On April 4, 2017 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported that preclinical data on RXDX-106 – which represents a novel class of immunomodulatory agents that appears to restore innate immunity in preclinical models via potent inhibition of the TYRO3, AXL and MER (or TAM) family of receptors – will be presented at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Washington D.C (Press release, Ignyta, APR 4, 2017, View Source [SID1234518457]). In addition, the company will also showcase its first ever data in hematological malignancies for entrectinib – an orally available, CNS-active tyrosine kinase inhibitor targeting tumors that harbor TRK, ROS1 or ALK fusions – in molecularly defined acute myeloid leukemia (AML). Entrectinib is currently being studied in a registration-enabling Phase 2 clinical trial known as STARTRK-2.

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"We continue to be excited by our pipeline progress, including the emerging preclinical profile of RXDX-106 and its potential to restore and enhance a patient’s immune response to cancer," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Our preclinical data confirm TAM receptors as novel immuno-oncologic targets in the fight against cancer, highlighting both the single agent activity of RXDX-106, as well as a possible synergistic effect when combined with other immuno-oncology treatments such as checkpoint inhibitors. Furthermore, the preclinical data on entrectinib activity in AML highlight the rationale for studying entrectinib in molecularly defined hematological malignancies in a clinical setting, in addition to the ongoing clinical studies of entrectinib in solid tumors."

In the RXDX-106 data to be presented, researchers studied the activity of RXDX-106 in a commonly studied syngeneic mouse colon carcinoma model in matched immunocompetent and immunocompromised mice, finding that RXDX-106 had greater tumor growth inhibition in the immunocompetent animals, which suggested that RXDX-106 effects in this system were modulated by the immune system. Immuno-phenotypic modulation by RXDX-106 was also observed in the mouse model, including an increase in tumor infiltrating lymphocytes (TILs), an increase in the ratio of M1/M2 macrophages, and an increase in expression of CD69 and PD-1 on CD8 T Cells. In another syngeneic mouse model, RXDX-106 inhibited tumor growth as a single agent and demonstrated further tumor growth inhibition in combination with anti-PD-1 or anti-CTLA-4 antibodies, which was accompanied by increased levels of IFNɣ in the blood. In a separate preclinical investigation of RXDX-106 targets, AXL and MER fusion proteins were shown to independently act as oncodrivers and, therefore, may be viable therapeutic targets for patients harboring such molecular alterations. The preclinical data to be presented at the AACR (Free AACR Whitepaper) Annual Meeting suggest that RXDX-106 can act as both an anti-tumor immuno-modulator and TAM oncodriver inhibitor and support clinical development of RXDX-106 in a wide variety of cancers (Abstract number 4698; Abstract number 4191).

Researchers will also present new preclinical data investigating entrectinib as a potential treatment for patients with NTRK rearranged acute myeloid leukemias. Entrectinib treatment inhibited cell proliferation in vitro with sub-nanomolar EC50 values. In a mouse model, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow (Abstract number 5158). Based on these data, we intend to evaluaute entrectinib further in molecularly defined hematological malignancies.

On April 4, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), reported the presentation of preclinical data outlining the potential therapeutic utility of CYC140, a polo-like kinase (PLK) 1 inhibitor, for the treatment of esophageal cancer and acute leukemia (Press release, Cyclacel, APR 4, 2017, View Source [SID1234518455]). The findings were presented during the American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 1-5, in Washington, D.C.

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"We believe these findings further validate the potential utility of CYC140 and its selection as a clinical candidate," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "CYC140 is a potent and selective inhibitor of PLK1, an oncogenic regulator of cell division. These preclinical data suggest that CYC140 can be targeted against esophageal cancer and acute leukemia. In addition, the data demonstrate the potential for CYC140 to be used in synergistic combinations with other targeted agents, including EGFR inhibitors and PI3K pathway inhibitors, to enhance cancer cell death or growth suppression. CYC140 was discovered and developed in-house, drawing on our strong scientific experience in cell cycle biology. Based on these results and the conclusion of IND-directed development we plan to make an Investigational New Drug submission for CYC140."

Esophageal cancer and acute leukemia were identified as highly sensitive cancer indications from a panel of 300 cancer cell lines and non-malignant comparators following short exposure to CYC140. CYC140 demonstrated good selectivity over non-malignant cell lines. Potent, dose-dependent antitumor activity of CYC140 was demonstrated in preclinical xenograft models of esophageal cancer and acute leukemia with tumor growth delay, tumor regression and cures observed.

In esophageal cancer cell lines CYC140 combined synergistically with EGFR inhibitors or PI3K pathway inhibitors and can also be combined with approved cytotoxics such as cisplatin. Consistent with PLK1 inhibition, CYC140 reduced phosphorylation of nucleophosmin, a PLK1 substrate, and caused accumulation of mitotic cells in vitro and in vivo.

The study concluded that CYC140 is a selective PLK1 inhibitor which preferentially induces growth inhibition and cell death in malignant versus non-malignant cells. Identification of several pharmacodynamic markers and demonstration of activity in a majority of malignant cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and esophageal cancer support prospective clinical development of CYC140, alone and in potential combination with targeted agents.

Abstract: 4178
Title: The novel PLK1 inhibitor, CYC140: Identification of pharmacodynamic markers, sensitive target indications and potential combinations
Date/Time: Tues. April 4, 2017: 1 p.m. – 5 p.m. EDT
Location: Section 7, Poster Board 1
Session Title: Targeting Protein Kinases and DNA
Authors: Sylvie Moureau, Craig MacKay, Chiara Saladino, Elizabeth Pohler, Karin Kroboth, Jonathan Hollick, Daniella Zheleva, Sheelagh Frame, David Blake. Cyclacel Ltd, Dundee, United Kingdom
The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.

About PLK inhibition

Polo kinases were discovered by Professor David Glover, Cyclacel’s Chief Scientist. They are a family of enzymes that regulate cell cycle progression through mitosis or cell division. PLKs are part of the biological machinery that regulate spindle formation and activation of CDK/cyclin complexes during mitosis. Activity of the mitotic kinase PLK1 is strongly associated with cancer progression. Several studies have shown correlations between elevated PLK1 expression, histological grade and poor prognosis in several types of cancer. PLK1 may have a role in oncogenesis through its regulation of tumor suppressors, such as p53 and BRCA2. Inhibition of PLK1 by small molecules or siRNA has been shown to interfere with several stages of mitosis. PLK1 inhibition offers an opportunity to treat cancer with a targeted anti-mitotic approach.

About CYC140

Cyclacel employed high throughput screening, in silico screening and de novo ligand design approaches to discover multiple PLK1 inhibitor series. The lead series includes potent and highly selective PLK1 inhibitors with broad anti-proliferative activity across a range of tumor cell lines, which are highly active in xenograft models of human cancers when dosed orally. CYC140 was selected as a clinical candidate following optimization for drug-like properties, cellular activity and pharmacokinetic profile. CYC140 has recently completed IND-enabling studies.

A grant of approximately $3.7 million from the U.K. Government’s Biomedical Catalyst has supported IND-directed development of CYC140.

On April 4, 2017 Corvus Pharmaceuticals, Inc. (NASDAQ:CRVS), a clinical-stage biopharmaceutical company focused on the development and commercialization of novel immuno-oncology therapies, reported interim safety and efficacy results from its ongoing Phase 1/1b study (Press release, Corvus Pharmaceuticals, APR 4, 2017, View Source [SID1234518454]). The data showed that treatment with CPI-444 as a single agent and in combination with atezolizumab (Tecentriq) was well tolerated and resulted in anti-tumor activity in patients with multiple types of advanced solid tumors, including those resistant or refractory to prior treatment with anti-PD-1 or anti-PD-L1 antibodies. CPI-444 is a selective and potent inhibitor of the adenosine A2A receptor. Atezolizumab, developed by Genentech, a member of the Roche Group, is a monoclonal antibody designed to target and bind to a protein called PD-L1 (programmed death ligand-1).

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The interim data were presented today in an oral plenary session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 in Washington, D.C., by Leisha Ann Emens, M.D., Ph.D., study investigator and associate professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

"The data obtained to date are the first report of clinical activity of adenosine receptor blockade in cancer and indicate that CPI-444 provides disease control and induces tumor regression in a number of patients with extensive disease in several tumor types, many of whom are resistant/refractory to prior therapy with an anti-PD-(L)1 antibody," said Richard A. Miller, an oncologist and co-founder, president and chief executive officer of Corvus. "In addition to the previously announced expansion of the single-agent renal cell cancer cohort, we have expanded three more cohorts — the single agent non-small cell lung cancer patient cohort as well as the renal cell and non-small cell lung cancer patient cohorts treated with the combination therapy."

Interim safety data on 113 patients and efficacy data for 96 patients enrolled in the study were presented at the AACR (Free AACR Whitepaper) conference. Patients with the following histologies were enrolled: 28% triple negative breast cancer (TNBC); 25% non-small cell lung cancer (NSCLC); 12% melanoma (MEL); 12% renal cell cancer (RCC) and 23% others. The median age of the patients was 64 years. All patients had failed approved therapies for their disease, having received a median of two prior treatment regimens (range: 1-5), and 56 percent were resistant or refractory to prior treatment with anti-PD-(L)1 antibodies. Ninety percent of patients had visceral metastases including 37% with liver and 9% with brain metastases. For patients with RCC and NSCLC, the median number of prior therapies was 4 and 3, respectively. Seventy nine percent and 75%, of RCC and NSCLC patients, respectively, were resistant/refractory to prior anti-PD-(L)1 therapy. The efficacy endpoints of the study are response rate and disease control rate (defined as complete response, partial response or stable disease).

Interim results showed that disease control (with a median follow up of 16 weeks, range 4-44 weeks) was observed in 38 percent of those receiving CPI-444 as a single agent (N=52) and in 39% of those receiving the combination (N=44), for an overall disease control rate of 38% in 96 evaluable patients. Disease control rates by tumor type and treatment are shown in the following table.


CPI-444
(N=52) CPI-444 / ATEZOLIZUMAB
(N=44) ALL SUBJECTS
(N=96)
ALL SUBJECTS 20 (38%) 17 (39%) 37 (38%)
PRIOR ANTI-PD-(L)1 EXPERIENCE
– NAÏVE
– ANTI-PD-(L)1 RESISTANT
OR REFRACTORY
13/29 (45%)
7/23 (30%)


5/18 (28%)
12/26 (46%)


18/47 (38%)
19/49 (39%)

DISEASE HISTOLOGY
– NSCLC
– MEL
– RCC
– TNBC
– OTHERS
4/14 (29%)
2/5 (40%)
3/5 (60%)
7/17 (41%)
4/11 (36%)
5/10 (50%)
2/6 (33%)
5/5 (100%)
3/14 (21%)
2/9 (22%)
9/24 (38%)
4/11 (36%)
8/10 (80%)
10/31 (32%)
6/20 (30%)

Additional results presented showed:

Of 14 patients with tumor regression, three experienced a partial response (reduction of tumor volume > 30% ) and 11 experienced minor tumor regression (change in tumor volume of 0% to reduction of tumor volume ≤ 30%). Nine of these patients were resistant or refractory to prior anti-PD-(L)1 therapy.
– The three patients who experienced a partial response included one renal cell cancer patient who received single-agent CPI-444, and one non-small cell lung cancer patient and one colorectal cancer patient who both received the combination therapy
– The 11 patients who experienced minor regression of their tumor included seven patients who received single-agent CPI-444 and four who received the combination therapy
Of the 37 patients who showed evidence of disease control, 23 remain on treatment
CPI-444 has been well tolerated to date. The most common adverse events in patients treated in the single-agent CPI-444 cohorts were Grade 1 and 2 nausea (14%), pruritis (10%), fatigue, abdominal pain, rash, diarrhea, fever, decreased appetite and chills (each 5%). No Grade 3 or 4 adverse events were seen with single agent CPI-444. The most common adverse events in patients treated in the combination cohorts were Grade 1 and 2 nausea (13%), pruritis (9%), fatigue, fever, decreased appetite (each 7%). In the combination cohorts, three serious adverse events, in two patients, were observed: one patient with Grade 3 Coombs positive autoimmune hemolytic anemia and one patient who experienced both Grade 4 aseptic autoimmune meningoencephalitis and thrombocytopenia. Both cases of these autoimmune toxicities, which have been observed with anti-PD-(L)1 therapies, resolved when treatment was discontinued.
ADDITIONAL DATA PRESENTED IN POSTER SESSIONS AT AACR (Free AACR Whitepaper)
Additional data on CPI-444 will be featured in poster sessions tomorrow at the AACR (Free AACR Whitepaper) Annual Meeting as follows:

Analysis of tumor biopsies from patients in the Phase 1/1b study showed that CPI-444 alone and in combination with atezolizumab increased frequencies of activated immune cells and increased immune cell infiltration in tumors (Abstract #5593).
In preclinical studies, the combination of CPI-444 with an anti-CTLA-4 antibody was synergistic in eliminating tumors and prolonging survival. Similarly, CPI-444 enhanced the activity of multiple targeted and cytotoxic chemotherapy agents with diverse mechanisms that result in cell death and induction of immune infiltration. These findings provide rationale for clinical studies of CPI-444 in combination with additional established immune therapies beyond anti-PD-(L)1 therapy, and in combination with chemotherapy in patients with solid tumors (Abstract #5598).
CPI-444 is effective in augmenting efficacy of adoptively transferred T-cells in preclinical vaccine models. CPI-444 as a single agent improved the ratio of CD8 to T-regulatory cells and enhanced T-cell killing in a HER-2/neu expressing animal model by inhibiting the adenosine A2A receptor. These results provide a rationale for expanding CPI-444 into other new modalities of cancer therapy such as vaccines and cell based therapies (Abstract #5579).
Preclinical data on Corvus’ humanized monoclonal anti-CD73 antibody, CPX-006, that is currently in IND-enabling studies will also be presented tomorrow in a poster session (Abstract #5577). Elevated CD73 expression has been observed in human tumors and shown by others to be prognostic in some indications. Corvus’ data shows that CD73 protein is broadly expressed across multiple tumor types in both immune cells and tumor cell compartments and that complete inhibition of CD73 enzyme activity is essential to overcome immune-suppression in vitro. In contrast to other antibodies tested, CPX-006 completely inhibits CD73 catalytic activity in primary human cells and restores T-cell proliferation and cytokine secretion in an adenosine-mediated immunosuppressive environment.

PHASE 1/1B TRIAL DESIGN
The Phase 1/1b trial is designed to examine the activity of CPI-444 as a single agent and in combination with Genentech’s atezolizumab, an anti-PD-L1 antibody. Patients with non-small cell lung cancer (NSCLC), melanoma, renal cell cancer (RCC), triple-negative breast cancer (TNBC), MSI-H colorectal cancer, head and neck cancer, bladder cancer and prostate cancer who have failed standard therapies are eligible. The efficacy endpoints of the study are response rate and disease control rate which is defined as complete response, partial response (reduction of > 30% tumor volume) or stable disease (change in tumor volume of between 20% growth of tumor and 30% reduction of tumor volume). Patients with minor tumor responses are those with changes in tumor volume of 0% to ≤ 30% reduction in tumor volume. Patients are treated until disease progression or evidence of Grade 3 or 4 toxicity.

The dose-selection part of the study included four cohorts of 12 patients each (N=48) – three cohorts treated with single agent CPI-444 (100 mg twice daily for 14 days; 100 mg twice daily for 28 days; 200 mg once daily for 14 days) and one cohort treated with the combination (CPI-444 50 mg or 100 mg twice daily for 14 days combined with atezolizumab). A treatment cycle is 28 days. Based on biomarker analyses showing sustained, complete blockade of the adenosine A2A receptor in peripheral blood lymphocytes, and evidence of immune activation in circulating lymphocytes, an optimum single agent and combination dose of 100 mg twice a day for 28 days was selected for the second part of the study. As defined in the protocol, patients in the dose-selection stage of the trial receiving the dose and schedule selected for evaluation in the second part of the study are included in the disease-specific cohort efficacy analysis.

The second part of the study is evaluating CPI-444 as a single agent in five disease-specific cohorts (NSCLC, MEL, RCC, TNBC, and a category of "other" that includes MSI-H colorectal cancer, bladder cancer and prostate cancer) and CPI-444 in combination with atezolizumab in five additional matched disease-specific cohorts. Each of the 10 cohorts is initially enrolling 14 patients, but may be expanded based on efficacy. To date, the following cohorts have been expanded in size: the single-agent and combination cohorts of patients with renal cell cancer and the single agent and combination cohorts of patients with non-small cell lung cancer.

On April 4, 2017 Bristol-Myers Squibb Company (NYSE:BMY) reported that the U.S. Food and Drug Administration (FDA) accepted a supplemental Biologics License Application (sBLA) that seeks to extend the use of Opdivo (nivolumab) to patients with mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (CRC) after prior fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy (Press release, Bristol-Myers Squibb, APR 4, 2017, View Source [SID1234518453]). The FDA granted the application priority review, and the FDA action date is August 2, 2017.

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"We look forward to working with the FDA towards the goal of providing a new treatment option for patients with metastatic colorectal cancer defined by dMMR or MSI-H biomarkers. These patients have a distinct unmet need, as they are less likely to benefit from conventional chemotherapy and have a shorter overall survival than patients with metastatic colorectal cancer without these biomarkers," said Ian M. Waxman, M.D., development lead, Gastrointestinal Oncology, Bristol-Myers Squibb. "This milestone illustrates Bristol-Myers Squibb’s continued efforts to evaluate the potential of Immuno-Oncology in a broad range of cancers and represents an important advancement in our approach to translational medicine."

The submission was based on data from the ongoing Phase 2 CheckMate -142 trial evaluating Opdivo in patients with dMMR or MSI-H metastatic CRC. The efficacy endpoints include investigator-assessed and blinded independent central review committee-assessed objective response rate (ORR) based on the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, duration of response, progression-free survival and overall survival. Data from this study were presented at the 2017 Gastrointestinal Cancers Symposium in January.

About Colorectal Cancer and dMMR or MSI-H Colorectal Cancer

Colorectal cancer (CRC) is cancer that develops in the colon or the rectum, which are part of the body’s digestive or gastrointestinal system. In the U.S., CRC is the third most common cancer and the second leading cause of cancer-related deaths among men and women combined, with more than 134,000 new cases expected to be diagnosed annually.

Mismatch repair deficiency (dMMR) occurs when the proteins that repair mismatch errors in DNA replication are missing or non-functional, which leads to microsatellite instability-high (MSI-H) tumors in certain types of cancer, including CRC. Approximately 15% of CRC patients and 4-5% of metastatic CRC patients have dMMR or MSI-H biomarkers. Patients with dMMR or MSI-H metastatic CRC are less likely to benefit from conventional chemotherapy and typically have a poor prognosis, with lower survival rates on conventional chemotherapy than patients whose tumors are mismatch repair proficient. Routine testing to confirm dMMR or MSI-H status should be conducted for all CRC patients.

On April 4, 2017 Amgen (NASDAQ:AMGN) reported the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) and an application for a variation to the marketing authorization to the European Medicines Agency (EMA) for XGEVA (denosumab) (Press release, Amgen, APR 4, 2017, View Source [SID1234518452]). The submissions to regulatory authorities seek to expand the currently approved XGEVA indication for the prevention of skeletal-related events (SREs) in solid tumors to include patients with multiple myeloma. The applications include new data from the pivotal Phase 3 head-to-head ‘482 study, the largest international multiple myeloma trial ever conducted.

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XGEVA is a fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is currently indicated for the prevention of SREs in patients with bone metastases from solid tumors based on results from three previous pivotal Phase 3 head-to-head studies. In these Phase 3 studies, XGEVA demonstrated superiority in the solid tumors studied compared to zoledronic acid. In the U.S., XGEVA has a limitation of use noting that it is not indicated for the prevention of SREs in patients with multiple myeloma.

"Bone lesions are a hallmark of multiple myeloma and often result in bone complications, which can be devastating for patients. Current treatment options for bone complications are limited to bisphosphonates, which are associated with renal toxicity. Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "XGEVA’s unique mechanism of action may offer multiple myeloma patients a novel treatment option that is not renally cleared. We look forward to collaborating with regulatory authorities to make XGEVA available to this patient population with an important unmet medical need."

The sBLA is based on efficacy and safety data from the pivotal Phase 3 ‘482 study, which demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study SRE in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85, 1.14; p=0.01). The secondary endpoints of superiority in delaying time to first SRE and delaying time to first-and-subsequent SRE were not met in this study. Overall survival (OS), another secondary endpoint, was also in favor of XGEVA over zoledronic acid (HR=0.90, 95 percent CI: 0.70, 1.16; p=0.41); however, it was not statistically significant. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival (PFS) was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median PFS difference between arms was 10.7 months in favor of XGEVA. These results were presented during the late-breaking abstract session at the 16th International Myeloma Workshop.

Adverse events observed in patients treated with XGEVA were consistent with the known safety profile of XGEVA. The most common adverse events (greater than 25 percent) were diarrhea (33.5 percent XGEVA and 32.4 percent zoledronic acid) and nausea (31.5 percent XGEVA and 30.4 percent zoledronic acid).

About ‘482 Study (NCT01345019)
The ‘482 study was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of SREs in adult patients with newly diagnosed multiple myeloma and bone disease. In the study, a total of 1,718 subjects (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study SRE and first-and-subsequent on-study SRE and evaluation of OS. PFS was an exploratory endpoint. The safety and tolerability of XGEVA were also compared with zoledronic acid.

About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is typically characterized by osteolytic bone lesions, which are part of diagnosis (CRAB criteria).3,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

More than 90 percent of patients develop osteolytic lesions during the course of the disease.3 Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and associated with renal toxicity, which is a common complication with myeloma patients.5 Approximately 60 percent of all multiple myeloma patients have or will develop renal impairment over the course of the disease.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.7

About XGEVA (denosumab)
XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. XGEVA is indicated for the prevention of SREs in patients with bone metastases from solid tumors and for treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma.

U.S. Important Safety Information

Hypocalcemia
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Monitor calcium levels, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA is administered with other drugs that can also lower calcium levels. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.

Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia (denosumab).

Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving XGEVA, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA and periodically during XGEVA therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA. Consider temporarily interrupting XGEVA therapy if an invasive dental procedure must be performed.

Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.

Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons
Clinically significant hypercalcemia has been reported in XGEVA treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity
XGEVA can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA. Apprise the patient of the potential hazard to a fetus if XGEVA is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA.

Adverse Reactions
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.

The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Denosumab is also marketed as Prolia in other indications.

Please visit www.amgen.com or www.xgeva.com for Full U.S. Prescribing Information.

Important EU Product Safety Information

Special Warnings and Precautions: Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA. Hypocalcaemia can occur at any time during therapy. Monitor calcium prior to initial dose, within two weeks of initial dose and if suspected symptoms of hypocalcaemia occur. Severe symptomatic hypocalcaemia has been reported. Consider additional monitoring of calcium level in patients with risk factors for hypocalcaemia or if otherwise indicated based on clinical condition of the patient. If hypocalcaemia occurs while receiving XGEVA, additional calcium supplementation and additional monitoring may be necessary.

Patients with severe renal impairment (creatinine clearance < 30ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia; this risk and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels in these patients is especially important.

Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with XGEVA. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventive dentistry and an individual benefit-risk assessment is recommended prior to treatment. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with XGEVA. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to XGEVA administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ.

Atypical femoral fracture (AFF) has been reported in patients receiving XGEVA. Discontinuation of XGEVA therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. XGEVA is not recommended in patients with growing skeletons. Clinically significant hypercalcaemia has been reported in XGEVA-treated patients with growing skeletons weeks to months following treatment discontinuation. Patients being treated with XGEVA should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications) or with bisphosphonates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA.

Adverse reactions in patients receiving XGEVA to prevent the occurrence of skeletal related events: very common (≥ 1/10) dyspnea, diarrhea and musculoskeletal pain; common (≥ 1/100 to < 1/10) hypocalcaemia, hypophosphatemia, tooth extraction, hyperhidrosis and osteonecrosis of the jaw; rare (≥ 1/10,000 to < 1/1000) drug hypersensitivity, anaphylactic reaction, atypical femoral fracture. In three phase III clinical trials, ONJ was confirmed in 1.8% of patients treated with XGEVA and 1.3% of patients treated with zoledronic acid (primary treatment phase). Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/or use of a dental appliance. Hypocalcaemia was reported in 9.6% of patients treated with XGEVA and 5.0% of patients treated with zoledronic acid. Neutralizing antibodies have not been observed in clinical studies. In the postmarketing setting, severe symptomatic hypocalcaemia (including fatal cases), hypersensitivity (including rare events of anaphylactic reaction) and musculoskeletal pain (including severe cases) have been reported. Please consult the SmPC for a full description of undesirable effects.

Contraindications: Severe, untreated hypocalcaemia; hypersensitivity to the active substance or to any of the excipients; unhealed lesions from dental or oral surgery.