in the sixth codon of the beta-globin chain gene. This in turn affects the hemoglobin’s ability to carry oxygen and causes it to polymerize. This results in decreased solubility thereby distorting the shape of the red blood cells, increasing their rigidity and resulting in red blood cells that are sickle shaped rather than biconcave. These sickle shaped red blood cells limit oxygen delivery to the tissues by restricting the flow in blood vessels, leading to severe pain and organ damage (vaso-occlusive crises). Oxidative stress is an important contributing factor to hemoglobin polymerization with polymer formation occurring only in the deoxy state. HbS/b-0 thalassemia (double heterozygote for HbS and b-0 thalassemia) is clinically indistinguishable from HbSS disease.

L-glutamine is a precursor for the synthesis of essential metabolic Oxidation-Reduction cofactors including Nicotinamide Adenine Dinucleotide (NAD). It has been shown in previous studies that there is higher L-glutamine utilization in Sickle Cell Anemia resulting in its depletion and thereby contributing to oxidative stress. Based on a phase II study showing favorable outcomes with ENDARI® compared with placebo, a phase III, randomized trial was conducted, in which the safety and efficacy of ENDARI® was studied in 230 Sickle Cell disease or beta-0 thalassemia patients, who had at least two episodes of painful crises during the 12 months before screening. Patients were randomized in a 2:1 ratio to receive ENDARI® (N=152) or placebo (N=78). Enrolled patients were 5-58 yrs old and ENDARI® was administered orally at 0.3 mg/kg/day for 48 weeks followed by a 3 week tapering period. Two thirds of the patients were on Hydroxyurea. The effect of treatment was evaluated over 48 weeks.

Patients who were treated with ENDARI® experienced fewer hospital visits for Sickle Cell crises pain management with parenteral narcotics or Ketorolac compared to those who received a placebo, fewer hospitalizations for Sickle Cell pain , and fewer days in the hospital (median 6.5 days versus median 11 days) compared to those on placebo. Further, patients who received ENDARI® also had fewer occurrences of acute chest syndrome (a life-threatening complication of sickle cell disease), compared with patients who received a placebo (8.6% versus 23.1%). The common side effects of ENDARI® included, nausea, constipation, headache, abdominal pain, cough, pain in the extremities, back pain and chest pain.

It was concluded that the benefit with ENDARI® for patients with Sickle Cell disease, was seen in all age groups and there was a consistent advantage with ENDARI® regardless of whether the patient was on Hydroxyurea or not. ENDARI® is the first treatment approved for patients with Sickle Cell disease in almost 20 years. Phase 3 Study of L-Glutamine Therapy in Sickle Cell Anemia and Sickle ß0-Thalassemia Subgroup Analyses Show Consistent Clinical Improvement. Niihara Y, Viswanathan K, Miller ST, et al. Abstarct#1318. Presented at ASH 58th Annual Meeting & Exposition, San Diego, CA. December 3-6, 2016

Three Months of Adjuvant Therapy Adequate for Stage III Colon Cancer

RR

The IDEA Collaboration is a prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials, which included 12,834 patients from 12 countries. They concluded that a risk-based approach has to be taken when making adjuvant chemotherapy recommendations for patients with stage III colon cancer. Three months of adjuvant chemotherapy is adequate for patients with T1-3, N1 disease. This study data was presented at 2017 ASCO Annual Meeting.