On December 10, 2018 Merck KGaA, Darmstadt, Germany, a leading science and technology company, which operates its healthcare business in the U.S. and Canada as EMD Serono, reported that the US Food and Drug Administration (FDA) has granted orphan drug designation (ODD) to M7824, the first regulatory designation for the bifunctional immunotherapy, for the treatment of biliary tract cancer (BTC) (Press release, Merck KGaA, DEC 10, 2018, View Source [SID1234531987]). The FDA orphan drug designation follows the recent presentation of the first clinical data for M7824 in BTC at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) congress in October. M7824 is an investigational bifunctional immunotherapy designed to combine co-localized blocking of the transforming growth factor-β and anti-PD-L1 immune escape mechanisms.

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BTC is a collective term for a group of rare and aggressive gastrointestinal cancers, including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder carcinoma (GBC).[1] Approximately 16,000 cases of BTC are estimated to occur every year in the US and collectively these cancers present late in the majority of patients. [1],[2] Treatment options are limited and the median survival rate in the advanced setting is less than one year, objective tumor response with commonly used chemotherapy is typically less than 10% with short duration of response. [1],[3],[5]

"Biliary tract cancer is a rare, notoriously hard-to-treat tumor where existing treatment approaches, such as surgery or chemotherapy, are either not viable or simply don’t deliver acceptable patient outcomes," said Luciano Rossetti, Head of Global Research & Development at the Biopharma business of Merck KGaA, Darmstadt, Germany. "As the first regulatory designation for M7824, Merck KGaA, Darmstadt, Germany is excited about the potential of this new class of immunotherapy in a number of challenging cancers and settings."

The first clinical data for M7824 in BTC, presented at the ESMO (Free ESMO Whitepaper) congress in October, demonstrated clinical activity in Asian patients who had progressed after platinum-based first-line treatment. The ORR among the total of 30 patients was 20%, as assessed by IRC, and responses were observed across PD-L1 levels with a duration of response ranging from 8.3 months to 13.9+ months. Grade 3 or higher TRAEs were experienced by 10 patients (33.3%) and the most common Grade 3 TRAEs were rash (10%) and lipase increase (10%).

FDA Orphan Drug Designation (ODD) is granted to medicines intended to treat rare diseases or disorders that affect fewer than 200,000 people in the US, or those that affect more than 200,000 people but are unlikely to recover the costs of developing and marketing the drug. Medicines that meet the FDA’s ODD criteria qualify for a number of incentives to help support advancement.

M7824 is an investigational bifunctional immunotherapy that combines a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein. Designed to combine co-localized blocking of the two immunosuppressive pathways, M7824 is thought to control tumor growth by potentially restoring and enhancing anti-tumor responses. M7824 is an important part of a novel combination approach that seeks to harness the power of the immune system and address the tremendously complex nature of difficult-to-treat tumors. To-date, more than 670 patients with various types of solid tumors have been treated across the program with M7824. In addition to BTC, M7824 is being studied in solid tumor indications, including non-small cell lung, HPV associated tumors and gastrointestinal cancers, such as gastric cancer, esophageal squamous cell carcinoma and esophageal adenocarcinoma.

About M7824

M7824 is an investigational bifunctional immunotherapy that is designed to combine a TGF-β trap with the anti-PD-L1 mechanism in one fusion protein. M7824 is designed to combine co-localized blocking of the two immunosuppressive pathways – targeting both pathways aims to control tumor growth by potentially restoring and enhancing anti-tumor responses. M7824 is currently in Phase I studies for solid tumors, as well as a trial to investigate M7824 compared with pembrolizumab as a first-line treatment in patients with PD-L1 expressing advanced NSCLC. The multicenter, randomized, open-label, controlled study is evaluating the safety and efficacy of M7824 versus pembrolizumab as a monotherapy treatment.

About the FDA Orphan Designation

FDA orphan drug designation is granted to drugs intended to treat rare diseases or disorders that affect fewer than 200,000 people in the US, or those that affect more than 200,000 people, but are unlikely to recover the costs of developing and marketing the drug. Orphan drug designation by the FDA qualifies the sponsor for incentives provided for in the Orphan Drug Act, which can include protocol assistance for clinical trials, prescription drug user fee waivers, tax incentives and seven years of market exclusivity. The granting of an orphan drug designation does not alter the standard regulatory requirement to establish the safety and effectiveness of a drug through adequate and well-controlled studies to support approval. The orphan drug designation for M7824 applies only to BTC.

About Biliary Tract Cancer (BTC)

BTC is a collective term for a group of rare and aggressive gastrointestinal cancers, including intrahepatic cholangiocarcinoma (iCC), extrahepatic cholangiocarcinoma (eCC), and gallbladder carcinoma (GBC).[1] Surgery is the only curative treatment, but most patients present with advanced disease and therefore have a limited survival.[1] Approximately 140,000 cases of BTC are estimated to occur annually world-wide.[2] However, incidence of BTC varies in different parts of the world: the incidence of cholangiocarcinomas is rising in the Western world, with reports of up to 2 in 100,000[4]. By contrast, in Asian countries, the incidence is much higher.[4] GBC also has an incidence of 2 in 100,000, but is much more prevalent in parts of South America.[4]
Collectively these cancers present late in the majority of patients and long-term outcomes for resectable patients are poor with median survival in the advanced setting less than 1 year.[1],[3]

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On December 10, 2018 Genomic Health, Inc. (NASDAQ: GHDX) reported results from multiple Oncotype DX Breast Recurrence Score (RS) presentations at the 2018 San Antonio Breast Cancer Symposium (SABCS), reinforcing the value of the Oncotype DX test in optimizing treatment and outcomes in patients with both node-negative and node-positive early-stage breast cancer (Press release, Genomic Health, DEC 10, 2018, View Source [SID1234532003]).

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Among the data presented at SABCS are two presentations from investigators involved in the landmark TAILORx (Trial Assigning IndividuaLized Options for Treatment (Rx)) trial, which provided independent analysis using the Oncotype DX test to gain further information about chemotherapy benefit across ethnic groups and chemotherapy effect on quality of life. Other presentations included the first report of long-term outcomes from the Surveillance, Epidemiology, and End Results (SEER) registry program of the National Cancer Institute (NCI) on early-stage patients with node-positive disease not treated with chemotherapy and the first study specifically focused on the Oncotype DX test in women less than 40 years of age.

"With the practice-changing results of TAILORx and new real-world evidence in more the 80,000 patients, the Oncotype DX test is being increasingly used in the United States and around the world to contribute to smarter cancer care and improved outcomes for breast cancer patients," said Steven Shak, M.D., chief scientific officer and chief medical officer, Genomic Health.

Independent Analyses Reinforce TAILORx Conclusions
As follow-up to the TAILORx results that were published by the ECOG-ACRIN Cancer Research Group in the New England Journal of Medicine in June 2018, Kathy S. Albain, M.D., FACP, professor of medicine, Loyola University Chicago Stritch School of Medicine, evaluated outcomes among patients of different races and/or ethnic backgrounds. These findings reported at SABCS reinforce the original TAILORx results, showing that chemotherapy in early-stage breast cancer can be safely avoided if the Recurrence Score result is less than 26 in women of all races/ethnicities, including Black, Hispanic and Asian women.

Results of a separate TAILORx sub-study, presented at SABCS by Lynne I. Wagner, Ph.D., professor, Social Sciences and Health Policy at Wake Forest School of Medicine, provide additional evidence regarding the negative impact of chemotherapy on patient quality of life. These results underscore the value of the Oncotype DX Breast Recurrence Score in avoiding unnecessary chemotherapy in the majority of patients with node-negative breast cancer.

Additionally, real-world evidence from a more than 80,000 patient study based on an analysis of data from the SEER registry program of the NCI reinforced findings from multiple clinical trials, including TAILORx, and confirmed that the Oncotype DX Breast Recurrence Score result is predictive of chemotherapy benefit in patients with node-negative disease (p=0.009), with no chemotherapy benefit with RS results less than 26. In patients with node-negative disease and RS results less than 26 not treated with chemotherapy, the Breast Cancer Specific Survival (BCSS) was greater than 96 percent at nine years. In patients with node-positive disease not treated with chemotherapy and RS results less than 18, BCSS was greater than 97 percent at nine years.

"The SEER nine-year real-world evidence supports the new TAILORx-defined paradigm for Recurrence Score-guided chemotherapy treatment using the cutoff of 26," said Gabriel N. Hortobagyi, M.D., FACP, program director, Department of Breast Medical Oncology, Division of Susan G. Komen Interdisciplinary Breast Fellowship Program, The University of Texas MD Anderson Cancer Center. "Importantly, these long-term SEER results also support the option of hormone therapy alone for patients with one to three positive nodes and an Oncotype DX Recurrence Score less than 18."

Finally, investigators at Dana-Farber led a multi-center study to prospectively analyze Oncotype DX test results in 500 young women with node-positive and node-negative breast cancer. The findings showed very good outcomes for those with a RS of 0 to 25 who were not treated with chemotherapy. These results provide further evidence of the unique value of the Oncotype DX test to guide chemotherapy treatment decision-making in early-stage breast cancer in patients age 40 or younger.

About Oncotype DX
The Oncotype DX portfolio of breast, colon and prostate cancer tests applies advanced genomic science to reveal the unique biology of a tumor in order to optimize cancer treatment decisions. The company’s flagship product, the Oncotype DX breast cancer test, has been shown to predict the likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer. Additionally, the test predicts the likelihood of recurrence in a pre-invasive form of breast cancer called DCIS. With more than 950,000 patients tested in more than 90 countries, the Oncotype DX tests have redefined personalized medicine by making genomics a critical part of cancer diagnosis and treatment. To learn more about Oncotype DX tests, visit www.OncotypeDX.com or www.MyBreastCancerTreatment.org.

On December 8, 2018 Context Therapeutics, a clinical-stage biotechnology company, reported new preclinical data on Apristor (onapristone extended release), its first-in-class full progesterone receptor antagonist, showing that the investigational medicine inhibits tumor cell line growth in hormone receptor positive (HR+) breast cancer cell lines (Press release, Context Therapeutics, DEC 8, 2018, View Source [SID1234531939]). Additionally, it was shown that Apristor is synergistic with current standard of care therapies for HR+ metastatic breast cancer, including the Cdk4/6 inhibitor Ibrance (palbociclib) and the selective estrogen receptor degrader Faslodex (fulvestrant).

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"Progesterone receptor is the forgotten target", said Carol Lange, PhD, Professor of Medicine at the University of Minnesota and principal investigator of the research presentation. "HR+ breast cancer is driven by two hormones, estrogen and progesterone. While there are over half a dozen approved medicines to block estrogen and estrogen-related signaling, there are no FDA approved medicines in cancer to block progesterone. The data presented shows that blocking progesterone-related signaling via Apristor is not only active alone in tumor models but it also enhances the activity of medicines that either directly or indirectly target estrogen."

The data presented shows that:

Progesterone / progesterone peceptor (PR) is a unique target distinct from estrogen / estrogen receptor

PR is critical for in vitro growth of HR+ breast cancer cells

PR antagonism via Apristor reduces the expression of cancer promoting genes

PR antagonism is synergistic with Cdk4/6 inhibitors and a SERD

"We are encouraged by these new preclinical data, which speak to the important role PR plays in facilitating HR+ breast cancer disease progression," said Deepak Lala, PhD, Chief Technology Officer of Context. "This is the first study to show that PR antagonism is synergistic with new treatment modalities, including Cdk4/6 inhibition. "

About Apristor

Apristor (onapristone extended release) is Context’s wholly owned, first-in-class, orally active extended release formulation of onapristone, a full progesterone receptor antagonist. Progesterone receptor [PR] plays a critical role in facilitating breast cancer disease progression as well as therapeutic resistance to first line antiestrogen and/or Cdk4/6 inhibitor therapies. Apristor is the only full PR antagonist that is being developed to target breast cancer. Apristor has the potential to transform the treatment of breast cancer, through the potent inhibition of PR signaling thereby blocking breast cancer cell proliferation and overcoming resistance to first line antiestrogen and Cdk4/6 inhibitor therapy.

On December 8, 2018 Samsung Bioepis Co., Ltd. reported the results of an additional one-year follow-up study comparing event-free survival (EFS) of SB3, a biosimilar candidate referencing HERCEPTIN 1 (trastuzumab), to reference trastuzumab (TRZ) by antibody-dependent cell-mediated cytotoxicity (ADCC) activity (Press release, Samsung Bioepis, DEC 8, 2018, View Source [SID1234531973]). ADCC is a key mechanism of action for trastuzumab. The study results are being presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) which is being held December 4-8, 2018 in San Antonio, Texas.

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For the study, patients with HER2 positive early or locally advanced breast cancer were randomly assigned to receive SB3 or TRZ concurrently with chemotherapy. Patients then underwent surgery followed by treatment with SB3 or TRZ. Following completion of such therapy, 367 patients participated in a long-term follow-up study, 186 of whom were treated with SB3 and 181 of whom were treated with TRZ. Within the group of 181 patients who received TRZ, 126 patients who were exposed to at least one kit from the TRZ lots with expiry dates between August 2018 and December 2019 during neoadjuvant period were considered "Exposed," while the remaining 55 patients were considered "Unexposed." Upon monitoring the quality attributes of TRZ for the development of SB3, a marked downward shift in ADCC activity was observed in some of the TRZ lots with expiry dates between August 2018 and December 2019.

Following 30.1 months of SB3 treatment and 30.2 months of TRZ treatment, there was no statistically significant difference in EFS between SB3 (96.7%) and the Unexposed arm (98.2%) (HR 1.19, 95% CI 0.23-6.18; p-value=0.8376). However, the results did show statistically significant difference in EFS between the Unexposed (98.2%) and Exposed (92.5%) arms within the TRZ treatment group (HR 0.07, 95% CI 0.01-0.58, p-value=0.0137). In addition, while there was no statistically significant difference in events between SB3 (4.8%) and the Unexposed (3.6%) arms, there was statistically significant difference in events within the TRZ treatment group between the Unexposed (3.6%) and Exposed (10.3%) arms. An event was defined as disease recurrence or progression, or death due to any cause. The study authors are currently looking into longer-term effects of SB3 and hope to publish these results at a later date.

"This study builds on the robust evidence for SB3, and demonstrates the trastuzumab biosimilar candidate’s comparable efficacy and safety profiles to the reference biologic over a longer time period," said Chul Kim, Senior Vice President and Head of Clinical Science, Samsung Bioepis. "We remain committed to advancing our strong pipeline of biosimilar candidates, so that more patients and healthcare systems may be able to benefit from biosimilar medicines."

The poster for this study will be exhibited at SABCS, as follows:

[P6-17-09] EVENT-FREE SURVIVAL BY ADCC STATUS FROM A FOLLOW-UP STUDY COMPARING SB3 (TRASTUZUMAB BIOSIMILAR) WITH REFERENCE TRASTUZUMAB FOR HER2 POSITIVE BREAST CANCER IN NEOADJUVANT SETTING [POSTER SESSION 6, December 8, 2018, 07:00AM – 09:00AM]

On December 8, 2018 Generon BioMed Holding Ltd. (Generon), reported at the annual San Antonio Breast Cancer Symposium (SABCS), positive results from a placebo-controlled trial with F-627, a recombinant human Granulocyte Colony Stimulating Factor (rhG-CSF) protein, designed using Generon’s DikineTM technology platform (Press release, Generon (Shanghai), DEC 8, 2018, View Source [SID1234531974]).

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Led by Principle Investigator Dr. John Glaspy, Estelle, Abe and Marjorie Endowed Chair in Cancer Research at the Jonsson Comprehensive Cancer Center of UCLA, this global study of 122 woman with stage II-IV breast cancer receiving Myelotoxic chemotherapy demonstrates that subcutaneous administration of F-627 significantly reduced the duration of Grade 4 (severe) neutropenia in chemotherapy cycle 1 (P<0.0001); the mean treatment difference was 2.8 days (1.1 days vs. 3.9 days in the placebo arm). F-627 administration also resulted in lower incidence and shorter duration of Grade 4, Grade 3 and Grade 2 neutropenia. Other significant results included the finding that treatment with F-627 significantly reduced the incidence of febrile neutropenia (FN) (P<0.0016). The incidence of FN in the experimental arm was 4.8% and 28.2% in the placebo arm during cycle 1. Subjects in the experimental arm also had lower rates of antibiotic medication and pain medication use. In this study, F-627 was shown to be safe and well tolerated with no deaths, no injection site reactions and less gastrointestinal AEs (diarrhea, vomiting, stomatitis, and gastritis) than the placebo arm. During cycle 1 in the experimental arm, the five most common TEAEs (incidence rate >10%) were leukopenia, anemia, thrombocytopenia, nausea, and alopecia. Across all cycles, there were 17 SAEs from 15 subjects of which 15 were FN.

A single subcutaneous injection of F-627 significantly reduced the duration and incidence of severe neutropenia and febrile neutropenia while maintaining an excellent safety profile in patients with breast cancer undergoing high-dose chemotherapy.

Dr. Glaspy indicated that F-627 would provide an alternative treatment for patients with breast cancer and severe neutropenia secondary to myelotoxic chemotherapy. "The successful completion of this phase III trial exemplifies our continued commitment to developing innovative medicines on our various platforms that have the potential to treat patients with cancer" said Dr. William Daley, Generon’s Chief Medical Officer.

Dr. Daley also indicated that Yifan Pharmaceuticals, a controlling parent company of Generon, congratulated Generon’s team on the continued effort to develop innovative therapies. "This is yet another milestone and goal for Generon this year and is a significant step towards our mission of Innovating for Life. Generon is committed to bringing innovative oncology therapies to patients in China and the world" he commented.

About F-627

F-627, a rhG-CSF dimer, is a once-per-cycle therapy for the preventive management of neutropenia. Produced in Chinese Hamster Ovary (CHO) cells in serum-free cultures, F-627 leverages Generon’s proprietary Dimeric Cytokine (DiKineTM) technology platform to create an immunoglobulin-like dimeric structure, providing improved efficacy and a longer half-life. This product candidate is intended to treat cancer patients with neutropenia secondary to myelotoxic chemotherapy.