Category: Hem/Onc Updates

White Wine May Increase Melanoma Risk in UV-spared sites

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SUMMARY: It is estimated that in the US, about 87,110 new cases of melanoma will be diagnosed in 2017 and about 9,730 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. Alcohol related cancers account for 5.8% of all cancer deaths worldwide and there is compelling epidemiological evidence supporting that alcohol causes cancer of the oropharynx, larynx, oesophagus, liver, colon, rectum and breast (seven sites).

The mechanism of alcohol related carcinogenesis is not well understood and may vary from each target organ. Alcohol is predominantly metabolized in the liver to acetaldehyde, which is a carcinogen. Acetaldehyde is then converted into acetic acid radicals also known as acetyl radicals. There is strong evidence to suggest that acetaldehyde damages DNA. This mechanism of alcohol related carcinogenesis has been implicated in cancer of the oropharynx, larynx, esophagus and liver. With regards to breast cancer, breast tissue may be more susceptible to alcohol than other sites. Even moderate alcohol intake has been associated with increased levels of circulating sex hormones which in turn can activate cellular proliferation.

Even though the association between alcohol consumption and increased risk of numerous cancers is well known, there has been little or no evidence to associate alcohol consumption to melanoma. The authors in this study investigated whether alcohol intake was associated with risk of melanoma, by using data from three large prospective cohort studies, which included 210,252 participants. These individuals were followed for a mean of 18.3 years. The participants responded to questionnaires approximately every 4 years from 1984 to 2007 and provided information on their alcohol intake. A standard drink was defined at 12.8 grams of alcohol (one drink is considered to be 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of hard liquor).

In this pooled analysis, a total of 1,374 cases of invasive melanoma were documented during the follow up period. Higher alcohol intake was associated with an increased incidence of invasive melanoma (HR=1.14; P=0.04). When analyzed by the type of alcoholic beverages and after adjusting for other alcoholic beverages, white wine consumption was associated with an increased risk of melanoma (HR 1.13; P<0.01). It was also noted that alcohol consumption-related melanoma risk, was higher in the UV-spared sites such as the torso which receives less sun exposure, compared with UV-exposed sites such as head, neck, or extremities. Individuals who consumed 20 grams or more of alcohol a day were 73% more likely to be diagnosed with melanomas of the trunk compared to nondrinkers (HR=1.3;P=0.02), whereas only 2% of the individuals were more likely to be diagnosed with melanoma of the head, neck and extremities compared with non drinkers (HR=1.02; P=0.25).

The researchers noted that there was no evidence that age, smoking history, caffeine intake, physical activity, hair color, mole count or BMI, modified the association between alcohol intake and melanoma, when these results were stratified by those variables. It was hypothesized that white wine may have higher levels of pre-existing acetaldehyde (which gives the pleasant fruity aroma), than beer or hard liquors and the antioxidants in the red wine may offset the carcinogenic risks associated with acetaldehyde.

The authors concluded that these findings support the American Cancer Society Guidelines for Cancer Prevention, to limit alcohol intake, and alcohol consumption was associated with a modest increase in the risk of melanoma, particularly on parts of the body that are less sun exposed. Alcohol Intake and Risk of Incident Melanoma: A Pooled Analysis of Three Prospective Studies in the United States. Rivera A, Nan H, Li T, et al. Cancer Epidemiol Biomarkers Prev. 2016;25:1550-1558

FDA Approves OPDIVO® for Bladder Cancer

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SUMMARY: The FDA on February 2, 2017 granted accelerated approval to OPDIVO® (Nivolumab), for the treatment of patients with locally advanced or metastatic urothelial carcinoma, who have disease progression during or following platinum containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. Urothelial carcinoma accounts for 90 percent of all bladder cancers and can originate in the renal pelvis, ureter and urethra. The American Cancer Society’s estimates that in 2017, approximately 79,030 new cases of Bladder Cancer will be diagnosed and 16,870 patients will die of the disease. Treatment options for patients who progress after platinum based chemotherapy are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%.

The treatment paradigm for solid tumors has been rapidly evolving, with a better understanding of the Immune checkpoints or gate keepers. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), as well as Programmed cell Death Ligands (PD-L1) that are expressed by cells in the tumor micro environment. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody that has demonstrated antitumor efficacy in multiple tumor types. The FDA approval of OPDIVO® for patients with previously treated locally advanced or metastatic urothelial carcinoma, was based on CheckMate-275 trial which is an international, multicenter, phase II study, in which 270 patients with metastatic or surgically unresectable locally advanced urothelial carcinoma received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity. All patients had prior platinum based therapy. The median age was 66 years. The primary endpoint was overall Objective Response Rate confirmed by blinded independent review committee, in all treated patients and by tumor PD-L1 expression (5% or more and 1% or more). The follow up for this study is still ongoing. The median follow up for overall survival was 7 months.

The Objective Response Rate across all treated patients was 19.6% and the responses were durable and the median duration of response has not been reached. There was a higher likelihood of response with increasing tumor PD-L1 expression. The Objective Response Rate was 28.4% in patients with PD-L1 expression of 5% or greater, 23.8% in patients with PD-L1 expression of 1% or greater and 16.1% in those with PD-L1 expression of less than 1%. The most common adverse events were fatigue, musculoskeletal pain, nausea, and decreased appetite.

The authors concluded that single agent therapy with OPDIVO® in previously treated patients with metastatic or surgically unresectable urothelial carcinoma, resulted in durable response rate, irrespective of PD-L1 expression and was associated with an acceptable safety profile. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Sharma P, Retz M, Siefker-Radtke A, et al. The Lancet Oncology. Published: 25 January 2017, DOI: http://dx.doi.org/10.1016/S1470-2045(17)30065-7

The FDA recommends against using screening tests for ovarian cancer screening FDA Safety Communication

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SUMMARY: The American Cancer Society estimates that about 22,440 women will be diagnosed with ovarian cancer in the United States for 2017 and about 14,080 will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Women who have reached menopause, women who have a family history of ovarian cancer, and women with the BRCA1 or BRCA2 genetic mutations have the highest risk for developing ovarian cancer. Over 75% of patients with ovarian cancer have advanced disease at the time of diagnosis. The FDA Safety Communication noted that despite extensive research and published studies there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results.

The 2 tests used most often to screen for ovarian cancer are TransVaginal UltraSound (TVUS) and serum marker CA-125. TVUS is unable to differentiate benign from malignant ovarian mass. Serum marker CA-125 is usually associated with high-grade serous ovarian cancer, but is also expressed in normal tissues of the body such as the lungs and other reproductive organs. An increase in the serum marker CA-125 can be seen in non-malignant conditions such as endometriosis, peritonitis and in women with uterine fibroids. Even though serum marker CA-125 when elevated in patients, with an established diagnosis of ovarian cancer, is often used to follow the course of the disease, it has never been proven as an effective screening test for the early detection of ovarian cancer.

Nonetheless, numerous companies continue to claim that their commercially available diagnostic tests can effectively screen and detect ovarian cancer, with no data to support their claims. The FDA is concerned that women and their health care providers may rely on these inaccurate test results to make treatment decisions. Women with a false-positive result may undergo additional medical tests and/or unnecessary surgery, and may experience complications related to both. Conversely, women with a false-negative test may delay or not seek surgery or other treatment interventions for ovarian cancer. The later is particularly relevant for patients with BRCA mutations. Approximately 40% of BRCA1-mutation carriers and 18% of BRCA2-mutation carriers will develop ovarian cancer by age 70. It is recommended that patients who have BRCA1 mutations consider risk-reduction surgery (hysterectomy and bilateral bilateral salpingo-oophorectomy) by age 40 and those with BRCA2-mutations consider risk-reduction surgery no later than age 50.

Even though screenings for breast, colon and cervical cancers are successfully used for early detection and prevention of cancer-related deaths, a screening test for ovarian cancer with valid scientific data presently does not exist, and the FDA recommends against using currently offered tests to screen for ovarian cancer.

Recommendations:

For women, including those at increased risk of developing ovarian cancer

• Be aware that there is currently no safe and effective ovarian cancer screening test

• Do not rely on ovarian cancer screening test results to make health or treatment decisions

• Talk to your doctor about ways to reduce your risk of developing ovarian cancer, especially if you have a family history of ovarian cancer, or have the BRCA1 or BRCA2 genetic mutations

For physicians

• Do not recommend or use tests that claim to screen for ovarian cancer in the general population of women

• Be aware that testing higher risk asymptomatic patients for ovarian cancer has no proven benefit and is not a substitute for preventive actions that may reduce their risk

• Consider referring women at high risk of developing ovarian cancer, including those with BRCA mutations, to a genetic counselor or gynecologic oncologist, or other appropriate health care provider for more specialized care

U.S. Food and Drug Administration: The FDA recommends against using screening tests for ovarian cancer screening: FDA Safety Communication. Issued September 7, 2016. Available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm519413.htm

Deep Clinical Responses and MRD Negativity with DARZALEX® 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, 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. The recent new drugs approved for the treatment of relapsed/refractory Multiple Myeloma include a Histone Decetylase inhibitor (FARYDAK®) and 2 monoclonal antibodies, Daratumumab (DARZALEX®) and Elotuzumab (EMPLICITI®).

Testing for MRD (Minimal Residual Disease) is standard practice in hematological malignancies such as Chronic Myeloid Leukemia (CML) which is characterized by a defined genetic abnormality ie. Philadelphia Chromosome, and CML also has very effective therapies. Unlike CML, multiple myeloma is a heterogeneous disorder and very effective therapies are only now becoming available. Effective combination regimens for myeloma has resulted in high response rates and therefore achievement of MRD negativity may be a primary endpoint in the near future. MRD negativity has been associated with prolonged Progression Free Survival (PFS) and Overall Survival (OS), in several meta-analyses.

Daratumumab (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 authors in this publication prospectively evaluated Minimal Residual Disease (MRD) status of patients enrolled in two large phase III trials, the POLLUX and CASTOR studies, and assessed the ability of DARZALEX® to yield deep clinical responses beyond complete remission. In the POLLUX study, 569 patients with relapsed or refractory multiple myeloma were randomized in a 1:1 ratio to receive either DARZALEX®, REVLIMID® (Lenalidomide) and Dexamethasone or REVLIMID® and Dexamethasone. In the CASTOR study, 498 patients with relapsed or refractory multiple myeloma were randomized in a 1:1 ratio to receive either DARZALEX®, VELCADE® (Bortezomib) and Dexamethasone or VELCADE® and Dexamethasone. In both these studies, the addition of DARZALEX® resulted in significant improvements in median PFS (HR=0.37; P<0.001 in the POLLUX study and HR=0.39; P<0.0001) in the CASTOR study), compared to the control group.

The researchers in this study, assessed MRD of bone marrow aspirate samples using ClonoSEQ next-generation sequencing–based assay. In the POLLUX study, MRD was assessed at the time of suspected Complete Response (CR), and at 3 and 6 months after. In the CASTOR study, MRD was assessed at the time of suspected CR, and at 6 months and 12 months after the first dose. The MRD sensitivity thresholds were 0.01% (1 cancer cell per 10,000 nucleated cells, or 10-4), 0.001% (10-5), and 0.0001% (10-6). The MRD negativity rate was defined as the proportion of patients with negative MRD results at any point during the studies. The median follow-up was 13.5 months for the POLLUX study and 7.4 months for the CASTOR study.

In the POLLUX study, the addition of DARZALEX® to REVLIMID® and Dexamethasone improved the MRD-negative status rates from 8.8% to 31.8% at the 10-4 threshold, from 5.7% to 24.8% at the 10-5 threshold, and from 2.5% to 11.9% at the 10-6 threshold. In the CASTOR study, the addition of DARZALEX® to VELCADE® and Dexamethasone improved the MRD-negative status rates from 3.6% to 18.3% at the 10-4 threshold, from 2.4% to 10.4% at the 10-5 threshold, and from 0.8% to 4.4% at the 10-6 threshold. It was noted that the MRD negativity was consistently higher in patients treated with DARZALEX® and DARZALEX® induced MRD negativity in three times as many patients as those treated with standard regimens. Further, MRD negativity was noted as soon as 3 months, with many patients continuing to achieve MRD negativity over time. High risk patients {t(4;14), t(14;16), del17p} benefited as well, with 18% of high risk patients in the POLLUX study and 14% of those in the CASTOR study achieving MRD negativity. Patients with sustained MRD negativity following treatment with DARZALEX®, had a significantly longer PFS compared with the control group.

It was concluded that the addition of DARZALEX®, in relapsed/refractory multiple myeloma, to standard treatment regimens, induced MRD negativity in three times as many patients as those treated with standard regimens. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Avet-Loisseau H, Casneuf T, Chiu C, et al. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 246

A Tool to Predict Chemotherapy Related Toxicity in Elderly Patients

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SUMMARY: Cancer in general is a disease of the elderly with two thirds of all cancers and close to three fourths of cancer mortality occurring in individuals 65 years of age or older. Elderly patients are less likely to be offered chemotherapy, as these patients are at an increased risk for chemotherapy related toxicity, compared to their younger counterparts. This may be due to a variety of reasons including decreased bone marrow reserve with aging and an increased risk of chemotherapy-related myelosuppression, inability to endure treatment due to decreased physiologic reserves, as well as impaired clearance of chemotherapy drugs due to decreased renal function. Further, cognitive and hearing impairment along with a poor support system also play an important role in the elderly, not seeking medical care, in a timely manner. Unfortunately, elderly patients are often excluded from participating in clinical trials, which makes it even more difficult to weigh the risks and benefits of chemotherapy in this patient group. Patient Performance Status is often taken into consideration to predict tolerance to chemotherapy as well as outcomes, although it remains unclear if this is a valid predictor of toxicity in elderly patients. Identifying elderly patients who are at risk for developing chemotherapy related toxicity, remains an unmet need.

In this study, researchers developed a predictive model for chemotherapy toxicity, which consisted of 11 questions pertaining to age, tumor type, treatment, lab values and geriatric assessment, using data collected from a prospective longitudinal study of 500 patients, 65 years or older. Based on the answers to the 11 questions, a score for the risk of chemotherapy toxicity was calculated and three risk groups were created – Low (0-5 points), Medium (6-9 points) and High (10-19 points). In this Development cohort, the risk for chemotherapy toxicity correlated with an increasing risk score with 53% of patients experiencing grade 3 or higher chemotherapy toxicity.

The authors then validated the predictive model in an independent cohort of elderly adults (N=250) with a median age of 73 years. It was noted that more than one half of patients in the Validation cohort (58%) experienced grade 3 or more toxicity of whom 34% experienced hematologic toxicity and 55% experienced nonhematologic toxicity. The risk of toxicity increased with increasing risk score (36.7% for low risk cohort, 62.4% for medium risk cohort and 70.2% for high risk cohort; P<0.001). These findings were not statistically different from the Development cohort. Interestingly, there was no association between Karnofsky Performance Status and chemotherapy toxicity (P=0.25).

In elderly patients receiving chemotherapy, this tool is best used to distinguish low and high risk patients but is unable to distinguish moderate and high risk patients. Further, this model was only able to predict grade 3 or more toxicity but not grade 2 toxicity, and this may be equally relevant in elderly patients. Because patients included in this study had solid tumors and did not receive biologics or high-dose chemotherapy, these results apply primarily to patients with solid tumors who receive chemotherapy.

The authors concluded that this prediction model is easy to use in clinical practice and allows Oncology Health Care Providers to help elderly patients make informed decisions and also anticipate potential toxicities in high risk elderly patients and take preventive measures accordingly. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults with Cancer. Hurria A, Mohile S, Gajra A, et al. J Clin Oncol 2016;34:2366-2371

ESR1 Mutations Predict Response to Endocrine Therapy in Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Estrogen Receptor (ER) positive breast cancer cells are driven by estrogens. Approximately 60-65% of breast tumors express Estrogen Receptors and/or Progesterone Receptors and this is a predictor of response to endocrine therapy. These patients are often treated with anti-estrogen therapy which is the cornerstone of their treatment. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol, in extragonadal/peripheral tissues. NOLVADEX® (Tamoxifen) is a nonsteroidal Selective Estrogen Receptor Modulator (SERM) and works mainly by binding to the Estrogen Receptor and thus blocks the proliferative actions of estrogen on the mammary tissue. ARIMIDEX&reg; (Anastrozole), FEMARA® (Letrozole) and AROMASIN® (Exemestane) are Aromatase Inhibitors (AIs) that binds to the Aromatase enzyme and inhibit the conversion of androgens to estrogens in the extra-gonadal tissues. FASLODEX® (Fulvestrant) is an estrogen antagonist and like NOLVADEX®, binds to estrogen receptors (ERs) competitively, but unlike NOLVADEX® causes rapid degradation and loss of ER protein (ER downregulator), and is devoid of ER agonist activity.

Upon development of metastatic disease, a subgroup of these patients, develop resistance to endocrine therapy. The most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting are the ESR1 mutations. These mutations promote ligand independent estrogen receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER-positive breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315) ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER positive, HER negative advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% vs 11%).

Droplet digital Polymerase Chain Reaction (ddPCR) is a highly sensitive and specific technique and can detect ESR1 mutations in the plasma. Retrospective studies have shown that ESR1 mutations detected in plasma cfDNA (cell free DNA) by ddPCR were associated with a lack of response to subsequent AI therapy. The authors in this publication used baseline plasma samples and assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials, the SoFEA trial and PALOMA-3 trial, which are representative of the current standard of care for ER positive advanced breast cancer.

In the SoFEA trial (Study of Faslodex With or Without Concomitant Arimidex), AROMASIN® (Exemestane), a steroidal AI, was compared with FASLODEX® (Fulvestrant)-containing regimens, in patients with prior sensitivity to nonsteroidal AIs (Letrozole and Anastrozole). In the PALOMA3 trial (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, FASLODEX® plus placebo was compared with FASLODEX® plus IBRANCE® (Palbociclib), in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital Polymerase Chain Reaction. (Multiplex PCR amplifies several different DNA sequences simultaneously and more information can be obtained from a single test run).

In the SoFEA trial, ESR1 mutations were found in 39.1% of patients of whom 49.1% were polyclonal. Polyclonal ESR1 mutations suggest that biopsy from a single metastatic site would fail to show capture these mutations. Patients with ESR1 mutations on FASLODEX® had improved Progression Free Survival (PFS) compared with AROMASIN® (HR=0.52; P=0.02). Patients with wild-type ESR1 had similar PFS after receiving either treatment (HR=1.07; P=0 .77). Ability to detect these mutations was not impacted by delays in processing of archival plasma. In the PALOMA3 trial, ESR1 mutations were found in the plasma of 25.3% of patients of whom 28.6% were polyclonal ESR1 mutations. The combination of FASLODEX® plus IBRANCE® improved PFS compared with FASLODEX® plus placebo in both ESR1 mutant (HR=0.43; P=0.002) and ESR1 wild-type patients (HR=0.49; P<0.001).

The authors concluded that plasma analysis for ESR1 mutations after progression on prior AI therapy may help direct choice of further endocrine-based therapy. Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer. Fribbens C, O’Leary B, Kilburn L, et al. J Clin Oncol. 2016;34:2961-2968

XARELTO® for Heparin Induced Thrombocytopenia

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SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality. Heparin Induced Thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies to complexes of Platelet Factor 4 (PF4), a protein present in the platelet alpha granules and heparin and the incidence of HIT varies from 3-5% in patients treated with unfractionated heparin. The frequency of thromboemboli in HIT patients is 30-50% and women diagnosed with HIT are at a 1.7 times greater risk for thrombotic manifestations than men.

There are two types of HIT. Type 1 HIT is a non-immune disorder that results from the direct effect of heparin on platelet activation and manifests within the first 2 days after heparin exposure to heparin, and the platelet count normalizes with continued heparin therapy. Type 2 HIT however is an immune-mediated disorder that typically occurs 4-10 days after exposure to heparin and can result in life threatening thrombotic complications. Patients with HIT more often experience thrombotic events such as Deep Venous Thrombosis, Pulmonary Embolism and sometimes Arterial thrombosis rather than bleeding episodes. The 4 T’s that raise clinical suspicion for HIT include Thrombocytopenia, Timing of thrombocytopenia, Thrombosis and ruling out oTher causes of thrombocytopenia. Once a diagnosis of HIT is established, all heparin products should be stopped and alternative anticoagulants should be considered such as ARGATROBAN®, REFLUDAN® (Lepirudin), ANGIOMAXreg; (Bivalirudin) and ARIXTRA® (Fondaparinux). Warfarin may cause microthrombosis in patients with HIT and should be avoided and should be started only after the platelet count exceeds 150 x 109/L. IVC filters should be avoided as well.

The currently approved therapies for the treatment of HIT however are parenteral preparations and require laboratory coagulation monitoring. XARELTO® is a direct oral anti-Xa inhibitor and is presently approved by the FDA for the prevention and treatment of Deep Vein Thrombosis and Pulmonary Embolism as well as prevention of thromboembolic events in patients with Atrial Fibrillation. XARELTO® could be an ideal agent for patients with HIT, as it can be administered orally at a fixed dose and does not require routine coagulation monitoring.

The purpose of this study was to determine the safety and efficacy of XARELTO® in patients suspected or confirmed to have HIT. The authors in this multicenter, single-arm, prospective cohort study, reviewed the data of 22 consecutive adults with suspected or confirmed HIT. Patients received XARELTO® 15 mg PO BID until a local HIT assay result was available. Patients with a positive local assay result continued XARELTO® 15 mg PO BID until platelet recovery (or until day 21 if they had acute thrombosis at the time of entry into the study). The dose of XARELTO® was then changed to 20 mg PO daily, until day 30. This study was slated to enroll 200 patients but the study was terminated early after 22 patients were enrolled, because of difficulty in recruitment.

It was noted that the incidence of new, symptomatic, objectively confirmed, venous or arterial thromboembolism at 30 days in the HIT positive group (Primary endpoint), was 4.5% and one HIT-positive patient required limb amputation despite platelet recovery. Nine out of 10 HIT-positive patients with thrombocytopenia had platelet recovery.

It was concluded that based on this small study, XARELTO® was effective for treating patients with confirmed HIT, and also facilitated platelet recovery. This first prospective study of XARELTO® in HIT patients has a limited number of patients and the 22 patients in this study were enrolled over a 2.5 year period, which demonstrated the difficulty in enrolling patients in this study. Nonetheless, it is unlikely that larger studies will be designed to compare XARELTO® to one of the parenteral preparations. Based on the available data, XARELTO® may fulfill an unmet need for the management of patients with Heparin Induced Thrombocytopenia. Rivaroxaban for treatment of suspected or confirmed heparin-induced thrombocytopenia study. Linkins LA, Warkentin TE, Pai M, et al. J Thromb Haemost 2016;14:1206-1210.

First Line KEYTRUDA® Superior to Chemotherapy in Advanced NSCLC

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2017 about 222,500 new cases of lung cancer will be diagnosed and over 155,000 patients will die of the disease. Non Small Cell Lung Cancer accounts for approximately 85% of all lung cancers. The FDA in October, 2016 approved KEYTRUDA® (Pembrolizumab) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC), whose tumors have high PD-L1 expression (Tumor Proportion Score greater than or equal to 50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment for metastatic NSCLC.

KEYTRUDA® is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. High level of Programmed Death-Ligand 1 (PD-L1) expression is defined as membranous PD-L1 expression on at least 50% of the tumor cells, regardless of the staining intensity. It is estimated that based on observations from previous studies, approximately 25% of the patients with advanced Non Small Cell Lung Cancer (NSCLC) have a high level of PD-L1 expression and high level of PD-L1 expression has been associated with significantly increased response rates to KEYTRUDA®.

KEYNOTE-024 is an open-label, randomized, phase III trial in which KEYTRUDA® administered at a fixed dose was compared with investigator’s choice of cytotoxic chemotherapy, as first line therapy, for patients with advanced NSCLC, with tumor PD-L1 expression of 50% or greater. Three hundred and five (N=305) treatment naïve patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, were randomly assigned in a 1:1 ratio to receive either KEYTRUDA® (N=154) or chemotherapy (N=151). Enrolled patients had no sensitizing EGFR mutations or ALK translocations. Treatment consisted of KEYTRUDA® administered at a fixed dose of 200 mg IV every 3 weeks for 35 cycles or the investigator’s choice of platinum-based chemotherapy for 4-6 cycles. Pemetrexed (ALIMTA®) based therapy was permitted only for patients who had non-squamous tumors and these patients could receive ALIMTA® maintenance therapy after the completion of combination chemotherapy. The primary end point was Progression Free Survival and secondary end points included Overall Survival, Objective Response Rate and safety.

The median PFS was 10.3 months in the KEYTRUDA® group versus 6.0 months in the chemotherapy group (HR=0.50; P<0.001). This benefit was observed across all patient subgroups including tumor histologic type and chemotherapy regimen administered. The estimated Overall Survival at 6 months was 80.2% in the KEYTRUDA® group versus 72.4% in the chemotherapy group (HR=0.60; P=0.005). Patients in the KEYTRUDA® group experienced higher Response Rates than in the chemotherapy group (44.8% vs. 27.8%) as well as longer median duration of response (Not Reached versus 6.3 months). These benefits were realized even after 43.7% of the patients in the chemotherapy group following progression, had crossed over to receive KEYTRUDA®. Adverse events of any grade were less frequent in the KEYTRUDA® group compared to the chemotherapy group, with diarrhea, fatigue and pyrexia being more common in the KEYTRUDA® group whereas anemia, nausea and fatigue were more often noted in the chemotherapy group. As expected, immune-mediated adverse events (including pneumonitis) occurred more frequently with KEYTRUDA® whereas cytopenias occurred more frequently with chemotherapy.

It was concluded that in treatment naïve patients with advanced NSCLC and a PD-L1 tumor proportion score of 50% or greater, KEYTRUDA® was associated with significantly longer Progression Free and Overall Survival and with fewer adverse events, compared with platinum-based chemotherapy. This landmark trial is practice changing for advanced NSCLC. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. Reck M, Rodríguez-Abreu D, Robinson AG, et al. for the KEYNOTE-024 Investigators. October 9, 2016DOI: 10.1056/NEJMoa1606774

Bone Metastases – ZOMETA® every 12 Weeks Non-Inferior to Every 4 Weeks Schedule

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SUMMARY: Bones are the third most common site of metastatic disease and approximately 100,000 cases of bone metastasis are reported in the United States each year. Cancers originating in the breast, prostate, lung, thyroid and kidney, are more likely to metastasize to the bone. Bisphosphonates inhibit osteoclast-mediated bone resorption and both oral and IV bisphosphonates reduce the risk of developing Skeletal Related Events (SRE’s) and delay the time to SRE’s in patients with bone metastases. Bisphosphonates can also reduce bone pain and may improve Quality of life. Intravenous bisphosphonates, Pamidronate (AREDIA®) and Zoledronic acid (ZOMETA®) have been approved in the US for the treatment of bone metastases. ZOMETA®, a third generation amino-bisphosphonate, has however largely replaced AREDIA® because of its superior efficacy, reducing pain and the incidence of Skeletal Related Events, by 25% to 40%. Both AREDIA® and ZOMETA® are administered IV every 3 to 4 weeks, following diagnoses of bone metastases. However, the optimal treatment schedule has remained unclear. Further, renal toxicity, long bone fractures and OsteoNecrosis of the Jaw (ONJ) have been identified as potential toxicities and the incidence of these toxicities increase with cumulative drug exposure.

The purpose of this study was to determine whether ZOMETA® administered every 12 weeks was non-inferior to ZOMETA® administered every 4 weeks. In this open-label, non-inferiority trial, 1822 patients were enrolled (Breast,N=855, Prostate,N=689 and Myeloma,N=278), and were randomly assigned in a 1:1 ratio to receive ZOMETA® every 4 weeks or every 12 weeks, for 2 years. The median age was 65 yrs and patients had at least one site of bone involvement. The Primary endpoint was incidence of at least one Skeletal Related Event within 2 years (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) after randomization. Secondary endpoints included skeletal morbidity rates (mean number of Skeletal Related Events per year), performance status, pain using the Brief Pain Inventory and incidences of ONJ and renal dysfunction. Both treatment groups were well matched. Patients in this trial were stratified by disease and analyses by disease, was pre-planned.

In the 795 patients who completed the study at 2 years, 29.5% of patients receiving ZOMETA® every 4 weeks and 28.6% of patients receiving ZOMETA® every 12 weeks experienced at least 1 Skeletal Related Event and this was not significantly different. With regards to Secondary endpoints, there were still no significant differences between the two treatment groups with regards to Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction.

The authors concluded that ZOMETA® administered every 3 months for 2 years is non-inferior to ZOMETA®administered every 4 weeks for 2 years, among patients with breast cancer, prostate cancer and multiple myeloma, with bone metastases. A less frequent dosing of ZOMETA® compared with the standard monthly dosing, may also be more convenient for the patients and cost effective. XGEVA®, a RANK ligand (RANKL) inhibitor is also approved in the US for the treatment of bone metastases from solid tumors. A study is underway comparing XGEVA® administered every 4 weeks to every 12 weeks, in patients with metastatic breast and prostate cancer. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases. A Randomized Clinical Trial. Himelstein AL, Foster JC, Khatcheressian JL, et al. JAMA. 2017;317:48-58

A New Treatment Algorithm for the Upfront Treatment of Chronic Lymphocytic Leukemia

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SUMMARY: The American Cancer Society estimates that approximately 18,960 new cases of Chronic Lymphocytic Leukemia (CLL) were diagnosed in 2016 and approximately 4660 patients died from the disease. CLL is a disease of the elderly and the average age at the time of diagnosis is 72 years. A new treatment algorithm for the upfront treatment of CLL divides treatment naïve CLL patients into three groups and therapy should be chosen accordingly:

GROUP 1 consists of elderly patients with comorbidities who are unfit for aggressive interventions. The goal of therapy for this patient group should be to minimize toxicity rather than achieve long term remissions. In elderly CLL patients with comorbid conditions, Chlorambucil was often considered as a standard first-line therapy because of the higher rate of toxicities associated with FLUDARA® (Fludarabine) and TREANDA® (Bendamustine). The preferred choice for this group now is IMBRUVICA® (Ibrutinib). IMBRUVICA® is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling.

In CLL patients 65 years or older with relapsed or refractory disease (94%), or who were treatment-naive (85%), long term treatment and follow up with single-agent IMBRUVICA® resulted in high response rates across all subgroups of patients. It was noted that there has been increasing Complete Response Rate with each follow up in the treatment naïve group with a Complete Response Rate of 26%. (2015 AACR Annual Meeting. Abstract CT132). Of the 94 patients treated with IMBRUVICA®, at 45 months of follow up, the Progression Free Survival (PFS) at 30 months was 96% and Overall Survival (OS) rate was 96% in treatment-naive group, whereas the 30 month PFS was 76% and OS rate was 87% in relapsed/refractory patient group. The median PFS in patients with del(17p) was 32.4 month compared to 12 months with previously published best front line therapies.

In the RESONATE trial, which compared IMBRUVICA® to ARZERRA® (Ofatumumab) in patients with relapsed/refractory CLL (N Engl J Med 371:213-223, 2014), median PFS was not reached with IMBRUVICA® compared to a median PFS of 8.1 months with ARZERRA®, representing a 78% reduction in the risk of progression (HR=0.22; P<0.001). IMBRUVICA® also significantly improved Overall Survival (HR=0.43; P=0.005). The Overall Response Rate was also significantly higher in the IMBRUVICA® group than in the ARZERRA® group (42.6% versus 4.1%; P<0.001). Toxicities with IMBUVICA® are mild and include diarrhea and ecchymoses. Atrial fibrillation is seen in approximately 8% of elderly patients and needs attention.

GROUP 2 includes young fit patients with IGVH mutations for whom more aggressive combination therapy should be recommended for long term benefit. This group of patients should be offered three drug regimen consisting of FCR – FLUDARA®/Cyclophosphamide/RITUXAN® (Rituximab). The long term follow up of the pivotal FCR300 study revealed that 40% of patients were progression free at 14 years with a plateau noted in the PFS curve (Blood 127:303-309, 2016). About 60% of the patients with the IGVH mutation who were negative for Minimal Residual Disease (MRD) at the end of treatment, were progression free at 14 years. It was also demonstrated in a subsequent cohort that testing negative for Minimal Residual Disease after a response to FCR regimen was the most important determinant of Progression Free and Overall Survival. Among responders to FCR who were MRD negative, there was only one progression and no deaths after 4 years. Patients with IGVH-mutated disease had a 2.7-fold higher chance of being MRD negative after treatment with FCR. Bendamustine/RITUXAN® regimen is also often recommended for young and fit patients with Chronic Lymphocytic Leukemia, as the risk of neutropenia and infections are lower. However, FCR is associated with longer remissions by at least one year compared to Bendamustine/RITUXAN®.

GROUP 3 comprises of fit patients who are IGVH mutation-negative and will not achieve long remissions with combination chemotherapy. FCR regimen will not achieve 10-15 year remissions in this patient group and these patients should either be treated with IMBRUVICA® or enrolled in clinical trials.

ZYDELIG® (Idelalisib) is a highly selective oral inhibitor of the enzyme phosphoinositide 3-kinase (PI3K) and specifically blocks the delta isoform of PI3K enzyme and its signaling pathway. In the pivotal trial of previously treated patients with recurrent CLL (N Engl J Med 370:997-1007, 2014), the median PFS for the RITUXAN®/ ZYDELIG® combination group has not yet been reached, whereas the median PFS for the RITUXAN®/placebo arm was 5.5 months (HR=0.15; P<0.0001). This suggested an 85% reduction in the risk of progression. Further, the PFS was favorable in the poor prognosis patients with either a 17p deletion or p53 mutation, when ZYDELIG® was combined with RITUXAN® (HR=0.12). An improvement in the Overall Survival (OS) was also noted in the ZYDELIG® group compared with patients in the RITUXAN® alone group (HR=0.28; P=0.018). The combination of ZYDELIG® and RITUXAN® had an Overall Response Rate of 81% compared with 13% in the RITUXAN® alone group (P<0 .0001). Patients treated with a combination of ZYDELIG® and RITUXAN® also had a higher decrease in lymphadenopathy (93%) compared with 4% in the RITUXAN® alone group (P<0.0001). Lymphocytosis resolves more slowly with ZYDELIG® than with IMBRUVICA® and therefore, ZYDELIG® is combined with RITUXAN®. ZYDELIG® should not be used as first line therapy due to associated toxicities such as colitis, elevated transaminases and pneumonitis seen more so in treatment naïve patients, as these patients have less T-cell depletion.

Chronic Lymphocytic Leukemia with del(17p)

IMBRUVICA® is the preferred first line therapy. VENCLEXTA® (Venetoclax) is a second generation, oral, selective, small molecule inhibitor of BCL2 and restores the apoptotic processes in tumor cells. In a pivotal study, VENCLEXTA® monotherapy in patients with Relapsed/Refractory del(17p) CLL resulted in a ORR of 79.4% with 8% Complete Responses and some patients attained MRD-negative status in their peripheral blood which is remarkable (N Engl J Med 374:311-322, 2016). The median Duration of Response (DoR) has not been reached. This drug should be considered as second line therapy.

Dr O’Brien concluded that this new evidence based treatment algorithm stratifies patients differently from the traditional algorithm. O’Brien SM: How do we sequence the best treatment options for patients with CLL based on age and prognostic features? 2016 Pan Pacific Lymphoma Conference. Presented July 22, 2016. Koloa, HI, United States