On June 6, 2017 NantKwest and Nantworks reported at the 2017 Annual American Society for Clinical Oncology meeting (ASCO) (Free ASCO Whitepaper) in Chicago, IL the expansion of the company’s existing NANT Cancer Vaccine program in pancreatic cancer (ClinicalTrials.gov NCT03136406) to target a number of additional tumor types (Press release, NantKwest, JUN 6, 2017, http://ir.nantkwest.com/phoenix.zhtml?c=254059&p=RssLanding&cat=news&id=2279115 [SID1234519440]).

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The NANT Cancer Vaccine program is a personalized, molecularly-informed therapy guided by NantHealth’s GPS Cancer test that includes the simultaneous combination of off the shelf natural killer cells (NK) with the endogenous activation of dendritic, T cell and NK cells to more fully enhance the innate and adaptive immune system of cancer patients.

The NANT Cancer Vaccine is the first combination immunotherapy protocol formulated to include the novel delivery of metronomic, low-dose chemotherapy and radiation with molecularly-informed, tumor-associated antigen vaccines, together with NantKwest’s NK cell therapy, to induce immunogenic cell death while avoiding the ravages of toxic high dose chemotherapy.

By inducing immunogenic cell death and enhancing a patient’s innate and adaptive immune system, the NANT Cancer Vaccine is designed to attain a long-term, durable response in multiple cancer types with lower toxicity and higher efficacy in comparison with current standards of care.

"Current therapeutic approaches to the treatment of cancer are often inadequate to fully activate a patient’s immune response. Through the NANT Cancer Vaccine program, we believe we can help facilitate a paradigm shift in cancer care with the first clinical program formulated to incorporate low dose, metronomic chemotherapy and radiation, combined with molecularly-informed tumor associated antigens that are designed to activate dendritic and T cells by adenoviral and yeast vaccine vectors, together with both endogenous (IL-15) and exogenous (off the shelf) activation of NantKwest’s NK cell therapy," said Patrick Soon-Shiong, Chairman and CEO of NantKwest.

Dr. Soon-Shiong continued, "In addition to the previously announced Pancreatic Cancer Vaccine, we are now actively working to initiate multiple clinical trials across a wide range of cancer types which include: Lung, breast, head and neck cancer, colon, melanoma, ovarian, urothelial, Hodgkins and non-Hodgkins lymphoma, sarcoma, and Merkel cell carcinoma, all based on a similar treatment protocol and designed to more fully harness the power of the immune system and improve cancer patient outcomes."

On June 6, 2017 Celgene Corporation (NASDAQ:CELG) and Agios Pharmaceuticals, Inc. (NASDAQ:AGIO) reported new efficacy and safety data from the ongoing Phase 1 dose-escalation and expansion study evaluating investigational oral IDHIFA (enasidenib) in patients with relapsed or refractory acute myeloid leukemia (R/R AML) and an isocitrate dehydrogenase-2 (IDH2) mutation (Press release, Agios Pharmaceuticals, JUN 6, 2017, View Source [SID1234519436]).

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IDHIFA is an investigational first-in-class, oral, targeted inhibitor of the mutant IDH2 enzyme, which demonstrated an overall response rate of 40.3 percent, including a complete response rate of 19.3 percent in the study. The data were presented in an oral session at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and simultaneously published online in the journal Blood.*

"The updated results, including duration of response, from the Phase 1 study reinforce the potential for enasidenib as a first-in-class therapy for patients with relapsed or refractory AML and an IDH2 mutation," said Michael Pehl, President, Hematology/Oncology at Celgene. "Patients have very few treatment options for relapsed or refractory AML, so we are eager to advance this potential targeted therapy as quickly as possible."

As of April 15, 2016, a total of 239 patients with advanced hematologic malignances and an IDH2 mutation were enrolled into the Phase 1 study, of which 176 patients had R/R AML. Data reported include patients receiving enasidenib at total daily doses ranging from 50 mg to 650 mg in the dose-escalation arm and 100 mg once daily in the Phase 1 expansion arms. A maximum tolerated dose was not reached. The median age of the patients enrolled in the study is 70 (ranging from 19-100). Patients with R/R AML received a median of two prior lines of therapy (ranging from one to 14).

The overall safety profile observed for enasidenib was consistent with previously reported data. Twenty-four percent of patients had treatment-related serious adverse events (SAEs), notably IDH differentiation syndrome (8%), leukocytosis (4%), tumor lysis syndrome (3%) and hyperbilirubinemia (2%). The most common treatment-emergent AEs were nausea (46%) hyperbilirubinemia (45%), diarrhea (40%) and fatigue (40%).

Data from 176 R/R AML patients with an IDH2 mutation demonstrated a 40.3 percent (71 of 176 patients) overall response rate, which was the primary endpoint of the study. Further, the complete response rate was 19.3 percent (34 of 176 patients). Median duration of response was 5.8 months [95% CI 3.9, 7.4] for all patients who responded and 8.8 months [95% CI 6.4, NR] for patients who achieved a CR. Median time to first response was 1.9 months (0.5-9.4) and median time to CR was 3.8 months (0.5-11.2). Median overall survival (OS) for R/R AML patients as observed in the study was 9.3 months [95% CI 8.2, 10.9]. Additional results including qualitative improvement in response over time, improvement in hematological parameters over time, OS for patients achieving a CR and transfusion independence were also reported.

"In addition to the complete response in this study, we also observed changes in responses and hematologic parameters over time," said Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "This suggests that differentiation of myeloblasts – made possible by inhibition of mutated IDH2 – may drive the clinical efficacy of enasidenib."

"Targeting IDH mutations is thought to allow for the differentiation of malignant cells and introduces a new paradigm in the treatment of AML," said Chris Bowden, M.D., chief medical officer of Agios. "These data show that IDH inhibition plays an important role in segments of AML and will continue to inform our research into this novel class of potential therapies."

Additional Data Available – IDH Differentiation Syndrome & Translational Analyses

A separate analysis of IDH-inhibitor-associated differentiation syndrome (IDH-DS) associated with enasidenib was also presented as a poster discussion during the ASCO (Free ASCO Whitepaper) meeting and detailed the findings of an independent Differentiation Syndrome Review Committee (DSRC). The committee reviewed investigator reported IDH-DS cases and determined that 13 of the 27 potential cases were consistent with IDH-DS (11.9% of 109 patients). These data demonstrate that the signs and symptoms of IDH-DS are recognizable. IDH-DS represents a novel clinical finding in patients with mutated IDH2 AML treated with enasidenib, and is likely due to its purported mechanism of action, differentiation of leukemic cells.

In addition to the clinical data publication, additional analyses describing the mechanism of action of enasidenib were also published online in Blood. An analysis of patient samples confirmed that the preclinical efficacy and mechanism of action of mutated IDH2 inhibition by enasidenib is through differentiation of AML cells. The authors conclude that the data provide insights into enasidenib resistance to inform future mechanism-based combination treatment studies.

Clinical Development

Enasidenib continues to be studied in the following ongoing clinical trials:

Phase III IDHENTIFY study evaluating the efficacy and safety of enasidenib versus conventional care regimens in older patients with R/R AML with an IDH2 mutation (NCT02577406)
Phase 1b study of either enasidenib or ivosidenib in combination with standard induction and consolidation chemotherapy in newly diagnosed AML (NCT02632708)
Phase 1/2 study of either enasidenib or ivosidenib in combination with azacitidine in newly diagnosed AML (NCT02677922)
The New Drug Application (NDA) for IDHIFA is currently under Priority Review with the U.S. Food and Drug Administration for the treatment of patients with relapsed or refractory AML with an IDH2 mutation. The NDA has been given a Prescription Drug User Fee Act (PDUFA) action date of Aug. 30, 2017.

Ivosidenib (AG-120, wholly owned by Agios) is an investigational, oral, targeted inhibitor of the mutant IDH1 enzyme.

About AG221-C-001

Study AG221-C-001 includes three parts: a Phase 1 dose escalation, a part 1 (Phase 1) expansion and a Phase 2 expansion.

The Phase 1 dose escalation study was designed to determine the maximum tolerated dose and recommended Phase 2 dose, and to evaluate efficacy and safety of enasidenib (AG-221/CC-90007) in subjects with advanced hematologic malignancies with an IDH2 mutation. The Part 1 expansion further evaluated the safety, tolerability, and efficacy of enasidenib in subjects with R/R AML, untreated AML, myelodysplastic syndrome or other advanced hematologic malignancies with an IDH2 mutation. Based on the clinical activity observed in R/R AML subjects, the Phase 2 expansion was designed to assess efficacy of enasidenib at recommended 100 mg daily dose and to further evaluate safety in subjects with R/R AML and with IDH2 mutation. The study was not designed or statistically powered to reach a conclusion on OS. A phase 3 randomized controlled trial with OS as a primary endpoint has been initiated.

About Acute Myelogenous Leukemia (AML)

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. The vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH2 mutations are present in about 8 to 19 percent of AML cases.

On June 6, 2017 Eleven Biotherapeutics, Inc. (NASDAQ:EBIO), a late-stage clinical oncology company advancing a broad pipeline of novel product candidates based on its Targeted Protein Therapeutics (TPTs) platform, reported the signing of a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) on the development of Eleven’s targeted therapeutic, ViciniumTM in combination with AstraZeneca’s immune checkpoint inhibitor, ImfinziTM (durvalumab), for the treatment of non-muscle invasive bladder cancer (NMIBC) (Press release, Eleven Biotherapeutics, JUN 6, 2017, View Source [SID1234519435]).

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"Despite current therapies and surgical regimens, there remains a large unmet need for patients with recurring or progressing NMIBC that is no longer responding to Bacillus Calmette-Guérin (BCG)," said Stephen Hurly, President and Chief Executive Officer of Eleven Biotherapeutics. "While we remain internally focused on advancing our Phase 3 registration trial of Vicinium as a monotherapy, preclinical data suggests that Vicinium also has the ability to potentiate the activity of immuno-oncology agents. We are pleased to enter into this collaboration with the National Cancer Institute and AstraZeneca, which broadens the scope of our ongoing clinical program and enables us to evaluate Vicinium together with Imfinzi, a PD-L1 checkpoint inhibitor. We look forward to generating additional data, as we continue to advance Vicinium and work expeditiously to bring it forward as a new treatment option for patients with NMIBC."

Vicinium, like Eleven’s other TPTs, is a single protein molecule composed of an antibody fragment genetically fused to a potent cytotoxic payload. Vicinium selectively binds to epithelial cell adhesion molecules (EpCAM), a cell surface marker that is highly expressed on many cancers, including high grade NMIBC, but that is present at minimal to no levels on healthy bladder tissue. After binding to EpCAM on the surface of the tumor cell, Vicinium is internalized into the cell where its potent cytotoxic cell killing payload, Pseudomonas Exotoxin A (ETA), is released, disrupting protein synthesis and leading to cell death.

At the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April 2017, new preclinical data were presented demonstrating that cancer cells treated with VB4-845, the active pharmaceutical ingredient used to formulate Vicinium, undergo immunogenic cell death (ICD). ICD is known to stimulate host immune responses against cancer. This supports the hypothesis that Eleven’s TPTs not only directly kill tumor cells, but also induce a host immune cell-mediated anti-tumor response. This suggests that they are differentiated from existing treatments, and that they may have synergy with checkpoint inhibitors and other immuno-oncology compounds.

Under the terms of the CRADA, the NCI, led by principal investigator Dr. Piyush Agarwal of the NCI Center for Cancer Research, Urologic Oncology Branch, will conduct a Phase 1 clinical trial in patients with high-grade NMIBC to evaluate the safety, efficacy, and biological correlates of the Vicinium and durvalumab combination therapeutic strategy. Patients will be evaluated for response and recurrence throughout the study. For referrals, please contact Sonia Bellfield, Research Nurse, at 301-435-6255.

Vicinium is currently in a Phase 3 registration trial for the treatment of high-grade NMIBC. Eleven expects to complete patient enrollment in the second half of 2017, and to report topline 3-month data in the second quarter of 2018. Imfinzi, in development by AstraZeneca and its biologic research arm, MedImmune, is a human monoclonal antibody directed against programmed death ligand-1 (PD-L1), that has accelerated approval by the FDA for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy, regardless of PD-L1 status.

About ViciniumTM

Vicinium is a single protein anti-epithelial cell adhesion molecule (anti-EpCAM) fusion protein fused with Pseudomonas Exotoxin A (ETA) designed to specifically target and deliver a potent anti-cancer payload directly into tumor cells. Vicinium is currently in a Phase 3 registration clinical trial for the treatment of high-grade non-muscle invasive bladder cancer (NMIBC) in subjects who have previously received two courses of Bacillus Calmette-Guérin (BCG) and whose disease is now BCG-unresponsive. Eleven Biotherapeutics intends to enroll 134 subjects in the trial, including 77 subjects with carcinoma in situ (CIS), at over 70 centers in the United States and Canada. Primary and secondary endpoints include complete response (CR) rate in CIS subjects, time to disease recurrence and event free survival.

About Imfinzi (durvalumab)

Imfinzi (durvalumab, previously known as MEDI4736) is a human monoclonal antibody directed against PD-L1, which blocks the interaction of PD-L1 with PD-1 and CD80.

Durvalumab is also being tested in the 1st-line treatment of patients with unresectable and metastatic bladder cancer as a monotherapy and in combination with tremelimumab, a checkpoint inhibitor that targets CTLA-4, as part of the DANUBE Phase III trial, which had the last patient commenced dosing during the first quarter of 2017 (global trial, excluding China). Additional clinical trials are ongoing to investigate durvalumab as monotherapy or in combination in multiple solid tumours and blood cancers.

On June 6, 2017 Affimed N.V. (Nasdaq: AFMD), a clinical stage biopharmaceutical company focused on discovering and developing highly targeted cancer immunotherapies, reported that the Company presented data on its preclinical AFM26 program to treat multiple myeloma (MM) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting being held in Chicago, IL, June 2-6, 2017 (Press release, Affimed, JUN 6, 2017, View Source [SID1234519434]).

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"NK-cells have been described to play a major role in the control of multiple myeloma, however, the recognition and elimination of malignant cells remain challenging," said Dr. Martin Treder, CSO of Affimed. "Our bispecific tetravalent NK-cell engager AFM26, a targeted therapeutic specifically binding BCMA on tumor cells, promises to address this need by unlocking NK-cell cytotoxicity in myeloma."

Affimed’s first-in-class tetravalent, bispecific antibody AFM26 binds to the tumor-specific B-cell maturation antigen (BCMA) on MM cells and to CD16A on NK-cells, thereby specifically directing NK-cell anti-tumor activity towards cells expressing BCMA.

In a poster presented June 5, 2017, the Company demonstrated that AFM26 induced NK-cellmediated lysis of primary myeloma cells and myeloma cell lines more potently than both daratumumab and elotuzumab, two monoclonal antibodies (mAbs) currently approved for myeloma treatment. AFM26 engages NK-cells with markedly higher avidity compared to classical mAbs. This translates into potent and efficacious target cell lysis and retained activity against cell lines that express very low BCMA levels (BCMA-low). Further differentiating Affimed’s NK-cell engager, the Company presented data showing that AFM26 potently induced lysis of BCMA-low cell lines that have been described as not sensitive to treatment with GSK2857916, a BCMA-targeting antibody drug conjugate currently in clinical development. Importantly, unlike daratumumab and elotuzumab, AFM26 did not elicit NK-cell depletion in vitro.

MM is characterized by high level production of monoclonal immunoglobulin (M-protein), which competes with classical mAbs for NK-cell binding. Affimed demonstrated that both NK-cell binding affinity and cell surface retention of AFM26 were largely unaffected by serum IgG, suggesting retained cytotoxic activity of the NK-cell engager in patients with high M-protein serum levels.

In addition, the Company presented data showing that AFM26, while effectively lysing target cells, elicited substantially lower cytokine release compared to a BCMA/CD3-specific T-cell engager (BiTE), indicating a potentially superior safety profile.

Addressing minimal residual disease (MRD) following high-dose therapy (HDT) and autologous stem cell transplant (ASCT) remains a significant unmet need in MM treatment as the majority of patients relapse. NK-cells are the first lymphocyte population to reappear after HDT/ASCT providing a specific treatment window for NK-cell-based immunotherapeutic approaches to target MRD shortly after transplant. Furthermore, adoptive transfer of NK-cells has recently been clinically investigated in the transplant setting suggesting a unique combination opportunity for AFM26 with this approach.

In summary, the data presented at ASCO (Free ASCO Whitepaper) highlight AFM26 as a promising first-in-class therapeutic with particular potential to address the unmet need in ASCT-eligible MM.

On June 6, 2017 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) announced today that the results of the global phase III study (the ALEX study) of Alecensa, conducted by F. Hoffmann-La Roche Ltd., in ALK fusion gene positive non-small cell lung cancer (NSCLC) patients, will be presented at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) held in Chicago (Press release, Chugai, JUN 6, 2017, View Source [SID1234519433]). The presentation will be held on oral abstract sessions on 6th June (Tue) 12:09-12:21 (CDT) as a late breaking subject.

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Abstract LBA9008
Alectinib versus crizotinib in treatment-naive advanced ALK-positive non-small cell lung cancer (NSCLC): Primary results of the global phase III ALEX study.

"In the ALEX study comparing the efficacy and safety of first line therapy of Alecensa with crizotinib, Alecensa showed a significant prolongation of PFS and reduced the risk of disease progression or occurrence by 84% in patients with or without brain metastasis at baseline. The study also showed that Alecensa was well tolerated. These results will encourage the patients to fight cancer," said Dr. Yasushi Ito, Senior Vice President, Head of Project & Lifecycle Management Unit. "We believe that Alecensa will also contribute to improving the outcomes of many ALK fusion gene positive NSCLC patients not just in Japan but in overseas as well."

The ALEX study was an open-label, randomized global phase III study that compares the efficacy and safety between Alecensa and crizotinib in the first line therapy. The ALEX study enrolled treatment-naïve 303 patients with ALK fusion gene positive NSCLC. The subjects were allocated to either the Alecensa arm or the crizotinib arm in a one to one ratio. The primary endpoint of the ALEX study was PFS as assessed by the investigator. The secondary endpoints included independent review committee (IRC)-assessed PFS, IRC-assessed time to CNS progression, objective response rate, overall survival, safety and other endpoints.

Summaries of the ALEX study results

Efficacy:

– At the primary data cut-off, Alecensa arm demonstrated statistically significant improvement superiority vs crizotinib arm, reducing risk of progression or death by 53% (HR=0.47, 95%CI: 0.34-0.65, stratified log-rank test, p<0.0001) by investigators’ assessment. Median PFS was not reached (95%CI: 17.7-not reached) in the Alecensa arm while it was 11.1 months (95%CI: 9.1-13.1) in the crizotinib arm.

– According to independent review committee, Alecensa arm demonstrated statistically significant improvement superiority vs crizotinib arm, reducing risk of progression or death by 50% (HR=0.50, 95%CI: 0.36-0.70). Median PFS was 25.7 months (95%CI: 19.9-not reached) in the Alecensa arm while it was 10.4 months (95%CI: 7.7-14.6) in the crizotinib arm.

– Alecensa arm demonstrated improvement vs crizotinib arm, reducing risk of CNS progression or death by 84% (HR=0.16, 95% CI: 0.10-0.28).

– Overall survival data are currently considered immature with only about a quarter of events being reported.

Safety:

– Grade 3-5 adverse events (AEs) were less frequent with Alecensa arm, 41%, vs 50% with crizotinib arm.

– No new safety findings were observed in either arm.

About Alecensa
Alecensa is a highly selective oral ALK inhibitor created by Chugai. It has been reported that approximately five percent of patients with NSCLC express a chromosomal rearrangement which leads to fusion of the ALK gene with another gene.1) ALK kinase signalling is constantly active in cells with such fusion genes, resulting in uncontrolled growth of tumour cells and transforming the cells into tumour cells.2, 3) Alecensa exerts its anti-tumour effect by selectively inhibiting ALK kinase activity to inhibit tumour cell proliferation and induce cell death.4) In addition, Alecensa is not recognized by the active efflux system in the blood brain barrier which actively pumps molecules out of the brain. Thus, Alecensa is able to remain active in the central nervous system and has proven activity against brain metastases.

Alecensa is currently approved in the United States, Kuwait, Israel, Hong Kong, Canada, South Korea, Switzerland, India, the EU, Australia, Taiwan and Singapore for the treatment of adult patients with ALK-positive, metastatic (advanced) NSCLC who have progressed on or those intolerant to crizotinib." In Japan, "Alecensa capsule 150mg" is available to patients with "ALK fusion gene positive unresectable, recurrent/advanced NSCLC" and is marketed by Chugai.

The approved dosage and administration in Japan is "300mg alectinib is administered orally twice daily for adult patient."

1) Biomarker committee of The Japan Lung Cancer Society, Guidelines for ALK gene tests in lung cancer patients
2) Soda et al., Nature. 448: 561-566 (2007)
3) Takeuchi et al., Clin Cancer Res. 15: 3143-3149 (2009)
4) Sakamoto et al., Cancer Cell. 19: 679-690 (2011)