On April 16, 2018 Bristol-Myers Squibb Company (NYSE: BMY) reported two-year overall survival (OS) data from CheckMate -141, a Phase 3 open-label, randomized trial evaluating Opdivo (nivolumab) compared with investigator’s choice chemotherapy (cetuximab, docetaxel or methotrexate) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) after failure on platinum-based therapy (Press release, Bristol-Myers Squibb, APR 16, 2018, View Source [SID1234525334]). Patients treated with Opdivo experienced a 32% reduction in the risk of death after a minimum two years of follow-up (HR 0.68; 95% CI: 0.54 to 0.86), with a median OS of 7.7 months (95% CI: 5.7 to 8.8) compared with 5.1 months (95% CI: 4.0 to 6.2) for standard chemotherapy. The two-year survival rate for Opdivo was 16.9% (95% CI: 12.4 to 22.0) versus 6.0% (95% CI: 2.7 to 11.3) for standard chemotherapy. The safety profile for Opdivo at two-year follow-up was consistent with previous analyses from the study.

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These data will be presented today as an oral presentation (Abstract #CT116) at 4:35 PM CDT, N Hall C (Level 1) during the Updates in Immuno-Oncology Trials session at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Chicago.

"The introduction of Immuno-Oncology has the potential to change the treatment landscape of squamous cell carcinoma of the head and neck, compared with the standard of care," said Robert L. Ferris, M.D., Ph.D., a cancer immunotherapist and Director, UPMC Hillman Cancer Center, Pittsburgh, PA. "The sustained overall survival benefit demonstrated by nivolumab in this study is encouraging in SCCHN, which historically has a median survival of less than six months."

The sustained Opdivo OS benefit was observed across PD-L1 expressors and non-expressors in patients with recurrent or metastatic SCCHN. At the two-year follow-up in patients treated with Opdivo whose tumors had PD-L1 expression ≥ 1%, risk of death was reduced by 45% (HR 0.55; 95% CI: 0.39 to 0.78). For patients treated with Opdivo whose tumors had PD-L1 expression <1%, risk of death at two years was reduced by 27% (HR 0.73; 95% CI: 0.49 to 1.09) versus standard chemotherapy.

"Opdivo is the only I-O treatment for squamous cell carcinoma of the head and neck to have shown a significant overall survival benefit versus chemotherapy at the primary analysis. These two-year follow-up data show a sustained long-term overall survival benefit for patients, across PD-L1 expression levels and regardless of HPV status," said Shinta Cheng, M.D., Ph.D., development lead, Bristol-Myers Squibb. "These data showing the durability of this benefit reinforce our ongoing commitment to continuing research with the hope of delivering what matters most to patients fighting cancer: long-term survival."

There were no statistically significant differences between the two arms for PFS (HR 0.87; 95% CI: 0.68 to 1.11) for Opdivo and investigator’s choice, respectively. The safety profile of Opdivo with a two-year follow-up was consistent with previous analyses and with prior studies of Opdivo in patients with melanoma and non-small cell lung cancer. Grade 3-4 treatment-related adverse reactions occurred in 15.3% of patients receiving Opdivo versus 36.9% of patients receiving investigator’s choice.

About CheckMate -141 (Abstract #CT116)
CheckMate -141 is a global phase 3, open-label, randomized trial evaluating Opdivo versus investigator’s choice chemotherapy in patients with recurrent or metastatic SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neo-adjuvant, primary (unresectable locally advanced) or metastatic setting. Patients were included regardless of their HPV or PD-L1 status. Patients were randomized 2:1 to receive Opdivo 3 mg/kg intravenously over 60 minutes every two weeks (n=240), or investigator’s choice (n=121) of methotrexate 40 to 60 mg/m2 intravenously weekly, docetaxel 30 to 40 mg/m2 intravenously weekly, or cetuximab 400 mg/m2 intravenously once then 250 mg/m2 weekly. The primary endpoint is OS. The trial’s secondary endpoints include progression-free survival (PFS) and objective response rate (ORR).

About Head & Neck Cancer
Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, the nose and the throat. Head and neck cancer is the seventh most common cancer globally, with an estimated 400,000 to 600,000 new cases per year and 223,000 to 300,000 deaths per year. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Squamous cell carcinoma of the head and neck (SCCHN) accounts for approximately 90% of all head and neck cancers, with global incidence expected to increase by 17% between 2012 and 2022. Risk factors for SCCHN include tobacco and alcohol consumption. The human papillomavirus (HPV) infection is also a risk factor leading to rapid increase in oropharyngeal SCCHN in Europe and North America. Quality of life is often impacted for SCCHN patients, as physiological function (breathing, swallowing, eating, drinking), personal characteristics (appearance, speaking, voice), sensory function (smell and hearing), and psychological/social function can be affected.

On April 16, 2018 Only a couple weeks after Takeda Pharmaceuticals reported it was interested in buying Shire, Shire sells its oncology business to France’s Servier for $2.4 billion (Press release, BioSpace, APR 16, 2018, View Source [SID1234525333]).

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It’s possible the sale will make Shire less desirable for Takeda, since Shire’s oncology business was part of the rationale for buying the company. It’s also possible it will make it more desirable by dropping the price slightly. Reuters notes, "The [Servier} deal suggests there is value locked up within Shire’s portfolio—despite a dismal share price performance in the past two years—as its management braces for a possible $50-billion bid battle with Japan’s biggest drugmaker."

Shire has suggested the proceeds from the sale may be returned to shareholders via a buyback. It also indicated that further sales of non-strategic assets were a possibility.
Shire is making it clear that is began looking to sell its oncology business in December and began the sale process in January. In other words, they want it understood that they didn’t quickly sell off the cancer unit to fend off an unwanted Takeda acquisition.

Under UK acquisition laws, Takeda has until April 25 to announce an official bid. The market value of Shire is about $47 billion. Reuters writes, "Buying Shire would be transformational for Takeda but would be a huge financial stretch, since the company is worth around $10 billion more than the Japanese group. Shire also had debt of around $19 billion as of the end of 2017."

Shire’s oncology business includes products such as Oncaspar (pegaspargase), part of a multi-agent treatment for acute lymphoblastic leukemia (ALL) and ex-U.S. rights to Onivyde (irinotecan pegylated liposomal formulation), part of a multi-agent treatment for metastatic pancreatic cancer after gemcitabine-based therapy, and Calaspargase Pegol (Cal-PEG), which is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of ALL and early stage immuno-oncology pipeline collaborations.

"This transaction is a key milestone for Shire, demonstrating the clear value embedded in our portfolio," said Flemming Ornskov, Shire’s chief executive officer, in a statement. "While the Oncology business has delivered high growth and profitability, we have concluded that it is not core to Shire’s longer-term strategy. We will continue to evaluate our portfolio for opportunities to unlock further value and sharpen our focus on rare disease leadership with selective disposals of non-strategic assets."
Last year the Oncology business created revenues of $262 million.

If Takeda does make an official bid for Shire, this sale might make it slightly more affordable. Last year Takeda acquired Ariad Pharmaceuticals for $4.7 billion. "Shire’s decision to buy back shares may also indicate a positive view of the bid, since increasing shareholder returns would make it easier to get approval for a deal, Kazuyoshi Saito, a senior analyst for Iwai Cosmo Securities Co." told Bloomberg in a phone interview. "I have an impression that Takeda and Shire are heading in the same direction," Saito said.

Meanwhile, buying Shire’s oncology business bolster’s Servier’s presence in oncology. Olivier Laureau, Servier Group President, said in a statement, "The acquisition of Shire’s oncology franchise enables Servier to meet its strategic ambitions to become a global key player in oncology. As an essential step in the evolution of the Group, this acquisition allows us to establish a direct commercial presence in the United States, the world’s leading pharmaceuticals market, and to strengthen our portfolio of marketed products in the territories where Servier is already present. Our goal is to bring these treatments to greater numbers of cancer patients around the world. We thoroughly look forward to welcoming Shire’s oncology teams who will join Servier after the closing."

On April 16, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported that preliminary clinical data from an ongoing Phase 1 trial of its investigational PARP inhibitor pamiparib in Chinese patients with locally advanced or metastatic high-grade non-mucinous ovarian cancer (HGOC), including fallopian cancer, or triple-negative breast cancer (TNBC), who had disease progression following at least one line of chemotherapy were presented at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, being held in Chicago (Press release, BeiGene, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342698 [SID1234525331]). Data presented from the dose-escalation phase of the ongoing Phase 1 trial confirmed the recommended Phase 2 dose (RP2D) of 60mg twice daily (BID) in Chinese patients and demonstrated that pamiparib showed antitumor activity and was generally well tolerated in these patients.

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"In these heavily pre-treated patients with ovarian and breast cancers, the preliminary results support the recommended pamiparib dosing regimen and demonstrated antitumor activity, including partial responses in platinum-resistant or refractory patients with ovarian cancer. We saw no dose-limiting toxicities and found pamiparib to be generally well tolerated among these patients," said Binghe Xu, M.D., Director of the Department of Medical Oncology, at the Cancer Hospital, Chinese Academy of Medical Sciences in Beijing, China, and the lead author of the poster presentation.

"In China, there are no currently approved PARP inhibitors, yet there are an aggregate of approximately 75,000 new cases of ovarian cancer1 and triple-negative breast cancer diagnosed each year1,2, and it is estimated that between 25 and 30 percent of ovarian cancer3 and between 15 and 204 percent of triple-negative breast cancer patients harbor a germline mutation in BRCA1/2 and therefore may benefit from a PARP inhibitor. We look forward to advancing pamiparib’s development in China as well as initiating a global Phase 3 trial," commented Amy Peterson, M.D., Chief Medical Officer for Immuno-Oncology of BeiGene.

Summary of Results from the Ongoing Phase 1 Trial
This open-label, multi-center Phase 1 dose-escalation trial of pamiparib (NCT03333915) was designed to confirm RP2D and to evaluate its safety, tolerability and antitumor activity in Chinese patients with locally advanced or metastatic HGOC, including fallopian and primary peritoneal cancer, or patients with TNBC. Patients were dosed at 20mg, 40mg, or 60mg BID. As of September 25, 2017, 15 female patients were enrolled, nine with HGOC and six with TNBC. Nine patients received four or more prior lines of therapies. All nine patients with HGOC were platinum-resistant (n=8) or refractory (n=1). Seven patients had a confirmed BRCA1/2 mutation (BRCAm), including five patients with HGOC and two patients with TNBC and the remaining patients had BRCA 1/2 wildtype (BRCA-WT). The median duration of treatment was 2.5 months (range: 8-260 days).

Pamiparib was shown to be generally well tolerated. No dose-limiting toxicities were reported across the dose range, with RP2D confirmed as 60mg BID. Asthenia (n=12) and nausea (n=12) were the most commonly reported treatment-emergent adverse events (AE). Severity of all adverse events was grade 3 or less. Overall, three patients experienced a serious AE (grade 2 abdominal infection, n=1; grade 3 pleural effusion, n=1; grade 3 ileus, n=1), none of which were considered related to treatment. Two of the serious AEs led to treatment withdrawal (abdominal infection, n=1; pleural effusion, n=1).

As of September 25, 2017, 13 of the 15 patients were evaluable for antitumor activity; five patients remained on treatment. Two of the nine HGOC patients achieved a confirmed partial response including one platinum-refractory patient with BRCA wildtype status and one platinum-resistant patient with BRCA1/2 mutation, six HGOC patients had stable disease (BRCAm, n=4 and BRCA-WT, n=2) and one patient discontinued before the first radiographic assessment. Of the six treated TNBC patients, five (BRCAm, n=1, BRCA-WT, n=4) experienced disease progression and one patient (BRCAm) discontinued before the first radiographic assessment. Four of these evaluable TNBC patients were BRCA-WT and all experienced disease progression during the previous platinum-based chemotherapy.

About Pamiparib
Pamiparib (BGB-290) is an investigational inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP–DNA complex trapping in preclinical models. Pamiparib is being evaluated in a pivotal clinical trial in China. It is currently in global clinical development as a monotherapy, and in combination with other agents, including BeiGene’s investigational anti-PD1 antibody, tislelizumab (BGB-A317), for a variety of solid tumor malignancies.

On April 16, 2018 BeiGene, Ltd. (NASDAQ:BGNE), a commercial-stage biopharmaceutical company focused on developing and commercializing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported that the first patient was dosed in a global Phase 2 clinical trial of tislelizumab, an investigational anti-PD-1 antibody, in patients with relapsed or refractory mature T- and natural killer (NK)-cell lymphomas (Press release, BeiGene, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342635 [SID1234525330]). Tislelizumab is also being studied in global Phase 3 trials in solid tumors, including non-small cell lung cancer, hepatocellular carcinoma, and esophageal squamous cell carcinoma, and two pivotal Phase 2 trials in China in relapsed/refractory classical Hodgkin lymphoma and urothelial cancer.

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"We are pleased to be enrolling patients in our first global Phase 2 study in hematology of tislelizumab, for which we maintain global development and commercial rights," commented John V. Oyler, Founder, Chief Executive Officer, and Chairman of BeiGene.

"We believe that patients with relapsed or refractory mature T-cell and NK-cell lymphomas represent a significant unmet need. There are no currently approved treatments for the majority of mature T-cell lymphomas, in particular extranodal NK/T-cell lymphomas. We believe that these virally-associated diseases represent logical targets for checkpoint inhibition and we are excited to evaluate tislelizumab as a potential treatment option for these patients," commented Jane Huang, M.D., Chief Medical Officer, Hematology, at BeiGene.

The Phase 2, open-label, multi-center trial is designed to assess the efficacy and safety of tislelizumab in patients with relapsed or refractory mature T- and NK-cell neoplasms. Patients will receive 200 mg of tislelizumab every three weeks in each of the trial’s two histological cohorts:

Cohort 1 – patients with relapsed or refractory extranodal NK/T cell lymphoma (nasal or non-nasal type); and
Cohort 2 – patients with other mature T-cell neoplasms, limited to histologies including peripheral T-cell lymphoma not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma.
Approximately 90 patients who had previously received appropriate first-line systemic therapy and experienced disease progression are planned to be enrolled in Greater China (including Hong Kong and Taiwan), Italy, Germany, France and the United States. The primary efficacy endpoint is objective response rate as determined by independent central review. Secondary endpoints include duration of response, progression-free survival, overall survival, rate of complete response or complete metabolic response, and time to response.
"Tislelizumab has shown promising anti-tumor activity and has been generally well-tolerated in clinical trials to-date in patients with a variety of cancers. We are excited to test the efficacy and safety of this agent in NK/-T cell lymphomas, where new treatment options are badly needed," said Huiqiang Huang, M.D., Chief Physician at the Sun Yat-sen University Cancer Center, Guangdong Province, China, and a member of the steering committee of the trial.
For more information about the trial, patients and physicians should email BeiGene at [email protected].
About Mature T- and NK-cell Neoplasms

T-lymphocytes (T-cells) are a type of white blood cell that can develop into lymphoma, or blood cancer. T-cell lymphomas account for approximately 10-15 percent of all non-Hodgkin’s lymphomas.i Natural killer (NK) cell neoplasms are more rare but are generally grouped with other T-cell lymphomas.ii The World Health Organization classifies several different types of leukemia under the term Mature (peripheral) T-cell Neoplasms (abnormal mass of tissue or blood), including: T-cell prolymphocytic leukemia, T-cell granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell lymphoma/leukemia (HTLV-1 positive), extranodal NK/T-cell lymphoma/ nasal type, enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, subcutaneous panniculities-like T-cell lymphoma, mycosis fungoides/Sezary syndrome, anaplastic large-cell lymphoma, T-/null cell, primary cutaneous type; peripheral T-cell lymphoma; angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma, T-/null cell, primary systemic type.

About Tislelizumab
Tislelizumab (BGB-A317) is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. Tislelizumab has demonstrated high affinity and specificity for PD-1. It is potentially differentiated from the currently approved PD-1 antibodies in an engineered Fc region, which is believed to minimize potentially negative interactions with other immune cells, based on preclinical data. Tislelizumab is being developed as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers. BeiGene and Celgene Corporation have a global strategic collaboration for the development of tislelizumab in solid tumor cancers outside of Asia (except Japan).

On April 16, 2018 Aptose Biosciences Inc. (NASDAQ:APTO) (TSX:APS) reported the presentation of preclinical data demonstrating the robust cell killing ability of CG’806, a pan-FLT3/pan-BTK inhibitor, in multiple types of AML and B-cell malignancies (Press release, Aptose Biosciences, APR 16, 2018, View Source;p=RssLanding&cat=news&id=2342648 [SID1234525329]). Data further demonstrated that CG’806 targets multiple pathways and overcomes drug resistance seen with other inhibitors. The data were presented in a poster on Sunday, April 15, 2018 at the 2018 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Conference being held April 14-18, in Chicago, IL.

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The poster, entitled CG’806, a first-in-class pan-FLT3/pan-BTK inhibitor, targets multiple pathways to kill diverse subtypes of acute myeloid leukemia and B-cell malignancy in vitro, explores the potency and molecular mechanisms of the pan-FLT3/pan-BTK inhibitor CG’806 in hematologic malignancies relative to other FLT3 or BTK inhibitors commercialized or in development. The Aptose research team led by Dr. Hannah Zhang, Senior Director of Research, demonstrated that in FLT3-ITD AML cells, CG’806 induced apoptosis through inhibition of FLT3 signaling, and CG806 was approximately 10-fold more potent than quizartinib. Although FLT3-ITD is found in approximately 30% of AML patient, most AML patients express wild type (WT) FLT3. CG’806 was superior to quizartinib, gilteritinib and crenolanib FLT3 inhibitors in FLT3-WT AML cell lines. In B cell malignancies, BTK signaling plays a pivotal pathogenic role. CG’806 decreased BTK phosphorylation in all malignant B cell lines tested and inhibited cell proliferation and colony formation 50-6,000 times more potently than ibrutinib, an effect explained by the ability of CG’806 to target multiple rescue pathways rather than merely the exclusive inhibition of BTK signaling.

CG’806 demonstrated the ability to target all wild type (WT) and mutant forms of FLT3 and BTK and to inhibit multiple signaling pathways, producing killing of diverse subtypes of hematologic malignancies driven by different genomic aberrations.

"This study directly compares CG’806 to other FLT3 or BTK inhibitors in development and confirms the potent and extended activity we have seen with the molecule," said William G. Rice, Ph.D., Chairman and Chief Executive Officer of Aptose. "As a pan-FLT3/pan-BTK multi-kinase inhibitor that can eliminate tumors in the absence of toxicity in animal models, CG’806 has demonstrated the ability to kill a broad range of AML and B-cell malignancies through inhibition of multiple oncogenic pathways. We are eager to pursue its clinical development."
Separately, Aptose and Oregon Health & Science University (OHSU) Knight Cancer Center researchers also announced new data on CG’806 presented at AACR (Free AACR Whitepaper) (see press release here). Both poster presentations will be published in the AACR (Free AACR Whitepaper) Conference Proceedings. The posters can also be accessed here or at the Publications & Presentations section of the Aptose website, www.aptose.com.

About CG’806
CG‘806 is an oral, first-in-class pan-FLT3/pan-BTK multi-kinase inhibitor. This small molecule demonstrates potent inhibition of wild type and mutant forms of FLT3 (including internal tandem duplication, or ITD, and mutations of the receptor tyrosine kinase domain and gatekeeper region), eliminates acute myeloid leukemia (AML) tumors in the absence of toxicity in murine xenograft models, and represents a potential best-in-class therapeutic for patients with AML. Likewise, CG’806 demonstrates potent, non-covalent inhibition of the wild type and Cys481Ser mutant forms of the BTK enzyme, as well as other oncogenic kinase pathways operative in B cell malignancies, suggesting CG’806 may be developed for various B cell malignancy patients (including CLL, MCL, DLBCL and others) that are resistant/refractory/intolerant to covalent BTK inhibitors. CG’806 is currently in preclinical development in partnership with CrystalGenomics.