On June 3, 2019 Innovent Biologics, Inc. (Innovent) (HKEX: 01801), a world-class biopharmaceutical company that develops and commercializes high quality medicines, reported that the results of extended follow-up on sintilimab, the anti-PD-1 antibody that co-developed with Eli Lilly and Company, for relapsed/refractory classical Hodgkin’s lymphoma (r/r cHL) (ORIENT-1) were presented by poster at the 55th annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) [Abstract #7533; Monday, June 3, 8:00 AM -11:00 AM CDT] (Press release, Innovent Biologics, JUN 3, 2019, View Source [SID1234536843]).

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As the top and most influential international oncology conference, ASCO (Free ASCO Whitepaper) Annual Meeting provides the most important platform for publishing and discussing cutting edge clinical studies. Under the theme "Caring for Every Patient, Learning from Every Patient," 2019 ASCO (Free ASCO Whitepaper) Annual Meeting has attracted numerous top oncologists, scholars, staff from regulatory and patient organizations to share the latest updates and achievements in clinical oncology, with the ultimate goal to help deliver more promising medicines and treatment options to cancer patients.

It is worth noting that more and more Chinese companies choose to participate and disclose their programs in ASCO (Free ASCO Whitepaper), showcasing the importance of emerging Chinese biotech industry. As a leading Chinese biotech company, Innovent will provide key result update of several clinical studies at the ASCO (Free ASCO Whitepaper) 2019 Annual Meeting. The results on the treatment of relapsed or refractory extranodal NK/T cell lymphoma (ORIENT-4) with sintilimab will be presented in an oral session, and key data from several other clinical studies will be presented by posters and other sessions.

ORIENT-1, led by Professor Yuan-kai Shi, Associate Dean of the Cancer Hospital of the Chinese Academy of Medical Sciences and Director of the Department of Oncology, is a multicenter, single-arm, Phase II study in China, evaluating the efficacy and safety of sintilimab for the treatment of patients with relapsed/refractory classical Hodgkin’s lymphoma. Currently, ORIENT-1 study has the largest cohort of cHL patients in China with a total of 96 patients involved.

The primary clinical endpoint is objective response rate (ORR) as assessed by an independent radiological review committee (IRRC) according to 2007 IWG criteria. Moreover, complete response rate (CRR) is a secondary endpoint.

As of the data cutoff on 16 Oct 2018, 72.9% of patients were continuing treatment with a median follow-up of 14 months. ORR was 85.4% (82/96, 95% CI: 76.7 ~ 91.8) based on IRRC review. Twenty-eight patients (29.2%) achieved complete response (CR) by PET scan. The median duration of response (DoR) and progression free survival (PFS) have not been reached. Sintilimab showed an acceptable safety profile during the study.

Based on the results of ORIENT-1 study, sintilimab was approved for treating patients with r/r cHL in China.

The extended follow-up shows that the primary endpoint, ORR, has increased to 85.4% and the secondary endpoint, CR by PET scan, has increased to 29.2 %. Innovent intends to continue updating the response and survival rate for patients who have received sintilimab in this clinical trial.

About Tyvyt (sintilimab injection)

Tyvyt (sintilimab injection) is an innovative drug jointly developed in China by Innovent and Eli Lilly and Company. Innovent is also conducting clinical studies of sintilimab injection in the United States. Tyvyt (sintilimab injection) is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1/ PD-1 Ligand-1 (PD-L1) pathway and reactivates T-cells to kill cancer cells. Tyvyt (sintilimab injection) is the only PD-1 antibody in China branded by both a local biopharmaceutical company and a global pharmaceutical company. Tyvyt (sintilimab injection) has been granted marketing approval by the National Medical Products Administration (NMPA) for relapsed or refractory classical Hodgkin’s lymphoma (r/r cHL) and has been included in the 2019 Guidelines of Chinese Society of Clinical Oncology (CSCO) for Lymphoid Malignancies. There are currently more than twenty clinical studies using sintilimab injection, including eight registration studies that evaluate the efficacy of sintilimab injection in other solid tumors.

On June 3, 2019 Brooklyn ImmunoTherapeutics, a biopharmaceutical company focused on exploring the role that cytokine-based therapy can have in treating patients with cancer, reported the presentation of an ongoing trial poster at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on May 31 – June 4, 2019 at the McCormick Place in Chicago, IL (Press release, Brooklyn ImmunoTherapeutics, JUN 3, 2019, View Source [SID1234536842]). The poster describes a Phase 1b study to evaluate the safety, determine the recommended Phase 2 dose and investigate the biologic and clinical activity of IRX-2 in combination with nivolumab in solid tumor indications (NCT03758781).

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IRX-2 is an allogeneic, cell-derived biologic with multiple active cytokine components, including IL-2, that act on various parts of the immune system associated with activation of the entire tumor microenvironment.

"Anti-PD-1 therapy in oncology has been demonstrated to be a safe and effective therapeutic approach in treating certain cancers and increased lymphocyte infiltration has been associated with improved patient outcomes," said Rohit K Jain, M.D. M.P.H., principal investigator on the Phase 1b trial and Assistant Member in Moffitt Cancer Center Department of Genitourinary Oncology. "In data collected to date, IRX-2 has demonstrated an increase immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival in a Phase 2 study in head and neck cancer. This clinically observed increased immune activation suggests the combination of IRX-2 therapy with PD-1 blockade with nivolumab could enhance outcomes compared to PD-1 blockade alone. This robust Phase 1b trial in up to five different indications will help us better understand the potential role of IRX-2 in oncology immunotherapy."

The Phase 1b clinical trial is taking place at Moffitt Cancer Center in Tampa, Florida and is currently recruiting patients.

"IRX-2 has been well-tolerated to date in clinical trials while demonstrating encouraging activity in squamous cell cancer of the head and neck," said Mark Leuchtenberger, interim President and CEO of Brooklyn ImmunoTherapeutics. "We believe the mechanism of action as well as the safety and clinical activity shown to date provides a strong rationale for combining IRX-2 with checkpoint inhibitors such as nivolumab for the treatment of solid tumor cancers. We look forward to the results of this important trial as well as the results of other ongoing studies, including the Phase 2B INSPIRE trial and an investigator-sponsored trial in squamous cervical intraepithelial neoplasia 3 or vulvar intraepithelial neoplasia 3."

About the Phase 1b Trial
Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. The IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections for 10 days every 3 months. Nivolumab is administered at 240 mg once every two weeks. Planned total enrollment of approximately 100 patients. The study will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies.

The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. The study is actively accruing patients.

On June 3, 2019 NantKwest Inc. (Nasdaq:NK), a pioneering, next generation, clinical-stage immunotherapy company focused on harnessing the unique power of our immune system using natural killer (NK) cells to treat cancer, infectious diseases and other diseases, reported that the company’s t-haNK investigational new drug application (IND) has cleared FDA review and the program has now transitioned to a first-in-human clinical trial targeting CD19 t-haNK in advanced B-cell lymphoma (Press release, NantKwest, JUN 3, 2019, View Source [SID1234536841]).

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CD19 is a transmembrane protein expressed in B cells and overexpressed in a large percentage of advanced leukemia and lymphoma representing a well validated therapeutic target. The CD19 t-haNK cell therapy is a novel, NK cell based immuno-oncology therapy that includes a CD19-based Chimeric Antigen Receptor (CAR) that has been engineered to create an NK cell that includes the high affinity CD16 (Fc receptor), which enhances an NK cell’s ability to bind and enhance monoclonal antibody activity. Use of a targeted, bi-specific NK cell is intended to enhance the cancer cell killing ability of this novel NK cell therapy.

"Based on extensive and encouraging preclinical results, we have enhanced our ability to modularly combine this proprietary off-the-shelf t-haNK-based therapy with a wide range of monoclonal antibodies using this multi-targeted approach," commented Dr. Patrick Soon-Shiong, Chairman and CEO of NantKwest. Dr. Soon-Shiong continued, "We are now ready to transition this innovation in NK cell based therapeutics to a Phase I human clinical trials designed to assess the safety, tolerability and efficacy of CD19 t-haNK cell therapy in advanced b-cell lymphoma. Upon completion of the safety phase, NantKwest intends to combine this CD19 t-haNK cell therapy with other synergistic, immunomodulatory agents as part of an integrative, combination therapy approach that we describe as the NANT Cancer Vaccine to further enhance the synergistic effectiveness of this novel therapeutic intervention."

CD19 t-haNK

NantKwest’s CD19-t-haNK cell therapy is designed to provide precise tumor-cell specificity through the use of a CAR construct that utilizes a CD19-specific scFv (single chain antibody fragment) engineered into the company’s proprietary NK cell that includes the CD16 (Fc high affinity receptor).

In pre-clinical studies, cytotoxicity of these GMP-grade, cryopreserved CD19 t-haNK cells were comprehensively evaluated against a panel of cancer cell lines with different levels of CD19 expression in vitro and in vivo, with these studies showing increased activity and selective cytotoxicity towards CD19-expressing tumor cells of various b-cell origins including leukemia.

To better inform routine patient care, these clinical trials will incorporate a state-of-the-art, biomarker analysis using GPS Cancer, which is an integrated, multi-omics, whole genome, transcriptomic platform, both provided by NantHealth, an affiliated company. These comprehensive molecular analysis tools are designed to provide critical information to the clinical study team regarding the unique molecular alterations associated with the patient’s cancer and response rates, potentially enhancing patient management.

Additional information regarding the CD19 t-haNK clinical study can be found at www.nantkwest.com or www.clinicaltrials.gov/.

About NantKwest

NantKwest, a member of the NantWorks ecosystem of companies, is an innovative clinical-stage immunotherapy company focused on harnessing the power of the innate immune system by using the natural killer cell to treat cancer and virally induced infectious diseases.

On June 3, 2019 Rainier Therapeutics, Inc., a privately held clinical stage drug development company, reported the first interim analysis results from its ongoing FIERCE-22 trial of vofatamab in patients with metastatic bladder cancer (Press release, Rainier Therapeutics, JUN 3, 2019, View Source [SID1234536840]). Results were presented at the 2019 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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FIERCE-22 is a Phase 1b/2 trial evaluating vofatamab, a FGFR3-targeted antibody, in combination with pembrolizumab, an immune checkpoint inhibitor, to determine safety, tolerability and preliminary efficacy in the treatment of patients with locally advanced or metastatic bladder cancer who have progressed following platinum-based chemotherapy and who have not received prior immune checkpoint inhibitor therapy.

The first interim analysis included data from 28 patients enrolled in the Phase 2 trial, which has a targeted total enrollment of approximately 74 patients. Results demonstrate that treatment with vofatamab and pembrolizumab was well tolerated. Five patients discontinued the study due to treatment emergent adverse events, none related to vofatamab. No dose reductions of vofatamab occurred.

An overall best response rate of 36 percent (8/22) was observed in patients with lesions evaluable by RECIST1.1 criteria, 7/22 (32%) were confirmed. Response rates were similar in both wild type and mutant fusion patients (33% and 43%, respectively). A majority of patients have received at least 8 cycles of therapy (1 cycle=21 days). Responses were notably increased in patients with luminal biology (6 of 9 patients). Paired biopsy data from this trial were recently presented at AACR (Free AACR Whitepaper) "Frontiers in Bladder Cancer" (see poster) showing vofatamab induced immune and inflammatory changes in patients with responses.

"These data provide very encouraging clinical evidence of the effect of vofatamab, an antibody targeted against both wild type and mutated FGFR3, in combination with pembrolizumab. Earlier results from this biopsy-driven trial suggested these responses in the wild type FGFR3 patient cohort occurred in urothelial cancers of luminal subtype which typically have immunologically cold tumors. Biopsies obtained post lead-in treatment with vofatamab showed upregulation of genes associated with an inflammatory response," said Arlene O. Siefker-Radtke, MD, The University of Texas MD Anderson Cancer Center. "Further studies are needed to understand the impact of FGFR3 inhibition in urothelial cancer."

"The evidence demonstrated vofatamab provided similar clinical benefits in these patients regardless of FGFR3 tumor status. We plan to continue the enrollment of both wild-type and mutant/fusion patients, and to complete the ongoing Phase 2 trial," said Esteban Abella, MD, Chief Medical Officer of Rainier Therapeutics.

In addition, results were presented from the Phase 2 portion of the FIERCE-21 trial evaluating vofatamab in combination with docetaxel and vofatamab as monotherapy in patients with locally advanced or metastatic bladder cancer with FGFR3 mutations or gent fusions who have relapsed after or are refractory to at least one prior line of chemotherapy. Data presented indicated vofatamab alone and in combination was well tolerated, with no observed long-term safety issues. Vofatamab monotherapy demonstrated single-agent activity in heavily pre-treated patients. In addition, a substantial portion of patients demonstrated long-term benefit from monotherapy and combination therapy.

About Vofatamab

Vofatamab (formerly B-701) is an antibody specifically targeted against the fibroblast growth factor receptor 3 (FGFR3), a known driver of bladder and potentially other FGFR-driven cancers. Vofatamab is the most advanced targeted antibody specific for FGFR3 known by Rainier Therapeutics to be in clinical development. Vofatamab is currently being evaluated in two clinical trials: FIERCE-22 and FIERCE-21.

On June 3, 2019 Aadi Bioscience, Inc (Aadi), a privately held clinical stage biopharmaceutical company,reported preliminary data on the ongoing nab-sirolimus (ABI-009) registration trial (AMPECT) for Advanced (metastatic or locally advanced) Malignant PEComa (perivascular epithelioid cell tumor) – a rare form of sarcoma for which there is no currently approved therapy (Press release, Aadi, JUN 3, 2019, View Source [SID1234536839]).

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Nanoparticle albumin-bound sirolimus (nab-Sirolimus), an mTOR inhibitor, received Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) in Dec 2018, "for the treatment of patients with advanced (metastatic or locally advanced) malignant perivascular epithelioid cell tumor (PEComa)."

The AMPECT trial was conducted at 9 U.S. sites and enrolled 34 adult patients, with 31 confirmed as PEComa by a central pathology laboratory. PEComa origin sites in these patients included the uterus, pelvis, retroperitoneum, lung, kidney, liver, brain, muscle, ovary, aorta and small bowel.

These data, demonstrating a 42 percent confirmed investigator-assessed objective response rate (ORR) across advanced PEComas originating in various tissues, were released in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 annual meeting in Chicago (abstract 11005). AMPECT Principal Investigator Andrew Wagner, M.D., Ph.D., from the Dana Farber Cancer Institute, said nab-sirolimus had delivered consistent and durable responses in advanced PEComa patients. "These responses were achieved with a manageable safety profile," Dr. Wagner said. "We saw a majority of the responding patients achieving a response by their first assessment at 6 weeks following initiation of therapy. Cytotoxic chemotherapies and other drugs approved for treatment of advanced sarcomas show only marginal benefit in PEComas. Activation of the mTOR pathway is common in PEComa and case reports have shown activity of mTOR inhibitors [1]. We are encouraged by the outcomes in this first-ever prospective clinical trial in advanced PEComa."

"The Aadi Bioscience team is proud to have contributed to this important study presented at ASCO (Free ASCO Whitepaper)," said Neil Desai, Ph.D., Chief Executive Officer of Aadi Bioscience. "We are grateful to the patients, families, and clinical trial teams who help push the boundaries of available care through their participation in clinical trials. These results are an important milestone in the ongoing development of nab-sirolimus across a wide range of diseases and therapeutic indications that are driven by mTOR activation and for which there is a need for new therapies." Dr. Desai added: "Results from the AMPECT study will serve as the basis for the ABI-009 New Drug Application (NDA) for nab-sirolimus, which the company expects to submit to the FDA in late 2019 or early 2020. The primary analysis for the NDA will rely upon central, independent radiology review, which will be performed in the second half of 2019. The company plans to release these data at a scientific meeting, which will also include additional patient follow-up, before the end of 2019."

Key Data Presented at ASCO (Free ASCO Whitepaper)

The primary efficacy outcome measure for the analysis presented at ASCO (Free ASCO Whitepaper) is investigator-assessed objective response rate (ORR) as measured by RECIST v 1.1. Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), PFS rate at 6 months (PFS6) and safety. The data presented at ASCO (Free ASCO Whitepaper) employed a May 10, 2019 data cut-off, summarized below, was based on response assessments as performed by each respective clinical trial site (local, investigator-assessed radiology). A separate response assessment performed by independent radiologists, not yet completed, will be required to support global regulatory filings.

Consistent with agreements with the FDA, advanced PEComa patients enrolled in the Phase 2 trial (AMPECT) contributed to the efficacy analysis. The data presented are based on 34 patients evaluable for safety and 31 patients evaluable for efficacy per defined criteria in the protocol.

Enrolled Patients with Confirmatory Response Data Available (n = 31)
Objective Response Rate
(ORR = all PRs) 42% (95% CI: 25% – 61%)
Stable Disease 35%
Disease Control Rate (PR+SD) 77%
Progressive Disease 23%

Sixty-two percent of patients (8/13) with responses are continuing on treatment which include 3 patients on therapy for more than 1 year and 3 patients on therapy for more than 2 years. Median DOR has not been reached; median time to response is 1.4 months (95% CI: 1.3, 2.7). Median PFS is 8.4 months (95% CI: 5.5, –), PFS rate at 3 months (PFS3) is 80% (95% CI: 60%, 90%), PFS6 is 61% (95% CI: 41%, 76%), and 32 percent of all patients enrolled remain on treatment.

For reference, per a meta-analysis of 10 years of phase 2 trials in advanced soft tissue sarcomas (STS) published by the EORTC STS and Bone Sarcoma Group [2], the PFS3 and PFS6 are widely accepted as a meaningful measure of activity of drugs in STS and may be utilized to determine acceptable criteria of benefit. Drugs yielding a PFS rate of ≥40% at 3 months and ≥14% at 6 months are considered to be ‘potentially active’ in advanced STS [2].

A protocol prespecified exploratory mutational and biomarker analysis was available for 25 patients on the AMPECT trial. Mutational status of the suspect genes TSC1 or TSC2 in the mTOR pathway were analyzed for association with patient response outcomes. Mutation or deletion of TSC1 or TSC2 (no overlap) occurred in 5 (20%) and 9 (36%) patients respectively, while 11 (44%) patients had no alterations in TSC1 or TSC2. Responses occurred in 9/9 (100%) patients with TSC2 mutations, 1/5 (20%) patients with TSC1 mutations and 1/11 (9%) of patients with no mutations in TSC1 or TSC2.

The safety data presented at ASCO (Free ASCO Whitepaper) was available for all 34 patients treated on the AMPECT trial. The most common treatment-related hematologic adverse events of any grades included anemia (47%) and thrombocytopenia (32%) and the most common nonhematologic treatment-related adverse events of any grades included mucositis (74%), rash (65%), fatigue (59%), nausea (47%), and diarrhea (38%). Most of these events were grade 1 and 2, were manageable with dose modifications and no grade 4 events were observed. Twelve patients (35%) required dose reductions due to adverse events. Two patients (6%) discontinued nab-sirolimus due to an adverse event.

The AMPECT Phase 2 registration trial for Advanced Malignant Perivascular Epithelioid Cell Tumors completed enrollment in late 2018. Aadi previously received agreement from the FDA that this open label study in approximately 30 efficacy evaluable patients with a primary endpoint of independently reviewed objective response rate could support the submission of an NDA for approval to treat this rare disease.