On July 21, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the EU Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for TECENTRIQ (atezolizumab) as a monotherapy for the treatment of adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) after they have been previously treated with chemotherapy (Press release, Hoffmann-La Roche, JUL 21, 2017, View Source [SID1234519843]). People with EGFR activating mutations or ALK positive tumour mutations should also have received targeted therapy before receiving TECENTRIQ. This positive recommendation is based on results from the large randomised Phase III OAK study and the randomised Phase II POPLAR study. The CHMP has also adopted a positive opinion for the use of TECENTRIQ as a monotherapy for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) who have been previously treated with a platinum based chemotherapy or who are considered ineligible for cisplatin chemotherapy. This positive opinion is based on results from the randomised Phase III IMvigor211 study and cohorts 1 and 2 from the single-arm Phase II IMvigor210 study.

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"This positive CHMP opinion represents great news for people living with either advanced lung or bladder cancer because, despite recent developments, long-term survival rates for people with these cancers are inferior to those with other common cancers," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "We are encouraged that the CHMP considered the totality of the data for TECENTRIQ including the importance of key clinical endpoints, such as long-term responses."
Based on this positive CHMP opinion, a final decision from the European Commisssion is expected in the near future. TECENTRIQ is already approved in the US and in a number of other countries for people with metastatic NSCLC; and for people with locally advanced or mUC and who are not eligible for cisplatin chemotherapy, or who have disease progression during or following platinum-containing therapy.
About the OAK study
OAK is a global, multicentre, open-label, randomised, controlled Phase III study that evaluated the efficacy and safety of TECENTRIQ compared with docetaxel. It enrolled 1225 patients with both squamous and non-squamous disease, regardless of the programmed death-ligand 1 (PD-L1) status of their tumours, and randomised them (1:1) to receive either TECENTRIQ administered intravenously at 1,200 mg every 3 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The co-primary endpoints were overall survival (OS) in the first 850 randomised patients (intention-to-treat population) and in a PD-L1-selected subgroup of this primary analysis population.
The OAK study showed that TECENTRIQ helped people in the overall study population live a median of 13.8 months – 4.2 months longer than those treated with docetaxel chemotherapy (median overall survival [OS]: 13.8 vs. 9.6 months; HR = 0.73, 95% CI: 0.62, 0.87).


CI=confidence interval; DOR=duration of response; IC=tumour-infiltrating immune cells; NE=not estimable; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1; *All comers refers to the primary analysis population consisting of the first 850 randomised patients ǂStratified by PD-L1 expression in tumour infiltrating immune cells, the number of prior chemotherapy regimens, and histology ** Based on the stratified log-rank test
About the POPLAR study
A phase II, multi-centre, international, randomised, open-label, controlled study, POPLAR, was conducted in patients with locally advanced or metastatic NSCLC who progressed during or following a platinum-containing regimen, regardless of PD-L1 expression. The primary efficacy outcome was overall survival. A total of 287 patients were randomised 1:1 to receive either TECENTRIQ (1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit) or docetaxel (75 mg/m2 by intravenous infusion on day 1 of each 3-week cycle until disease progression). Randomisation was stratified by PD-L1 expression status on IC, by the number of prior chemotherapy regimens and by histology.
An updated analysis with a total of 200 deaths observed and a median survival follow-up of 22 months showed a median OS of 12.6 months in patients treated with TECENTRIQ, vs. 9.7 months in patients treated with docetaxel (HR of 0.69, 95% CI: 0.52, 0.92). ORR was 15.3% vs. 14.7% and median DOR was 18.6 months vs. 7.2 months for TECENTRIQ vs. docetaxel, respectively.
About non-small cell lung cancer
Lung cancer is the leading cause of cancer death globally. Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day. Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.
About the IMvigor211 study
IMvigor211 is a Phase III study of TECENTRIQ compared to chemotherapy in people with advanced bladder cancer who were previously treated with a platinum-based chemotherapy. The study evaluated the efficacy and safety of TECENTRIQ compared to chemotherapy of physician choice (vinflunine, paclitaxel or docetaxel) administered every three weeks in 931 people with previously-treated mUC who progressed during or following a platinum-based regimen. The primary efficacy endpoint was OS and key secondary endpoints include objective response rate, progression-free survival, duration of response and safety. IMvigor211 study did not meet its primary endpoint of overall survival (OS) compared to chemotherapy. These data were presented in full at the EACR-AACR-SIC Special Conference 2017.
The primary efficacy endpoint, overall survival, was to be tested in a successive fashion (hierarchical testing) in study populations defined by PD-L1 expression. The first population tested was people with the highest levels of PD-L1 expression (IC2/3), followed by those with any observable level of PD-L1 expression (IC1/2/3), and followed by the overall study population (Intention-To-Treat; ITT). Per the pre-specified hierarchical testing order, the IC2/3 (≥5%) population was tested first, with an OS HR of 0.87 (95% CI: 0.63, 1.21; median OS of 11.1 vs. 10.6 months for TECENTRIQ and chemotherapy respectively). In the overall study population (intention-to-treat or ITT) people treated with TECENTRIQ achieved a mOS of 8.6 months (CI: 95%; 7.8, 9.6) compared to 8.0 months (CI: 95%; 7.2, 8.6) with chemotherapy (HR 0.85, 95% CI 0.73-0.99).
Statistical significance needed to be achieved for the study populations in the following order: IC2/3 (≥5%), IC1/2/3 (≥1%), and ITT group. However, because statistical significance was not achieved for OS in the IC2/3 population, results could not be evaluated for statistical significance in the IC1/2/3 and ITT populations and those analyses are considered descriptive in nature.
Overall Response Rates (ORR) were similar to those previously reported in the phase II IMvigor210 study and similar between the two study arms. The median duration of response (mDOR), a secondary endpoint, for those receiving TECENTRIQ was 21.7 months (95% CI: 13.0, 21.7) in the overall study population, compared to 7.4 months (95% CI: 6.1, 10.3) for those receiving chemotherapy. At the time of data cutoff, the majority (63%) of people who responded to treatment with TECENTRIQ continued to respond, compared to 21% of people treated with chemotherapy.
About the IMvigor210 study (Cohort 2)
In Cohort 2, the co-primary efficacy endpoints were confirmed ORR as assessed by an IRF using RECIST v1.1 and investigator-assessed ORR according to Modified RECIST (mRECIST) criteria. There were 310 patients treated with TECENTRIQ 1,200 mg by intravenous infusion every 3 weeks until loss of clinical benefit. The study met its co-primary endpoints in Cohort 2, demonstrating statistically significant ORRs per IRF-assessed RECIST v1.1 and investigator-assessed mRECIST compared to a pre-specified historical control response rate of 10%.
An analysis was also performed with a median duration of survival follow-up of 21.1 months for Cohort 2. The confirmed ORRs per IRF-RECIST v1.1 were 28.0% (95% CI: 19.5, 37.9) in patients with PD-L1 expression IC2/3 (≥ 5%), 19.3% (95% CI: 14.2, 25.4) in patients with PD-L1 expression IC1/2/3 (≥ 1%), and 15.8% (95% CI: 11.9, 20.4) in all comers. The confirmed ORR per investigator-assessed mRECIST was 29.0% (95% CI: 20.4, 38.9) in patients with PD-L1 expression ≥ 5%, 23.7% (95% CI: 18.1, 30.1) in patients with PD-L1 expression ≥ 1%, and 19.7% (95% CI: 15.4, 24.6) in all comers. The rate of complete response per IRF-RECIST v1.1 in the all comer population was 6.1% (95% CI: 3.7, 9.4). For Cohort 2, median DOR per IRF-RECIST v1.1 was not reached in any PD-L1 expression subgroup or in all comers, however was reached in patients with PD-L1 expression < 1% (13.3 months; 95% CI 4.2, NE). The OS rate at 12 month was 37% in all comers.
About the IMvigor210 study (Cohort 1)
The positive CHMP opinion for patients who are ineligible for cisplatin-based chemotherapy is based on results from Cohort 1, which consisted of 119 people with locally advanced or mUC who were ineligible for cisplatin-containing chemotherapy and were either previously untreated or had disease progression at least 12 months after neoadjuvant (before surgery) or adjuvant (after surgery) chemotherapy. The primary endpoint of the study was objective response rate (ORR).

CI=confidence interval; DOR=duration of response; IC= tumour-infiltrating immune cells; IRF= independent review facility; NE=not estimable; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response Evaluation Criteria in Solid Tumours v1.1.
Pooled Safety Profile
The safety of TECENTRIQ is based on pooled data in 2,160 patients with mUC and NSCLC. The most common adverse all grade reactions were fatigue (35.4%), decreased appetite (25.5%), nausea (22.9%), dyspnoea (21.8%), diarrhoea (18.6%), pyrexia (18.3%), rash (18.6%), vomiting (15.0%), arthralgia (14.2%), asthenia (13.8%) and pruritus (11.3%).
About metastatic urothelial carcinoma
Metastatic urothelial carcinoma (mUC) is associated with a poor prognosis and limited treatment options. It is a disease that has seen no major advances for more than 30 years outside of the US. UC is the ninth most common cancer worldwide, with 430,000 new cases diagnosed in 2012, and it results in approximately 145,000 deaths globally each year. Men are three times more likely to suffer from UC, compared with women, and the disease is three times more common in developed countries than in less developed countries.
About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1. TECENTRIQ is designed to bind to PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers
About Roche in cancer immunotherapy

On July 20, 2017 – CureVac AG, a fully-integrated biopharmaceutical company pioneering the field of mRNA-based drugs, reported it has been granted a Notice of Allowance from the European Patent Office (EPO) for its patent application (EP 2958588) entitled, "Combination of Vaccination and Inhibition of the PD-1 Pathway"(Press release, CureVac, JUL 20, 2017, View Source [SID1234519946]).

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The patent claims both composition of matter and methods of treatment for a vaccine/inhibitor combination comprising an mRNA vaccine and an anti-PD-1 antibody. Further, the patent covers a pharmaceutical composition and a kit of parts comprising such a vaccine/inhibitor combination, particularly for the prevention or treatment of tumor or cancer diseases and infectious diseases.

Dr. Franz-Werner Haas, Chief Corporate Officer of CureVac, stated, "We are convinced there is tremendous potential in combining mRNA-based vaccines with PD-1 checkpoint inhibitors for the treatment of a wide range of cancers and infectious diseases. Anti-PD-1 antibody therapy is becoming standard of care in several cancer indications, and combination approaches are now recognized as optimal for the development of mRNA cancer vaccines. Therefore, this patent adds considerable value to our company and our IP estate. Together with our extensive experience in the development of mRNA-based cancer vaccines this encourages us to advance and expand our RNActive Cancer Immunotherapy pipeline."

In total, CureVac holds a broad IP portfolio comprising more than 100 patent families covering different aspects of its mRNA platform enabling the use and production of mRNA across a wide range of treatment modalities and disease indications.

On July 20, 2017 Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the U.S. Food and Drug Administration (FDA) granted orphan-drug designation to gilteritinib in patients with acute myeloid leukemia (AML) (Press release, Astellas, JUL 20, 2017, View Source [SID1234519842]). The Orphan Drug Designation program assigns status to drugs and biologics intended for the safe and effective treatment, diagnosis or prevention of diseases or disorders that affect fewer than 200,000 people in the United States.

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"Fewer than 10,000 Americans will be diagnosed with FLT3 mutation-positive AML this year and while that may be a small percentage of the overall population, it is an important group of patients who are deserving of potential new treatments," said Steven Benner, M.D., senior vice president and global therapeutic area head, oncology development, Astellas. "We are grateful to the FDA for acknowledging the unique needs of rare diseases and for providing a path forward for gilteritinib in supporting these patients."

Gilteritinib is a receptor tyrosine kinase inhibitor of FLT3 and AXL, which are involved in the growth of cancer cells. Gilteritinib has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) as well as tyrosine kinase domain (TKD), two common types of FLT3 mutations that are seen in up to one third of patients with AML. AML is a cancer that impacts the blood and bone marrow and most commonly experienced in older adults. According to the American Cancer Society, in 2016 there were an estimated 21,000 new cases of AML diagnosed in the United States and about 10,600 cases resulted in death.

Astellas is currently investigating gilteritinib in various AML patient populations through several planned and already initiated Phase 3 trials, including the registrational ADMIRAL trial in relapsed/refractory FLT3+ AML.

The safety and efficacy of the agent discussed herein are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval and become commercially available for the uses being investigated. Information about pharmaceutical products (including products currently in development) which is included in this press release are not intended to constitute an advertisement or medical advice.

On July 20, 2017 Aptevo Therapeutics Inc. (Nasdaq:APVO), a biotechnology company focused on developing novel immuno-oncology and hematology therapeutics, and Alligator Bioscience (Nasdaq Stockholm: ATORX), a biotechnology company developing antibody-based pharmaceuticals for tumor-directed immunotherapy, reported that they have entered into an agreement to co-develop a novel immunotherapy bispecific antibody candidate, ALG (Press release, Aptevo Therapeutics, JUL 20, 2017, View Source [SID1234519840]).APV-527, based on Alligator’s first generation bispecific antibody, ATOR-1016. The new bispecific candidate was developed using Aptevo’s bispecific technology platform and includes proprietary binding elements generated by Alligator’s ALLIGATOR-GOLD antibody library. Initiation of cell line development for the manufacturing of clinical material is expected to begin shortly.

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Working under a previously executed material transfer agreement, the companies have engineered and selected ALG.APV-527 as a lead bispecific antibody candidate, featuring a novel mechanism of action targeting 4-1BB, a member of the TNFR superfamily of co-stimulatory receptors found on activated T cells, and an undisclosed tumor antigen widely overexpressed in a number of different types of cancer.

Under the terms of the agreement, the parties will jointly own and share equally in the development costs associated with advancing this candidate through to the end of Phase 2 clinical development. At that time, the parties may opt to out-license the candidate or continue further development separately or in partnership. In addition, the agreement provides an option for the companies to develop a second bispecific antibody candidate based on this novel mechanism of action, which would also be jointly owned and funded by Aptevo and Alligator.

The co-stimulatory receptor 4-1BB is known to play an important role in modulating and augmenting the immune response to cancer by promoting the activation, expansion and enhanced effector function of tumor-specific T cells. It is, therefore, an especially promising target for new immunotherapeutic approaches for cancer treatment. If successfully developed, this new bispecific antibody candidate could have utility in the potential treatment of a broad spectrum of cancers including breast, cervical, non-small-cell-lung, prostate, renal, gastric, colorectal and bladder cancers. While this tumor antigen is widely expressed in multiple types of solid tumors, it shows limited expression on normal tissues, suggesting the potential for tumor-directed immunotherapy with improved efficacy and fewer side effects.

"Our collaboration with Alligator Bioscience has unlocked tremendous synergies, enabling us to capitalize on our companies’ respective expertise in therapeutic antibody engineering," said Marvin L. White, President and Chief Executive Officer of Aptevo. "The addition of a 4-1BB bispecific candidate expands and diversifies Aptevo’s portfolio while demonstrating the flexibility of our ADAPTIR platform in addressing novel mechanisms of action, in addition to redirected T-cell cytotoxicity. Also, importantly, it allows us to pursue an exciting new therapeutic opportunity with broad potential application in the treatment of non-hematological cancers. If proven successful, this new approach would be a significant advance in cancer immunotherapy. We’re extremely pleased to collaborate with Alligator Bioscience in the development of novel tumor-targeting bispecific antibody therapies."

"With five immuno-oncology programs currently in development, each with first- or best-in-class potential, this partnership with Aptevo allows us to further build on the promise of bispecific therapeutics for tumor-directed immunotherapy," said Per Norlén, Chief Executive Officer of Alligator Bioscience. "Our technology platform enables the generation of highly functional antibodies with optimal stability and manufacturing properties, merged into an exceptional bispecific antibody using Aptevo´s ADAPTIR platform. We look forward to advancing our collaboration with Aptevo on this promising new therapeutic approach."