Impressive 5-Year Survival Rates for Patients with Metastatic Melanoma Treated with OPDIVO®

SUMMARY: It is estimated that in the US, approximately 76,380 new cases of melanoma will be diagnosed in 2016 and approximately 10,130 patients will die of the disease. The incidence of melanoma has been on the rise for the past three decades. A better understanding of Immune checkpoints has opened the doors for the development of various immunotherapies. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that targets PD-1 receptor. In 2014, Topalian and Colleagues reported their finding of an early phase I trial (J Clin Oncol 2014;32:1020-1030), in which patients with advanced Melanoma (N = 107) who had 1-5 prior systemic therapies received OPDIVO® monotherapy. The median age of patients in this study was 61 years and patients received OPDIVO® every 2 weeks for up to 96 weeks. The median Overall Survival for these patients was 16.8 months and 1 and 2 year survival rates were 62% and 43%, respectively. It was noted that some patients had durable responses that persisted even after treatment was discontinued. This patient group was followed for Overall Survival, Progression Free Survival (PFS), long term safety and response duration, after discontinuing treatment with OPDIVO®. The authors have now reported the results of this extended follow up, with 5 year Overall Survival (OS) data from this study.

The 5 year Overall Survival in all 107 patients was 34% and the median OS was 20.3 months for those who received the approved dose of 3 mg/kg of OPDIVO® and 17.3 months in all 107 patients. As a comparison, according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) data, the 5 year OS rate for metastatic Melanoma patients diagnosed during the study period was 16.6%. The OS rates in this study appeared to have plateaued at 48 months. The Progression Free Survival at 30 months following treatment was 25.7% for those who received the approved dose of 3 mg/kg of OPDIVO® and 18.6% for all patients. The most common side effects across the entire cohort included fatigue, rash, diarrhea, pruritus and nausea.

The authors concluded that this analysis represents the first and longest follow up to date, testing an anti–PD1 immunotherapy in any specific disease. Monotherapy with OPDIVO® in heavily pretreated advanced Melanoma patients can result in more than a third of patients (34%) being alive, 5 years after starting treatment. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial. Hodi FS, Kluger H, Sznol M, et al. 2016 AACR Annual Meeting. Abstract CT001

ZYPREXA® Combination Significantly Reduces Nausea and Vomiting in Patients Receiving Highly Emetogenic Chemotherapy

SUMMARY: Chemotherapy Induced Nausea and Vomiting (CINV) is one of the most common adverse effects of chemotherapy and is experienced by about 80% of patients receiving chemotherapy. The development of effective antiemetic agents has facilitated the administration of majority of the chemotherapy agents in an outpatient setting avoiding hospitalization. Acute CINV begins within the first 24 hours following chemotherapy administration, with most patients experiencing symptoms within the first four hours of treatment, whereas delayed nausea and vomiting occurs more than 24 hours after chemotherapy administration and can persist for several days. Delayed CINV is often underestimated and a third of the patients receiving chemotherapy may experience delayed nausea and vomiting without prior acute nausea or vomiting. Acute nausea and vomiting is dependent on Serotonin (5-hydroxytryptamine-5HT3) and its receptors, with the chemotherapeutic agents stimulating the release of Serotonin from the enterochromaffin cells of the small intestine. 5-HT3 receptors are located on vagal afferent pathway, which in turn activates the vomiting center to initiate the vomiting reflex. 5-HT3 receptors are also located centrally in the Chemoreceptor Trigger Zone of the area Postrema. Delayed nausea and vomiting is associated with the activation of Neurokinin 1 (NK1) receptors by substance P. NK1 receptors are broadly distributed in the central and peripheral nervous systems.

ZYPREXA® (Olanzapine) is an antipsychotic agent that has been shown to block multiple neurotransmitters including Dopamine at D1, D2, D3, and D4 receptors, Serotonin at 5-HT2, 5-HT3 receptors, as well as Catecholamines at alpha1-adrenergic receptors, Acetylcholine at muscarinic receptors and Histamine at H1 receptors in the central nervous system. By virtue of its mechanism of action, ZYPREXA® might have significant antiemetic properties. Based on its pharmacological properties, this study evaluated the efficacy of ZYPREXA® for the prevention of nausea and vomiting, in patients receiving highly emetogenic chemotherapy.

The authors conducted a randomized, double-blind, phase III trial in which patients receiving ZYPREXA® (N=192) were compared to patients receiving Placebo (N=188). Patients received either ZYPREXA® 10 mg PO or matching Placebo daily, on days 1-4 of chemotherapy cycles. All patients additionally received Dexamethasone, Aprepitant or Fosaprepitant, and a 5-HT3 receptor antagonist. Eligible patients had no previous chemotherapy and were receiving Cisplatin at or more than 70 mg/m2 or Cyclophosphamide and Doxorubicin combination. The primary endpoint was nausea prevention and a Complete Response defined as no emesis and no use of rescue medication, was the secondary endpoint.

It was noted that the proportion of patients with no chemotherapy induced nausea was significantly greater with ZYPREXA® than with placebo in the first 24 hours after chemotherapy (74% versus. 45%, P=0.002), the time interval from 25 to 120 hours after chemotherapy (42% versus 25%, P=0.002) and across the overall 120-hour period (37% versus 22%, P=0.002). The Complete Response Rate was also significantly increased with ZYPREXA® during the three periods: 86% versus 65% (P<0.001), 67% versus 52% (P=0.007), and 64% versus 41% (P<0.001), respectively. Sedation, which is a side effect of ZYPREXA®, was observed on day 2 of treatment, with severe sedation noted in 5% of the patients.

The authors concluded that ZYPREXA® significantly improved nausea prevention, as well as Complete Response rate when compared to placebo, among previously untreated patients receiving highly emetogenic chemotherapy. Olanzapine for the Prevention of Chemotherapy-Induced Nausea and Vomiting. Navari RM, Qin R, Ruddy KJ, et al. N Engl J Med 2016; 375:134-142

ARZERRA® (Ofatumumab)

The FDA on January 19, 2016 approved ARZERRA® for extended treatment of patients who are in complete or partial response after at least two lines of therapy, for recurrent or progressive Chronic Lymphocytic Leukemia (CLL). ARZERRA® was previously approved for the treatment of previously untreated patients with CLL for whom Fludarabine-based therapy was considered inappropriate and also for patients with CLL refractory to Fludarabine and Alemtuzumab. ARZERRA® is a product of Novartis Pharmaceuticals Corporation.

Increased Physical Activity Associated with Lower Risk of 13 Different Cancer Types

SUMMARY: The American Cancer Society estimates that in 2016, 1,685,210 new cancer cases will be diagnosed in the United States and 595,690 cancer deaths are projected. It is a well established fact that physical activity reduces the risk of heart disease and all-cause mortality. Additionally, previously published studies have shown reduced risks for Colon, Breast and Endometrial cancers with physical activity. However, it has remained unclear whether physical activity reduces risk of other cancers, which together constitute approximately 75% of all cancers in the United States.

It has been hypothesized that the link between physical activity and cancer is mediated through both hormonal as well as non-hormonal pathways. Hormonal systems such as sex steroids, insulin and insulin-like growth factors, and adipokines can initiate cancer cell growth. Intervention with physical activity by partly reducing adiposity, decreases the levels of estrone, estradiol and insulin in postmenopausal women. Non-hormonal mechanisms linking physical activity to cancer risk, include inflammation, immune function, oxidative stress, and for colon cancer, a reduction in transit time for waste to pass through the gastrointestinal tract.

The authors in this study examined pooled data from 12 prospective cohort studies involving 1.44 million participants, to find out whether there was an association of leisure-time physical activity with incidence of 26 different cancer types. They also examined whether these associations were evident regardless of body size or smoking history. Leisure-time physical activities were defined as activities done at an individual’s discretion, to improve or maintain fitness or health. This could include walking, running, swimming or other moderate- to vigorous-intensity activities. The median physical activity in this study was equivalent to 150 minutes of moderate-intensity activity every week and comparable to the current recommended minimum physical activity level for the US population. Leisure-time physical activity was assessed by self-reported surveys. The median age was 59 years and median BMI was 26.

Participants were followed for a median of 11 years during which period 187,000 new cases of cancer occurred. The authors noted that leisure-time physical activity was associated with lower risk of 13 of 26 cancer types which included Esophageal adenocarcinoma, Liver, Lung, Kidney, Gastric cardia, Endometrial, Myeloid Leukemia, Myeloma, Colon, Head and Neck, Rectal, Bladder and Breast. The greatest risk reduction was noted for Esophageal adenocarcinoma. These associations were evident regardless of body size or smoking history in most cases.

The authors concluded that leisure-time physical activity not only reduces risk of heart disease and risk of death from all causes, but also lowers risk of many types of cancer, regardless of body size or smoking history. Physical activity should therefore be promoted for population-wide cancer prevention and control. Association of Leisure-Time Physical Activity With Risk of 26 Types of Cancer in 1.44 Million Adults. Moore SC, Lee I, Weiderpass E, et al. JAMA Intern Med. 2016;176:816-825.

Short Course Neoadjuvant Radiation Therapy Effective and Less Toxic in Advanced Rectal Cancer

SUMMARY: The American Cancer Society estimates 39,220 new cases of Rectal cancer will be diagnosed in the United States in 2016. Rectal cancer diagnosed at an early stage such as Stage II (T3-T4, N0) or Stage III (Node positive disease without distant metastases) is potentially curable with a combination of neoadjuvant (preoperative) chemoradiation, surgery and postoperative chemotherapy. Unlike colon cancer, the risk of locoregional recurrence is high in Rectal cancer due to its close proximity to the surrounding pelvic organs and difficulty in obtaining a clear surgical margins. Further, there is no serosal tissue surrounding the rectum. For all these reasons, preoperative Radiation Therapy (RT) with concurrent Fluoropyrimidine based chemotherapy as a radiosensitizer, followed by postoperative chemotherapy, has been the standard intervention. Radiation consists of 45 Gy delivered in 25 fractions 5 days a week with a 5.4 Gy boost. Concurrent chemotherapy in the US has included 5-FU/Leucovorin, single agent 5-FU or single agent XELODA® (Capecitabine).

The authors in this study evaluated the efficacy of a short course of neoadjuvant radiation therapy for patients with unresectable cT3 or cT4 Rectal adenocarcinoma. The trial included 515 patients who were randomly assigned either to the control group (N=254), in which patients received RT at 50.4 Gy delivered in 28 fractions, given simultaneously with a regimen of 5-FU bolus, Leucovorin and ELOXATIN® (Oxaliplatin) or the experimental group (N=261) in which patients received a short Five day course of Radiotherapy at 5 Gy per day (Total 25 Gy), followed by three courses of FOLFOX4 delivered over 48 hours, during weeks 3, 5, and 7. Both treatment groups underwent surgery approximately 12 weeks after radiation was started and about 6 weeks following neoadjuvant treatment. ELOXATIN® inclusion in the chemotherapy regimen was at the discretion of the treating physician, due to increase in toxicity. Nonetheless, 70% of the patients had received ELOXATIN® at the end of the study. It should be noted that the NSABP protocol R-04 demonstrated that the addition of ELOXATIN® in the neoadjuvant chemotherapy regimen did not improve outcomes but resulted in significant toxicity. The median follow up was 35 months.

The primary endpoint of the rate of curative resection (R0) was 71% in the control group versus 77% in the experimental group. Pathological Complete Response rates were 11.5% in the control group and 16% in the experimental group. The 3 year Overall Survival rates for the control versus experimental group were 65% vs 73% and Disease Free Survival for the control versus experimental group were 52% vs 53%. These differences were not statistically significant. The local failure rates were similar in both treatment groups (22%).

The authors concluded that a short course of radiotherapy combined with three cycles of chemotherapy post radiation, can be more convenient with lower toxicity and this regimen would be an appealing option for patients with locally advanced Rectal cancer, with metastases in liver or lungs, for whom chemotherapy to control systemic disease can be started much earlier, following a short course of radiation therapy. Neoadjuvant chemoradiation for fixed cT3 or cT4 rectal cancer: Results of a Polish II multicentre phase III study. Bujko K, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 489)

FDA Approves AXUMIN® to Identify Prostate Cancer Recurrence in Patients with Rising PSA

SUMMARY: The FDA on May 27, 2016 approved AXUMIN® (Fluciclovine F18), a novel molecular radiopharmaceutical diagnostic agent, for Positron Emission Tomography (PET) imaging in men with suspected prostate cancer recurrence, based on elevated Prostate Specific Antigen (PSA) levels, following prior treatment. 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 180,890 new cases of prostate cancer will be diagnosed in 2016 and over 26,000 men will die of the disease.

The major source of PSA (Prostate Specific Antigen) is the prostate gland and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy, there is a gradual decline in PSA before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse.

Rising PSA is therefore a sign of recurrent disease and identifying the site of recurrence can be of immense value for the clinician and can help determine the best course of therapy. The diagnostic accuracy of standard imaging tests, for the identification of sites of recurrence in patients with biochemical recurrence, is low. Almost 90% of the standard imaging tests such as CT/MRI and Bone Scan may be negative. More accurate non-invasive imaging techniques for the detection of recurrent tumor is an unmet need. Prostascint, a Single Photon Emission Computerized Tomography (SPECT) radiopharmaceutical agent, was approved in 1999 for the diagnostic imaging of post-prostatectomy patients with a rising PSA. PET scans have largely superseded this study. FluDeoxyGlucose F18 (FDG), a glucose analogue is the most widely used PET radiotracer, but is not generally used as an imaging agent in prostate cancer. This is because good and reliable quality images are not feasible due to indolent growth of prostate cancers and the high urinary excretion of FDG. The other PET radiotracer that is available, Choline C11, has been shown to improve cancer detection in men with biochemical recurrent prostate cancer, but this agent has a short half life of 20 minutes, requires greater patient preparation including 6 hours of fasting prior to administration of Choline C11, delivers higher radiation dose to patients and image quality is poor.

AXUMIN® (Fluciclovine), a diagnostic radiopharmaceutical, is a synthetic amino acid that is preferentially transported into prostate cancer cells by amino acid transporters such as LAT-1 and ASCT2, which are upregulated in prostate cancer cells. This agent is neither metabolized nor incorporated into newly synthesized proteins. The visualization of the increased amino acid transport is facilitated by labeling AXUMIN® with F18 for PET imaging. The FDA approval of AXUMIN® was based on two retrospective trials (Trial 1 and Trial 2) which evaluated the safety and efficacy of AXUMIN® for imaging prostate cancer, in patients with recurrent disease. Trial 1 compared 105 (N=105) AXUMIN® scans in men with suspected prostate cancer, to the histopathology (study of tissue changes caused by disease) obtained by prostate biopsy and by biopsies of suspicious imaged lesions. PET/CT imaging generally included both abdomen and pelvic regions. Local radiologist read the scans initially and subsequently, three independent radiologists read the same scans in a blinded study. Trial 2 evaluated the concordance between 96 (N=96) AXUMIN® and Choline C11 scans, in patients with median PSA values of 1.44 ng/mL. Local radiologist read the Choline C11 scans, and the same three independent radiologists from Trial 1 read the scans, in this second blinded study.

The FDA reported that results of the independent scan readings were generally consistent and confirmed the local scan reading results, and both studies supported the safety and efficacy of AXUMIN® for imaging prostate cancer in men with elevated PSA levels, following prior treatment. It should be noted that a negative study does not rule out the presence of recurrent prostate cancer and a positive image does not confirm the presence of recurrent prostate cancer. Clinical correlation, which may include histopathological evaluation of the suspected recurrence site, is recommended. The most commonly reported adverse events in patients were injection site pain, redness and a metallic taste in the mouth.

It was concluded that AXUMIN® can determine the location of the recurrent prostate cancer in patients with low PSA levels.

ASCO Guidelines on Use of Biomarkers in Early Stage Breast Cancer – Part II

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, 246,660 new cases of invasive breast cancer will be diagnosed in 2016 and 40,450 women will die of the disease. Patients with early stage breast cancer often receive adjuvant therapy. Tumor biomarker assays have become an integral part of the treatment decision making process along with clinical and histologic tumor characteristics, further enabling customized care for patients with early-stage invasive breast cancer. Developed by an expert panel based on systematic reviews, meta-analyses, randomized controlled trials, prospective-retrospective studies and prospective comparative observational studies published from 2006 through 2014, these recommendations are meant to provide guidance to the Health Care Provider, as appropriate treatment is considered for patients with newly diagnosed, early-stage invasive breast cancer.

Two important questions were addressed by these guidelines – The Part I edition last week ( addressed the first clinical question. This week’s edition (Part II) addresses the second clinical question.

Clinical Question 2: For women with early-stage invasive breast cancer and with known estrogen receptor/progesterone receptor and HER2 status, which additional biomarkers have demonstrated clinical utility to guide the choice of specific drugs or regimens for adjuvant systemic therapy?


CYP2D6 polymorphisms should not be used to guide adjuvant endocrine therapy selection. The expression of p27 by IHC should not be used to guide adjuvant endocrine therapy selection.

Aromatase Inhibitors

Protein encoded by the MKI67 gene labeling index by IHC should not be used to guide adjuvant endocrine therapy.


Microtubule-associated protein Tau mRNA expression or mRNA expression by IHC should not be used to guide adjuvant chemotherapy selection. HER1/Epidermal Growth Factor Receptor expression by IHC should not be used to guide adjuvant chemotherapy selection.


TOP2A gene amplification or TOP2A protein expression by IHC should not be used to guide adjuvant chemotherapy selection. HER2 and TOP2A gene coamplification, CEP17 duplication, TIMP-1, FOXP3, or p53 should not be used to guide adjuvant chemotherapy selection.


If a patient has HER2 positive breast cancer, PTEN should not be used to guide adjuvant therapy selection. If a patient has HER2 positive breast cancer, soluble HER2 levels should not be used to guide the selection of the type of adjuvant therapy.

Harris LN, Ismaila N, McShane LM, et al: Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2016;34:1134-1150.

KEYTRUDA® (Pembrolizumab)

The FDA on December 18, 2015 expanded the label to include the approval of KEYTRUDA® injection for the treatment of patients with unresectable or metastatic Melanoma. This expansion now includes the initial treatment of patients with unresectable or metastatic Melanoma with KEYTRUDA®. KEYTRUDA® is a product of Merck Sharp & Dohme Corp.

ALECENSA® (Alectinib)

The FDA granted accelerated approval to ALECENSA® capsules for the treatment of patients with Anaplastic Lymphoma Kinase (ALK)-positive metastatic Non-Small Cell Lung Cancer (NSCLC), who have progressed on or are intolerant to Crizotinib. ALECENSA® is a product of Hoffmann-La Roche Inc.

VISTOGARD® (Uridine Triacetate)

The FDA on December 11, 2015 granted approval to VISTOGARD® granules for the emergency treatment of adult and pediatric patients following a Fluorouracil or Capecitabine overdose, regardless of the presence of symptoms, or who exhibit early-onset, severe or life-threatening toxicity affecting the cardiac or central nervous system and/or early-onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia), within 96 hours following the end of Fluorouracil or Capecitabine administration. VISTOGARD® is a product of Wellstat Therapeutics Corporation.