On September 24, 2015 Nerviano Medical Sciences and Servier together reported the start of a first in Human clinical trial of the drug S 81694 (NMS-P153), an inhibitor of the mitotic checkpoint kinase MPS1 discovered by Nerviano Medical Sciences and thereafter acquired and further developed by Servier (Press release, Nerviano Medical Sciences, SEP 24, 2015, View Source [SID1234522435]).

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The study is an open-label, non-randomized, multicenter international trial in patients with advanced or metastatic solid tumors who have failed previous therapies. An initial dose-escalation stage will be followed by expansion in specific solid tumors. The study is designed to confirm the safety and pharmacokinetics of S 81694, administered as a single agent. Secondary objectives include initial assessment of efficacy and determination of the recommended dose for phase 2.
Servier is the sponsor of the study, which is being conducted in Belgium and The Netherlands by Nerviano’s clinical affiliate Clioss. S 81694 is supplied by Nerpharma, the CMO affiliate of Nerviano.

Jean-Pierre Abastado, Ph.D., Director of the Oncology Innovation Therapeutic Pole at Servier, said: "We are very enthusiastic about the initiation of this study as S 81694 (NMS-P153) is a novel potent inhibitor of MPS1. MPS1 represents an original target overexpressed during the M phase in many types of cancers. S 81694 is highly selective for MPS1 and a brief exposure to S 81694 is sufficient to commit cancer cells to death".

Emmanuel Canet, M.D., PhD, President of Servier R&D stressed that "With the entry in clinical phase of this new antitumoral compound, Servier is reinforcing its commitment to provide innovative therapeutic solutions for unmet needs in patients with serious illnesses".

Arturo Galvani, Ph.D., Director of Drug Discovery at Nerviano Medical Sciences commented: "we have been working together with Servier, a company engaged in cutting-edge research in oncology, in an outstanding collaboration to successfully advance S81694 to clinical development and hope that this first step will further translate into clinical benefit for patients with cancer".

About MPS1:
MPS1 (also known as TTK) is a conserved kinase which is highly expressed in a number of human tumors of different origin. MPS1 plays a critical role in the control of a stage of the cell division cycle known as mitosis. During mitosis, MPS1 is involved in regulation of the spindle assembly checkpoint, a mechanism required for chromosome alignment and segregation. The activity of this checkpoint has been shown to be up-regulated in aneuploid tumors, comprising approximately 90% of solid and 70% of hematological cancers. In accelerating mitosis, MPS1 inhibitors have a novel mode of action as compared to currently available drugs targeting this stage of cell division.

On September 24, 2015 AstraZeneca, along with MedImmune, the company’s global biologics research and development arm, reported that they will illustrate the strength and depth of research underpinning its scientific leadership in oncology, at the European Cancer Congress (ECC) 2015 in Vienna, Austria (25-29 September 2015) (Press release, AstraZeneca, SEP 24, 2015, View Source;astrazeneca-advance-oncology-research-ecc [SID:1234507528]).

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19 oral and poster presentations, including data on AZD9291, durvalumab and olaparib, will provide confirmation and complementary analysis of previously presented results, as well as new data on:

AZD9291: pooled Phase II efficacy and safety data in pre-treated patients with non-small cell lung cancer (NSCLC) (Abstract # 3113) and analysis of patients with and without brain metastases (Abstract # 3083)
Durvalumab (MEDI4736) monotherapy: preliminary results investigating tumour indicators of response in patients with NSCLC (Late Breaker Presentation Abstract # 15LBA)
Olaparib: tumour biomarkers to suggest potential treatment activity in women with ovarian cancer without a BRCA1/2 mutation (Abstract # 435)
Mondher Mahjoubi, Senior Vice President, Global Product Strategy for Oncology at AstraZeneca, said: "Data published at ECC 2015 confirm the strength and rapid progress of our development plan in oncology. Our large and growing dataset for AZD9291 is a great example of this, as it highlights the robustness and consistency of the results we are seeing across a broad population of pre-treated non-small cell lung cancer patients."

AZD9291 in pre-treated patients with NSCLC

Data from an analysis of the AURA Phase II studies (AURA extension and AURA2) in pre-treated patients with NSCLC (Abstract # 3113) confirm findings already reported at previous congresses for AZD9291, a highly selective, irreversible inhibitor of both the activating epidermal growth factor receptor mutation (EGFRm) and the resistance mutation, T790M. Pooled data from over 400 pre-treated patients with EGFRm T790M showed an objective response rate (ORR) of 66% (95% confidence interval (CI) 61% to 71%). ORR was consistent across all sub-groups treated with AZD9291 including ethnicity, tumour mutation types and presence/absence of brain metastases. Preliminary median progression free survival (PFS) was 9.7 months (95% CI 8.3 months to non-calculable [NC]) and median duration of response (DoR) was non-calculable (95% CI 8.3 months to NC).

The safety profile was also in line with previous data readouts. The most common all-causality adverse events (AEs) were diarrhoea, 42% (1% ≥Grade 3) and rashes (grouped terms), 41% (1% ≥Grade 3).

Reported AEs of hyperglycaemia, interstitial lung disease (ILD) and QT prolongation remained consistent with data previously presented: ILD and pneumonitis 3% (2% ≥Grade 3), hyperglycaemia 1% (0% ≥Grade 3), QT prolongation 4% (1% ≥Grade 3). There was a low discontinuation rate: 4% of patients discontinued AZD9291 due to drug-related AEs (as assessed by the investigator).

An analysis of AURA Phase II studies (Abstract # 3083) will demonstrate the consistent activity of AZD9291 in patients with EGFRm T790M NSCLC with and without brain metastases; clinical anecdotes suggest that AZD9291 may have activity in the brain. Pre-clinical data showing that AZD9291 penetrates the blood-brain-barrier were recently presented at the World Congress on Lung Cancer (WCLC Abstract # ID410). The BLOOM (NCT02228369) study is investigating further the potential activity of AZD9291 in the brain.

The AZD9291 ASTRIS study (NCT02474355) is recruiting pre-treated patients with advanced or metastatic EGFRm T790M NSCLC in a real-world setting at multiple sites in Europe. In the US, an expanded access programme (NCT02451852) for AZD9291 for patients with advanced or metastatic EGFRm T790M NSCLC is available. AZD9291 is an investigational therapy and is not yet approved for any indication in any market.

Immuno-oncology programme progresses at pace

MedImmune will demonstrate advances in biomarker research that may identify patients most likely to respond to immunotherapies. The research will demonstrate the potential association between increased tumour expression of programmed death ligand-1 (PD-L1) and gamma interferon and response to the PD-L1 mAb, durvalumab (MEDI4736) (Abstract # 15LBA).

The new research is part of the extensive durvalumab clinical development programme in NSCLC, which includes the PACIFIC (NCT02125461), ATLANTIC (NCT02087423), ARCTIC (NCT02352948), MYSTIC (NCT02453282) and NEPTUNE (NCT02542293) trials discussed recently at WCLC and other conferences this year.

Robert Iannone, Head of Immuno-Oncology, Global Medicines Development at AstraZeneca, said: "Advances in our biomarker development will enable us to effectively identify patients who could benefit most from durvalumab monotherapy as well as those for whom the combination with other immunotherapies such as our anti- CTLA-4 inhibitor (tremelimumab) would be more effective. These insights will support progress with our extensive late-stage immuno-oncology programme, which now includes 17 clinical studies and more than 9,000 patients in lung, bladder, head and neck, and other cancers."

Olaparib shows activity beyond BRCA mutations

Exploratory biomarker data from a Phase II study of olaparib are contributing to an enhanced scientific understanding of why some women with ovarian cancer without a BRCA1/2 mutation demonstrate anti-tumour activity with poly ADP-ribose polymerase (PARP) inhibitor treatment (Abstract # 435). The data suggest that these women have tumours with mutations in other homologous recombination repair (HRR) genes that behave in a similar way to BRCA mutations.

The new biomarker analysis was carried out on tumour samples from 209 patients who took part in a Phase II trial of olaparib in platinum-sensitive relapsed serous ovarian cancer (NCT00753545, Study 19). In a sub-set of patients whose tumours did not carry the BRCA mutation, there was a trend towards greater olaparib efficacy in 21 women with other HRR gene mutations compared to 58 patients with no detectable mutations in other HRR genes.

Olaparib is the cornerstone of AstraZeneca’s industry-leading pipeline of personalised treatments targeting DNA damage and repair mechanisms in cancer cells. The potential of olaparib to target tumours with HRR mutations beyond those in BRCA genes is under investigation in ongoing clinical trials.

AstraZeneca delivering on oncology strategy

ECC marks another successful milestone for AstraZeneca and MedImmune in 2015, following the launch of LYNPARZA (olaparib) in the U.S. and Europe, the approval of IRESSA (gefitinib) in the US, rapid US and EU filings for AZD9291, key regulatory designations for further investigational compounds, and encouraging data supporting the company’s focus on combinations across immuno-oncology and small molecules.

As progress continues, the company is deepening its understanding of cancer biology and extending its research into a wider range of tumour types, with new data expected at congresses throughout 2016. AstraZeneca remains on track to achieve its bold ambition of delivering six new cancer medicines to patients by 2020.

AstraZeneca presents advances in oncology research at ECC 2015 with data on AZD9291, durvalumab and LYNPARZA (olaparib)

Thursday, 24 September 2015

AstraZeneca, along with MedImmune, the company’s global biologics research and development arm, will illustrate the strength and depth of research underpinning its scientific leadership in oncology, at the European Cancer Congress (ECC) 2015 in Vienna, Austria (25-29 September 2015).

19 oral and poster presentations, including data on AZD9291, durvalumab and olaparib, will provide confirmation and complementary analysis of previously presented results, as well as new data on:

AZD9291: pooled Phase II efficacy and safety data in pre-treated patients with non-small cell lung cancer (NSCLC) (Abstract # 3113) and analysis of patients with and without brain metastases (Abstract # 3083)
Durvalumab (MEDI4736) monotherapy: preliminary results investigating tumour indicators of response in patients with NSCLC (Late Breaker Presentation Abstract # 15LBA)
Olaparib: tumour biomarkers to suggest potential treatment activity in women with ovarian cancer without a BRCA1/2 mutation (Abstract # 435)
Mondher Mahjoubi, Senior Vice President, Global Product Strategy for Oncology at AstraZeneca, said: "Data published at ECC 2015 confirm the strength and rapid progress of our development plan in oncology. Our large and growing dataset for AZD9291 is a great example of this, as it highlights the robustness and consistency of the results we are seeing across a broad population of pre-treated non-small cell lung cancer patients."

AZD9291 in pre-treated patients with NSCLC

Data from an analysis of the AURA Phase II studies (AURA extension and AURA2) in pre-treated patients with NSCLC (Abstract # 3113) confirm findings already reported at previous congresses for AZD9291, a highly selective, irreversible inhibitor of both the activating epidermal growth factor receptor mutation (EGFRm) and the resistance mutation, T790M. Pooled data from over 400 pre-treated patients with EGFRm T790M showed an objective response rate (ORR) of 66% (95% confidence interval (CI) 61% to 71%). ORR was consistent across all sub-groups treated with AZD9291 including ethnicity, tumour mutation types and presence/absence of brain metastases. Preliminary median progression free survival (PFS) was 9.7 months (95% CI 8.3 months to non-calculable [NC]) and median duration of response (DoR) was non-calculable (95% CI 8.3 months to NC).

The safety profile was also in line with previous data readouts. The most common all-causality adverse events (AEs) were diarrhoea, 42% (1% ≥Grade 3) and rashes (grouped terms), 41% (1% ≥Grade 3).

Reported AEs of hyperglycaemia, interstitial lung disease (ILD) and QT prolongation remained consistent with data previously presented: ILD and pneumonitis 3% (2% ≥Grade 3), hyperglycaemia 1% (0% ≥Grade 3), QT prolongation 4% (1% ≥Grade 3). There was a low discontinuation rate: 4% of patients discontinued AZD9291 due to drug-related AEs (as assessed by the investigator).

An analysis of AURA Phase II studies (Abstract # 3083) will demonstrate the consistent activity of AZD9291 in patients with EGFRm T790M NSCLC with and without brain metastases; clinical anecdotes suggest that AZD9291 may have activity in the brain. Pre-clinical data showing that AZD9291 penetrates the blood-brain-barrier were recently presented at the World Congress on Lung Cancer (WCLC Abstract # ID410). The BLOOM (NCT02228369) study is investigating further the potential activity of AZD9291 in the brain.

The AZD9291 ASTRIS study (NCT02474355) is recruiting pre-treated patients with advanced or metastatic EGFRm T790M NSCLC in a real-world setting at multiple sites in Europe. In the US, an expanded access programme (NCT02451852) for AZD9291 for patients with advanced or metastatic EGFRm T790M NSCLC is available. AZD9291 is an investigational therapy and is not yet approved for any indication in any market.

Immuno-oncology programme progresses at pace

MedImmune will demonstrate advances in biomarker research that may identify patients most likely to respond to immunotherapies. The research will demonstrate the potential association between increased tumour expression of programmed death ligand-1 (PD-L1) and gamma interferon and response to the PD-L1 mAb, durvalumab (MEDI4736) (Abstract # 15LBA).

The new research is part of the extensive durvalumab clinical development programme in NSCLC, which includes the PACIFIC (NCT02125461), ATLANTIC (NCT02087423), ARCTIC (NCT02352948), MYSTIC (NCT02453282) and NEPTUNE (NCT02542293) trials discussed recently at WCLC and other conferences this year.

Robert Iannone, Head of Immuno-Oncology, Global Medicines Development at AstraZeneca, said: "Advances in our biomarker development will enable us to effectively identify patients who could benefit most from durvalumab monotherapy as well as those for whom the combination with other immunotherapies such as our anti- CTLA-4 inhibitor (tremelimumab) would be more effective. These insights will support progress with our extensive late-stage immuno-oncology programme, which now includes 17 clinical studies and more than 9,000 patients in lung, bladder, head and neck, and other cancers."

Olaparib shows activity beyond BRCA mutations

Exploratory biomarker data from a Phase II study of olaparib are contributing to an enhanced scientific understanding of why some women with ovarian cancer without a BRCA1/2 mutation demonstrate anti-tumour activity with poly ADP-ribose polymerase (PARP) inhibitor treatment (Abstract # 435). The data suggest that these women have tumours with mutations in other homologous recombination repair (HRR) genes that behave in a similar way to BRCA mutations.

The new biomarker analysis was carried out on tumour samples from 209 patients who took part in a Phase II trial of olaparib in platinum-sensitive relapsed serous ovarian cancer (NCT00753545, Study 19). In a sub-set of patients whose tumours did not carry the BRCA mutation, there was a trend towards greater olaparib efficacy in 21 women with other HRR gene mutations compared to 58 patients with no detectable mutations in other HRR genes.

Olaparib is the cornerstone of AstraZeneca’s industry-leading pipeline of personalised treatments targeting DNA damage and repair mechanisms in cancer cells. The potential of olaparib to target tumours with HRR mutations beyond those in BRCA genes is under investigation in ongoing clinical trials.

AstraZeneca delivering on oncology strategy

ECC marks another successful milestone for AstraZeneca and MedImmune in 2015, following the launch of LYNPARZA (olaparib) in the U.S. and Europe, the approval of IRESSA (gefitinib) in the US, rapid US and EU filings for AZD9291, key regulatory designations for further investigational compounds, and encouraging data supporting the company’s focus on combinations across immuno-oncology and small molecules.

As progress continues, the company is deepening its understanding of cancer biology and extending its research into a wider range of tumour types, with new data expected at congresses throughout 2016. AstraZeneca remains on track to achieve its bold ambition of delivering six new cancer medicines to patients by 2020.

NOTES TO EDITORS

About AZD9291

AZD9291 is a highly selective, irreversible inhibitor of both activating sensitising EGFRm and the resistance mutation, T790M, while sparing the activity of wild type EGFR. AZD9291 is designed to achieve minimal or no activity against two biological receptors, known as the
insulin receptor (IR) and insulin-like growth factor receptor (IGFR), in order to minimise the potential for hyperglycaemia (high blood sugar). Hyperglycaemia can lead to patients requiring treatment with additional medications.

Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe and 30-40 percent of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with the approved EGFR-TKIs, gefitinib or erlotinib or afatinib, this resistance is caused by the secondary mutation, T790M. There are currently no targeted therapies approved for the treatment of tumours with this resistance mutation.

Marketing authorisation applications for AZD9291 for the treatment of EGFRm T790M NSCLC have been submitted to the US Food and Drug Administration (FDA), the European Medical Agency (EMA) and other regulatory authorities. Recently, the FDA granted Priority Review to AZD9291, adding to the Breakthrough Therapy designation, Orphan Drug and Fast Track status already assigned by the regulatory body. AZD9291 has also been granted Accelerated Assessment by the EMA.

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against programmed death ligand-1 (PD-L1). Signals from PD-L1 help tumours avoid detection by the immune system. Durvalumab blocks these signals, countering the tumour’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, gastric, pancreatic, bladder and blood cancers.

About LYNPARZA

Olaparib is an innovative, first-in-class oral poly ADP-ribose polymerase (PARP) inhibitor that exploits tumour DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumour types with DNA repair deficiencies.

Olaparib is the first PARP inhibitor to be approved for patients with germline BRCA-mutated advanced ovarian cancer, and has been launched in the U.S. and Europe, with ongoing regulatory submissions across multiple markets.

In Europe, ovarian cancer is the fifth most commonly diagnosed cancer in women and the sixth leading cause of cancer death among women. Up to 15% of women with ovarian cancer have a BRCA mutation, which is the most common cause of homologous repair deficiency (HRD).

In addition to ovarian cancer, AstraZeneca is investigating the full potential of olaparib in multiple tumour types, with Phase III studies in second line gastric cancer, BRCA-mutated pancreatic cancer and adjuvant and metastatic BRCA-mutated breast cancers underway.

On September 23, 2015 OncoGenex Pharmaceuticals, Inc. (NASDAQ: OGXI) reported initial results from the Phase 2 Rainier study evaluating apatorsen in combination with ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) and gemcitabine compared to ABRAXANE and gemcitabine alone in patients with untreated metastatic pancreatic cancer (Filing, 8-K, OncoGenex Pharmaceuticals, SEP 23, 2015, View Source [SID:1234507534]). The addition of apatorsen to ABRAXANE and gemcitabine did not demonstrate a survival benefit compared to ABRAXANE and gemcitabine alone. The study was sponsored and conducted by Sarah Cannon Research Institute (SCRI) and further results will be presented by SCRI at a future medical meeting.

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Pancreatic cancer accounts for approximately 338,000 new cases each year worldwide. In the U.S., it continues to be the fourth leading cause of cancer death. Most pancreatic cancer patients will die within the first year of diagnosis, and five-year survival rates are less than 10 percent.

"Over the last decade, very few treatments have been able to demonstrate a survival benefit in this very difficult-to-treat cancer," said Johanna Bendell, MD, Director of the GI Cancer Research Program, SCRI, and a primary investigator on the trial. "We understand the dire need for new treatment options and are thankful to the patients who participated in this trial."
The most common grade 3/4 treatment-related toxicities on the apatorsen arm were anemia, neutropenia and fatigue, also consistent with the chemotherapy regimen side effects. These and other adverse events (AEs) observed on the apatorsen arm were similar to those seen in previous trials, with the exception of an increase in grade 4 or greater AEs and serious AEs in this pancreatic cancer trial. While patients in the apatorsen arm had fewer treatment discontinuations due to progressive disease, more patients discontinued therapy due to AEs.

"While we are disappointed with the Rainier results, we also recognize the challenges associated with developing effective treatments for such a lethal and complex disease. We remain confident in our broader apatorsen program, which includes ongoing Phase 2 clinical trials in lung, prostate and bladder cancers," said Scott Cormack, President and CEO of OncoGenex.

Recent Apatorsen Data
Results from an exploratory analysis of the Phase 2 Borealis-1 trial showed that patients with metastatic bladder cancer with poor prognostic features experienced a reduction in risk of death with the addition of 600 mg apatorsen added to first-line chemotherapy, compared to chemotherapy alone.

About Apatorsen and ORCA
Apatorsen (OGX-427) is a once-weekly intravenous (IV) experimental drug that is designed to inhibit production of heat shock protein 27 (Hsp27) to disable cancer cells’ defenses and overcome treatment resistance. Hsp27 in an intracellular protein that protects cancer cells by helping them survive, leading to resistance and more aggressive cancer phenotypes. Both the potential single-agent activity and synergistic activity of apatorsen with cancer treatments may increase the overall benefit of existing therapies and augment the durability of treatment outcomes, which could lead to increased patient survival. The ORCA (Ongoing Studies Evaluating Treatment Resistance in CAncer) program encompasses clinical trials of apatorsen. For more information on apatorsen and ORCA, please visit www. OncoGenex.com or www.orcatrials.com.

On September 23, 2015 Lytix reported they will present initial safety and efficacy data from the ongoing Phase I monotherapy trial with LTX-315 as a poster presentation at the 18th European Cancer Congress (ECC2015) in Vienna on September 26 (Press release, Lytix Biopharma, SEP 23, 2015, View Source [SID:1234507523]). These results follow the Proof of Concept declared in April 2015, after the immunotherapeutic oncolytic peptide showed a favorable safety profile and emerging evidence of clinical anti-tumour activity and immune effects. Adding to the strong preclinical synergy with LTX-315 and immune checkpoint inhibitors (ICIs), Lytix also presses forward with its plans to initiate the first combination trial early 2016.

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LTX-315 induces a potent stimulation of an extended range of tumour-specific T-cells attacking cancer, potentially increasing immune response in patients. It appears LTX-315 "pushes the accelerator" of the immune system through the release of potent immune stimulants. Furthermore, LTX-315 differentiates from many other cancer immunotherapies by inducing the release of an extended range of patient-specific tumour antigens.

Combinations of complementary immunotherapy treatments are expected to be an integral part of future cancer treatment delivering significant clinical benefit. ICIs "release the brakes" imposed by the tumour on the immune system. LTX-315 has the potential to augment efficacy of ICIs without adding toxicity.

Dr. James Spicer (King’s College London at Guys Hospital London, UK), principal investigator of the Phase I study and presenter at ECC2015 commented:

"Emerging evidence of anti-tumour activity and immune effects have been observed with LTX-315 in the ongoing Phase I study. With a manageable and predictable safety profile it is both attractive and appropriate to explore combination therapy of LTX-315 with immune checkpoint inhibitors."

Dr. Andrew Saunders, CMO of Lytix Biopharma commented on the development of LTX-315:

"We are moving forward rapidly in completing the Phase I study. We have 7 active centers and 2 new centers joining the study in EU and have filed an IND to have US participation. Based on these data, and the complementary mode of action to immune checkpoint inhibitors, we are planning to initiate a combination trial program."

On September 23, 2015 Amgen (NASDAQ:AMGN) reported the presentation of several studies evaluating Kyprolis (carfilzomib) for Injection, a next-generation proteasome inhibitor, at the 15th International Myeloma Workshop (IMW), from Sept. 23-26, 2015, in Rome (Press release, Amgen, SEP 23, 2015, View Source;p=RssLanding&cat=news&id=2089855 [SID:1234507524]). Kyprolis is approved in the United States (U.S.) for use in combination with lenalidomide and dexamethasone for the treatment of relapsed multiple myeloma, an incurable blood cancer. In the European Union (EU), Kyprolis is under accelerated assessment with the European Medicines Agency (EMA).

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"Multiple myeloma has historically been one of the most difficult to treat diseases because of the inherent complexities related to the recurring pattern of remission and relapse," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Data to be presented at IMW will help provide further insight into the potential of Kyprolis as an important treatment option for patients living with relapsed multiple myeloma."

The following Amgen-sponsored abstracts will be presented at the meeting:

Kyprolis

Efficacy and Safety of Carfilzomib, Lenalidomide, and Dexamethasone (KRd) vs Lenalidomide and Dexamethasone (Rd) in Patients (Pts) With Relapsed Multiple Myeloma (RMM) Based on Age: Secondary Analysis From the Phase 3 Study ASPIRE (NCT01080391)
A. Palumbo, Abstract BP-051, Friday, Sept. 25, 6:40 p.m. – 7:40 p.m. CEST (Poster Area)
Superior Health-Related Quality of Life with Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone in Patients With Relapsed Multiple Myeloma (MM): Results From the ASPIRE Trial
A.K. Stewart, Abstract BP-052, Friday, Sept. 25, 6:40 – 7:40 p.m. CEST (Poster Area)

Observational

Survival Analysis in Newly Diagnosed Multiple Myeloma Patients in the United States Medicare Database
A. A. Yusuf, Abstract PO-171, Thursday, Sept. 24, 6:40 – 7:40 p.m. CEST (Poster Area)
Hospitalization Rates for Newly Diagnosed Multiple Myeloma Patients in the United States Medicare Database
A.A. Yusuf, Abstract PO-179, Thursday, Sept. 24, 6:40 – 7:40 p.m. CEST (Poster Area)
In the U.S., Kyprolis is approved as a monotherapy and in combination with lenalidomide and dexamethasone. In Mexico, Israel, Argentina and Thailand, Kyprolis is approved as monotherapy for relapsed, refractory multiple myeloma. In the EU, Kyprolis is under accelerated assessment with the EMA. The EMA application for Kyprolis is based on data from the Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial and other relevant data. The study showed that patients treated with Kyprolis in combination with Revlimid (lenalidomide) and low-dose dexamethasone (regimen referred to as KRd) lived 50 percent longer (8.7 months) without their disease worsening compared to patients treated with lenalidomide and low-dose dexamethasone alone (regimen referred to as Rd). The median progression free survival was 26.3 months in those treated with KRd compared to 17.6 months in those treated with Rd (HR=0.69; 95 percent CI: 0.57-0.83; p<0.0001). The most common adverse events in the Kyprolis arm included pneumonia (1 percent), myocardial infarction (0.8 percent) and upper respiratory tract infection (0.8 percent).

About Multiple Myeloma
Multiple myeloma is the second most common hematologic cancer.1 Worldwide, more than 230,000 people are living with multiple myeloma with approximately 114,000 new cases diagnosed and 80,000 people dying of the disease each year.2,3 In the U.S., there are nearly 96,000 people living with, or in remission from, multiple myeloma.4 The estimated number of new cases of multiple myeloma in 2014 was more than 24,000 and the estimated number of deaths was 11,090.4 In Europe, it is estimated that more than 89,000 people are living with multiple myeloma. Approximately 39,000 new cases were diagnosed and 24,000 people died in 2012.3

About ASPIRE
The international, randomized Phase 3 ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with Relapsed Multiple MyEloma) trial evaluated Kyprolis in combination with lenalidomide and low-dose dexamethasone, versus lenalidomide and low-dose dexamethasone alone, in patients with relapsed multiple myeloma following treatment with one to three prior regimens. The primary endpoint of the trial was progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death. Secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DOR), disease control rate, health-related quality of life (HR-QoL) and safety. Patients were randomized to receive Kyprolis (20 mg/m2 on days 1 and 2 of cycle one only, escalating to 27 mg/m2 subsquently), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in 4 week cycles), versus lenalidomide and low-dose dexamethasone alone. In the Kyprolis arm, patients were given a 10 minute infusion on days 1, 2, 8, 9, 15 and 16. Kyprolis was omitted on days 8 and 9 during cycles 13-18 and not administered beyond 18 cycles.The study randomized 792 patients at sites in North America, Europe and Israel.

The OS results did not cross the pre-specified early stopping boundary for the interim analysis. At the time of the interim analysis, there were 143 deaths (36.1 percent) in the KRd group, compared to 162 deaths (40.9 percent) in the Rd group. The ORR was 87 percent with KRd and 67 percent with Rd. In the KRd and Rd groups, 32 percent versus 9 percent of patients achieved a complete response or higher (stringent complete response [sCR] or complete response [CR]), a measurement indicating depth of response. Median DOR was 28.6 months for patients receiving KRd (95 percent CI, 24.9 to 31.3 months) and 21.2 months for patients receiving Rd (95 percent CI, 16.7 to 25.8 months).

The rate of deaths due to adverse events (AEs) within 30 days of the last dose was balanced between the KRd arm and the Rd arm. The most common causes of death occurring in patients in the KRd arm compared to the Rd arm included cardiac disorders (3 percent versus 2 percent), infection (2 percent versus 3 percent), renal (0 percent versus less than 1 percent) and other AEs (2 percent versus 3 percent). Serious AEs were reported in 60 percent of the patients in the KRd arm and 54 percent of the patients in the Rd arm. The most common serious AEs reported in the KRd arm compared to the Rd arm were pneumonia (14 percent versus 11 percent), respiratory tract infection (4 percent versus 1.5 percent), pyrexia (4 percent versus 2 percent) and pulmonary embolism (3 percent versus 2 percent). Discontinuation due to any AE occurred in 26 percent of patients in the KRd arm versus 25 percent of patients in the Rd arm. Adverse events leading to discontinuation of Kyprolis occurred in 12 percent of patients.

The ASPIRE data were presented at the 56th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) and published in The New England Journal of Medicine in December 2014.

About Kyprolis (carfilzomib) for Injection
Kyprolis (carfilzomib) for Injection is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.

Kyprolis is also indicated under FDA accelerated approval as a single agent for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Kyprolis is a product of Onyx Pharmaceuticals, Inc. Onyx Pharmaceuticals is a subsidiary of Amgen and holds development and commercialization rights to Kyprolis globally, excluding Japan. Kyprolis is also approved for use in Argentina, Israel, Mexico and Thailand. For more information about Kyprolis, visit www.kyprolis.com.

Important Safety Information Regarding Kyprolis (carfilzomib) for Injection U.S. Indication
This safety information is specific to the current U.S. approved indication.

Cardiac Toxicities
New onset or worsening of preexisting cardiac failure (e.g., congestive heart failure, pulmonary edema, decreased ejection fraction), restrictive cardiomyopathy, myocardial ischemia, and myocardial infarction including fatalities have occurred following administration of Kyprolis. Death due to cardiac arrest has occurred within a day of Kyprolis administration.

Withhold Kyprolis for Grade 3 or 4 cardiac adverse events until recovery, and consider whether to restart Kyprolis based on a benefit/risk assessment.

Adequate hydration is required prior to each dose in Cycle 1. Monitor all patients for evidence of volume overload, especially patients at risk for cardiac failure. Adjust total fluid intake as clinically appropriate in patients with baseline cardiac failure or who are at risk for cardiac failure.

Patients ≥ 75 years, the risk of cardiac failure is increased. Patients with New York Heart Association Class III and IV heart failure, recent myocardial infarction, and conduction abnormalities may be at greater risk for cardiac complications.

Acute Renal Failure
Cases of acute renal failure and renal insufficiency adverse events (renal impairment, acute renal failure, renal failure) have occurred in patients receiving Kyprolis. Acute renal failure was reported more frequently in patients with advanced relapsed and refractory multiple myeloma who received Kyprolis monotherapy. This risk was greater in patients with a baseline reduced estimated creatinine clearance. Monitor renal function with regular measurement of the serum creatinine and/or estimated creatinine clearance. Reduce or withhold dose as appropriate.

Tumor Lysis Syndrome
Cases of Tumor Lysis Syndrome (TLS), including fatal outcomes, have occurred in patients receiving Kyprolis. Patients with multiple myeloma and a high tumor burden should be considered at greater risk for TLS. Adequate hydration is required prior to each dose in Cycle 1, and in subsequent cycles as needed. Consider uric acid lowering drugs in patients at risk for TLS. Monitor for evidence of TLS during treatment and manage promptly. Withhold Kyprolis until TLS is resolved.

Pulmonary Toxicity
Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, and acute diffuse infiltrative pulmonary disease such as pneumonitis and interstitial lung disease have occurred in patients receiving Kyprolis. Some events have been fatal. In the event of drug-induced pulmonary toxicity, discontinue Kyprolis.

Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) was reported in patients treated with Kyprolis. Evaluate with cardiac imaging and/or other tests as indicated. Withhold Kyprolis for PAH until resolved or returned to baseline and consider whether to restart Kyprolis based on a benefit/risk assessment.

Dyspnea
Dyspnea was reported in patients treated with Kyprolis. Evaluate dyspnea to exclude cardiopulmonary conditions including cardiac failure and pulmonary syndromes. Stop Kyprolis for Grade 3 or 4 dyspnea until resolved or returned to baseline. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Hypertension
Hypertension, including hypertensive crisis and hypertensive emergency, has been observed with Kyprolis. Some of these events have been fatal. Monitor blood pressure regularly in all patients. If hypertension cannot be adequately controlled, withhold Kyprolis and evaluate. Consider whether to restart Kyprolis based on a benefit/risk assessment.

Venous Thrombosis
Venous thromboembolic events (including deep venous thrombosis and pulmonary embolism) have been observed with Kyprolis. Thromboprophylaxis is recommended and should be based on an assessment of the patient’s underlying risks, treatment regimen, and clinical status.

Infusion Reactions
Infusion reactions, including life-threatening reactions, have occurred in patients receiving Kyprolis. Symptoms include fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of Kyprolis. Premedicate with dexamethasone to reduce the incidence and severity of infusion reactions. Inform patients of the risk and of symptoms of an infusion reaction and to contact a physician immediately if they occur.

Thrombocytopenia
Kyprolis causes thrombocytopenia with recovery to baseline platelet count usually by the start of the next cycle. Thrombocytopenia was reported in patients receiving Kyprolis. Monitor platelet counts frequently during treatment with Kyprolis. Reduce or withhold dose as appropriate.

Hepatic Toxicity and Hepatic Failure
Cases of hepatic failure, including fatal cases, have been reported during treatment with Kyprolis. Kyprolis can cause increased serum transaminases. Monitor liver enzymes regularly. Reduce or withhold dose as appropriate.

Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (TTP/HUS)
Cases of TTP/HUS including fatal outcome have occurred in patients receiving Kyprolis. Monitor for signs and symptoms of TTP/HUS. Discontinue Kyprolis if diagnosis is suspected. If the diagnosis of TTP/HUS is excluded, Kyprolis may be restarted. The safety of reinitiating Kyprolis therapy in patients previously experiencing TTP/HUS is not known.

Posterior Reversible Encephalopathy Syndrome (PRES)
Cases of PRES have occurred in patients receiving Kyprolis. PRES was formerly known as Reversible Posterior Leukoencephalopathy Syndrome. Consider a neuroradiological imaging (MRI) for onset of visual or neurological symptoms. Discontinue Kyprolis if PRES is suspected and evaluate. The safety of reinitiating Kyprolis therapy in patients previously experiencing PRES is not known.

Embryo-fetal Toxicity
Kyprolis can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals.

Females of reproductive potential should be advised to avoid becoming pregnant while being treated with Kyprolis and the potential hazard to the fetus if Kyprolis is used during pregnancy.

ADVERSE REACTIONS
The most common adverse events occurring in at least 20% of patients treated with Kyprolis in monotherapy trials: anemia, fatigue, thrombocytopenia, nausea, pyrexia, decreased platelets, dyspnea, diarrhea, decreased lymphocyte, headache, decreased hemoglobin, cough, edema peripheral.

The most common adverse events occurring in at least 20% of patients treated with Kyprolis in the combination therapy trial: decreased lymphocytes, decreased absolute neutrophil count, decreased phosphorus, anemia, neutropenia, decreased total white blood cell count, decreased platelets, diarrhea, fatigue, thrombocytopenia, pyrexia, muscle spasm, cough, upper respiratory tract infection, decreased hemoglobin, hypokalemia.

Full prescribing information is available at www.kyprolis.com.