On June 3, 2016 Eli Lilly and Company (NYSE: LLY) reported results from the MONARCH 1 Phase 2 study of abemaciclib, a cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor, in patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (Press release, Eli Lilly, JUN 3, 2016, View Source [SID:1234512996]). The data, which were presented at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting by Maura Dickler, M.D., of Memorial Sloan Kettering Cancer Center, showed that single-agent activity was observed in metastatic breast cancer patients, for whom endocrine therapy was no longer a suitable treatment option. The MONARCH 1 results (abstract #510) confirmed objective response (ORR), durability of response (DoR), clinical benefit rate (CBR) and progression-free survival (PFS).

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The single-arm study, designed to evaluate the safety and efficacy of abemaciclib monotherapy, enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, having experienced progressive disease on or after prior endocrine therapy, and had received prior chemotherapy with one or two chemotherapy regimens for metastatic disease. The primary objective of the trial was investigator-assessed ORR, with secondary endpoints of DoR, CBR and PFS.

"After endocrine therapies are no longer considered appropriate for HR+ metastatic breast cancer patients, when the disease is refractory or aggressive, chemotherapy is the only option. The side effects can be distressing and may be long lasting, limiting the options for patients," said José Baselga, M.D., Ph.D., physician-in-chief and chief medical officer, Memorial Sloan Kettering Cancer Center, and senior study author. "To see this level of anti-tumor activity, combined with the toxicity profile observed in MONARCH 1, is compelling."

At the final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved an ORR of 19.7 percent (95% confidence interval (CI): 13.3 – 27.5%), with a median time to response of 3.7 months and a median DoR of 8.6 months. The median PFS was six months with a CBR (defined as patients who achieved complete response, partial response or stable disease for six months or longer) of 42.4 percent. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD).

"In this population of heavily pretreated patients with a particularly poor prognosis, abemaciclib has shown promising single agent activity and tolerability," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "These data reinforce our belief in abemaciclib as a potential best-in-class CDK 4 and CDK 6 inhibitor and add to the growing body of evidence that sustained target inhibition can lead to improved patient outcomes."

The safety and toxicity profile of twice daily, continuously dosed abemaciclib was consistent with previous Phase 1 experience. The most common grade 3 non-laboratory treatment emergent adverse events (AEs) were diarrhea (19.7%) and fatigue (12.9%), with no grade 4 non-laboratory events reported. The most common laboratory AEs were neutropenia (22.3% grade 3, 4.6% grade 4) and leukopenia (27.4% grade 3) in this population; 7.6 percent of patients discontinued treatment due to AEs, one due to diarrhea.

Beyond MONARCH 1, Lilly has an active clinical development program studying abemaciclib in breast cancer. Abemaciclib is being evaluated in two Phase 3 clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant for treatment of HR+, HER2- advanced or metastatic breast cancer in postmenopausal women, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in HR+, HER2- locoregionally recurrent or metastatic breast cancer in postmenopausal women.

Lilly plans to publish further data from the MONARCH 1 trial later this year.

About Metastatic Breast Cancer
Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.1 In the U.S. this year, approximately 246,660 new cases of invasive breast cancer will be diagnosed and about 40,450 people will die from breast cancer.2 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body. In addition, an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being stage IV, or metastatic.3 Metastatic breast cancer is considered incurable, but is generally treatable.

About Abemaciclib
Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK 4 and CDK 6. In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK 4 and CDK 6. Abemaciclib inhibits both CDK 4 and CDK 6, and was shown in cell-free enzymatic assays to be most active against Cyclin D 1 and CDK 4.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company’s Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

On June 3, 2016 Mylan N.V. (NASDAQ, TASE: MYL) and Biocon Ltd. (BSE code: 532523, NSE: BIOCON) reported the presentation of data from the HERITAGE study at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, June 3-7 (Press release, Mylan, JUN 3, 2016, View Source [SID:1234512980]). The study confirmed the efficacy, safety and immunogenicity of MYL-1401O, the proposed biosimilar trastuzumab co-developed by Biocon and Mylan, in comparison to branded trastuzumab.

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"As one of the first companies in the industry to successfully complete a confirmatory efficacy and safety study comparing a proposed biosimilar to a branded cancer drug, this is a significant milestone for Mylan’s biosimilar program," Mylan President Rajiv Malik said. "There is an urgent, unmet need for more affordable versions of biologic products and through our collaboration with Biocon we are well-positioned to be at the forefront to help deliver these complex products to patients around the world. We’re pleased that ASCO (Free ASCO Whitepaper) has recognized the importance of biosimilars in advancing cancer care and the significant role they will play in providing patients greater access to affordable treatment."

Kiran Mazumdar Shaw, Chairperson and Managing Director, Biocon, added: "The positive outcomes of the global Phase 3 clinical study with our proposed biosimilar trastuzumab for HER2-positive breast cancer patients are a significant milestone in our joint biosimilars development program with Mylan. The trial will enable regulatory filings of our product in the developed markets. Biocon remains committed to develop affordable biologics and these study results will help us in enhancing access for cancer patients, caregivers and healthcare systems across the globe."

Worldwide, nearly 2 million women are diagnosed with breast cancer each year, making it the second most common cancer in the world. HER2-positive metastatic breast cancer is an aggressive form of breast cancer that tests positive for the human epidermal growth factor receptor 2 (HER2), which promotes cancer cell growth. Approximately 20% to 30% of primary breast cancers are HER2-positive.

Trastuzumab is indicated for the treatment of HER2-positive metastatic breast cancer patients. It is also indicated for adjuvant treatment of HER2 overexpressing breast cancer and metastatic gastric cancer. It is a targeted therapy that interferes with the HER2 protein and impedes cancer cell growth.

"The HERITAGE study successfully met the predefined endpoints of response equivalency. We are proud of this international collaboration which puts us one step closer to approval of this proposed biosimilar. The response rates at 24 weeks were 69.6% with MYL-1401O combined with taxane chemotherapy versus 64% with branded trastuzumab combined with the same chemotherapy agent. The ratio of overall response and difference in overall response fell within a narrow, pre-defined equivalence margin suggesting equal efficacy of both products. Safety was comparable between treatment groups. The rates of serious adverse events were 38% with MYL-1401O and 36% with branded trastuzumab, and there was no difference in cardiac safety," commented lead study author Dr. Hope S. Rugo, professor of Medicine at the University of California, San Francisco.

Details of the sessions as on the ASCO (Free ASCO Whitepaper) website are as follows:
"Abstract 583: A pharmacokinetics (PK) bioequivalence trial of proposed trastuzumab biosimilar Myl-1401O (A) vs EU-Herceptin (B) and US-Herceptin ©"
June 5, 8-11 a.m. CDT (Poster Session)
Poster #71
Presenter: Cornelius F. Waller, MD, University of Freiburg Medical Center
Location: Hall A
Link to abstract on the ASCO (Free ASCO Whitepaper) website: View Source

"Abstract LBA503: HERITAGE: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin"
June 6, 2:15-2:27 p.m. CDT (Oral Abstract Session)
Presenter: Hope S. Rugo, MD, University of California, San Francisco
Location: Hall D1
Link to abstract on the ASCO (Free ASCO Whitepaper) website: View Source
The abstract for the HERITAGE study has also been selected for the Best of ASCO (Free ASCO Whitepaper) program this summer which will include several meetings across the globe.
Full session details and abstracts for the 2016 Annual Meeting can be found on the ASCO (Free ASCO Whitepaper) website at am.asco.org.

About the HERITAGE Study
HERITAGE is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of the proposed trastuzumab biosimilar, MYL-1401O, versus branded trastuzumab. Eligible patients had centrally confirmed, measurable HER2-positive metastatic breast cancer without prior chemotherapy or trastuzumab for metastatic disease. Patients were randomized to receive either MYL-1401O or branded trastuzumab with docetaxel or paclitaxel for a minimum of eight cycles. Trastuzumab was continued until progression. The primary endpoint is overall response at week 24 by blinded central evaluation using RECIST 1.1. Secondary endpoints include progression free survival, overall survival, and safety. A sample size of 456 patients was calculated to demonstrate equivalence in overall response at week 24 for MYL-1401O versus branded trastuzumab, defined as a 90% confidence interval for the ratio of best overall response within the equivalence margin (0.81, 1.24).

About Biosimilars
A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine and has demonstrated no clinically meaningful differences in safety, purity, and potency compared to that of the reference biologic. A biosimilar product and its reference biologic product are expected to have the same safety and efficacy profile and are generally used to treat the same conditions. Biosimilars may offer a less-costly alternative to existing biological medicinal products that have lost their exclusivity rights.

On June 3, 2016 CellAct Pharma, a developer of innovative treatments for cancer, reported that population pharmacokinetic (PK) data from a phase 2 study of CAP7.1 supports efficacy findings in biliary tract cancer patients. CAP7.1 is a newly designed prodrug of the well-established anticancer agent etoposide, converted by carboxylesterases into etoposide in selected tissues (Press release, CellAct Pharma, JUN 3, 2016, View Source [SID:1234512981]). Analysis of the population PK indicated higher blood concentrations of etoposide resulted in the majority of patients maintaining an increase in tumor size below 20%. Data were published in conjunction with the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract e15602).

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"Population pharmacokinetics is an important consideration in the drug development process as it helps to explain the variable effects of certain inter patient characteristics, such as age, body weight and co-medication, can have on a drug’s efficacy and safety. The data presented at ASCO (Free ASCO Whitepaper) will help in determining a standard dosing regimen for CAP7.1," explained Nalân Utku, MD, PhD, MDRA, Chief Executive Officer of CellAct Pharma. "These population PK data provide additional support to the results from our Phase 2 with CAP7.1, where encouragingly, planned interim analysis showed that more than half of therapy refractory, advanced stage biliary tract cancer patients met the primary objective of disease control, as presented at the ASCO (Free ASCO Whitepaper) GI Meeting in San Francisco."

Study Details

Data for the population PK model was analyzed from a total of 434 observations taken from 39 patients from Phase 1 and 2 studies. Using PK modeling software, etoposide AUC0-24h, cmax and cmin for each biliary cancer patient were simulated and compared with the individual changes in total target lesion (TTL) size. A higher AUC0-24h was found to be associated with a lower increase in TTL size (R2=0.172). Out of all patients for which PK information was available, 50% maintained a TTL size increase below 20%. This compared to 80% of patients with an 24hAUC > 120 h ug/mL who maintained a TTL size increase below 20%. Similarly, a higher cmax (R2=0.177) or cmin (R2=0.11) were associated with a larger effect on TTL size.

On June 3, 2016 Bayer and Orion Corporation reported the expansion of the global clinical development program for the investigational androgen receptor (AR) antagonist BAY-1841788 (ODM-201) in the area of prostate cancer (Press release, Bayer, JUN 3, 2016, View Source;sessionID=1464982658 [SID:1234512984]). A new Phase III study ARASENS will evaluate the compound in combination with standard androgen deprivation therapy (ADT) and the chemotherapy docetaxel in men with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), who are starting first line hormone therapy. BAY-1841788 (ODM-201) is an investigational oral AR-antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. The compound is currently in Phase III development ARAMIS study for high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). The new trial ARASENS is expected to start the enrolment of patients towards the end of 2016.

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"Although the treatment options for patients with advanced prostate cancer who are castration-resistant have evolved considerably in recent years, there were only few advances in the earlier, hormone-sensitive stage of metastatic disease. Novel treatment approaches are urgently needed for patients to delay the progress of the cancer and improve survival," said Dr. Joerg Moeller, member of the Executive Committee of Bayer AG’s Pharmaceutical Division and Head of Development. "Bayer’s commitment to prostate cancer research runs deep, and the initiation of ARASENS is the latest in a long line of studies designed to evaluate treatment options for patients with advanced disease."

Bayer and Orion have recently expanded the 2014 agreement to include the joint development of BAY-1841788 (ODM-201) for mHSPC. Under that agreement, Bayer will commercialize the product globally; Orion has the option to co-promote BAY-1841788 in Europe, and is responsible for the manufacturing of the product.

"We believe that the profile of ODM-201 makes it an excellent treatment candidate for patients with metastatic hormone-sensitive prostate cancer. This is another example of how Orion’s oncology research is aiming to contribute to the benefit of patients. We are also happy to see Bayer’s continuous commitment to ODM-201", said Dr. Reijo Salonen, Senior Vice President of R&D at Orion.

About ARASENS
ARASENS (A Randomized, double-blind, placebo-controlled Phase III study of ODM 201 versus placebo in addition to standard Androgen deprivation therapy and docetaxel in patients with metastatic castration SENSitive prostate cancer) is planned to be initiated towards the end of 2016. Approximately 1,300 patients will be randomized (1:1 ratio) to receive either BAY-1841788 or placebo in combination with an ADT of investigator’s choice (LHRH agonist/antagonists or orchiectomy), started ≤12 weeks before randomization. Six cycles of docetaxel will be administered after randomization. The primary endpoint of the study is overall survival, and secondary endpoints include time to castration-resistant prostate cancer (time to CRPC), time to initiation of subsequent antineoplastic therapy, symptomatic skeletal event free survival (SSE-FS), time to first symptomatic skeletal event (time to SSE), time to initiation of opioid use, time to pain progression, time to worsening of physical symptoms of disease and safety.

ARASENS adds to the ongoing clinical development program for BAY-1841788, which includes ARAMIS (NCT02200614), a randomized, Phase III, multicenter, double-blind, placebo-controlled trial evaluating patients with non-metastatic CRPC who are at high risk for developing metastatic disease. ARAMIS is currently enrolling patients.
 
About Metastatic Hormone-Sensitive Prostate Cancer
Prostate cancer (PC) is the second most common form of cancer worldwide and the fifth leading cause of cancer-related death in men. More than 1.1 million men worldwide were diagnosed with the disease in 2012.

At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately five percent of men will already suffer from prostate cancer with distant metastases when first diagnosed. Men with newly diagnosed metastatic hormone-sensitive prostate cancer (HSPC) will start their treatment with hormone therapy, such as ADT or a combination of the chemotherapy docetaxel and ADT. Despite this first line treatment, most men with metastatic HSPC will eventually progress to castration-resistant prostate cancer (CRPC), which can impact survival and quality of life.

About BAY-1841788 (ODM-201)
BAY-1841788 (ODM-201) is an investigational oral androgen receptor (AR) antagonist that has a unique chemical structure designed to block the growth of cancer cells through binding to the AR with high affinity and inhibiting the receptor function. In preclinical studies, BAY-1841788 and its main circulating metabolite are active also in known AR mutants (ex W742L, F877L), and have been found to have negligible blood-brain barrier penetration.

BAY-1841788 (ODM-201) is not approved by the U.S. Food and Drug Administration, the European Medicines Agency or any other health authority.

On June 2, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported that it has completed the sale of its European operations to Incyte Corporation and entered into the previously announced license agreement for Incyte to exclusively license Iclusig (ponatinib) in Europe and other select countries (Press release, Ariad, JUN 2, 2016, View Source;p=RssLanding&cat=news&id=2174467 [SID:1234512951]).

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ARIAD transferred all rights to its EU operations to Incyte, which has acquired all shares of ARIAD Pharmaceuticals (Luxembourg) S.a.r.l., the parent company of ARIAD’s European subsidiaries responsible for the commercialization of Iclusig in the licensed territory, for a payment to ARIAD at the closing of approximately $140 million (subject to customary post-closing adjustments). In addition, Incyte has now been granted an exclusive license to develop and commercialize Iclusig in the European Union and 22 other countries, including Switzerland, Norway, Turkey, Israel and Russia.

"With the closing of this transaction, we have completed a key outcome from our strategic review," stated Paris Panayiotopoulos, president and chief executive officer of ARIAD. "This agreement puts ARIAD in a strong financial position. It will allow us to focus our resources on our promising R&D initiatives and our efforts to achieve the full commercial potential of Iclusig and brigatinib, if approved, in the highly valuable U.S. market, while also maintaining future strategic flexibility through the buy-back provision for the licensed Iclusig rights."

In connection with the closing of the Incyte transaction, the previously disclosed amendments to ARIAD’s royalty financing agreement with PDL BioPharma, Inc. (PDL), entered into on May 9, 2016, became effective. ARIAD and PDL agreed to amend the agreement to, among other things, include net sales of Iclusig made by Incyte in the calculation of net sales under the PDL agreement and to restructure ARIAD’s option to receive additional funding so that ARIAD may require PDL to fund up to an additional $40 million (instead of the original $100 million) in July 2017, rather than between January and July 2016.

Baker & McKenzie LLP represented ARIAD in the Incyte transaction, and Mintz, Levin, Cohn, Ferris, Glovsky & Popeo, P.C. represented ARIAD in the PDL transaction.

About Iclusig (ponatinib) tablets

Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs.

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning, for additional important safety information.

In the EU, Iclusig is approved for the treatment of adult patients with chronic phase, accelerated phase or blast phase chronic myeloid leukemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation, or the treatment of adult patients with Philadelphia-chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.