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Juno Therapeutics’ Investigational CAR T Cell Product Candidate JCAR015 Shows High Response Rates in Adults with B-cell ALL

On June 4, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported that encouraging clinical data from JCAR015, a chimeric antigen receptor (CAR) T cell product candidate, support its strategic approach towards the commercialization of its first CAR T therapy (Press release, Juno, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175107 [SID:1234513024]). Updated results will be presented today in an oral presentation at the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Abstract #7003, Arie Crown Theater, 4:00 p.m. CT).
"The ongoing efficacy and duration of response for a large percentage of patients, specifically those who do not go on to stem cell transplant, continues to be impressive," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "These findings provide us with further confidence about our development strategy and the ongoing Phase II ROCKET pivotal trial."
In the Phase I study, presented by lead investigator Jae H. Park, M.D., of Memorial Sloan Kettering Cancer Center, 51 adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) were treated with either cyclophosphamide or fludarabine/cyclophosphamide followed by an infusion of JCAR015. At the time of treatment, 31 patients had morphologic disease burden and 20 patients had minimal disease burden. Median study follow-up was 8.5 months. Key results include:
Complete response (CR) was observed in 23/30 (77%) patients with morphologic disease and in 18/20 (90%) patients with minimal disease.
In patients who achieved a CR and had adequate evaluation for minimal residual disease by flow cytometry or polymerase chain reaction, complete molecular remission was observed in 19/21 (90%) patients with morphologic disease and in 14/18 (78%) patients with minimal disease.
Median overall survival (OS) for patients with minimal disease treated with JCAR015 was not reached, and that for morphologic patients treated with JCAR015 was 9 months; median OS follow-up for all patients was 13 months.
Durable responses and survival observed in patients who received JCAR015 were comparable between groups that received a subsequent stem cell transplant and those that did not.
Severe cytokine release syndrome (sCRS) was observed in 14/51 (27%) patients and Grade 3 or higher neurotoxicity was observed in 15/51 (29%) patients. For patients with minimal disease, 1/20 (5%) patients experienced sCRS and 4/20 (20%) patients had Grade 3 or higher neurotoxicity.
About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR015 is an investigational product candidate and its safety and efficacy have not been established.

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Foundation Medicine and AstraZeneca Enter Strategic Collaboration for Lynparza Companion Diagnostic Assay

On June 4, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) and AstraZeneca reported that they have entered into a definitive agreement to develop a novel companion diagnostic assay for Lynparza (olaparib) to support its global development program (Press release, Foundation Medicine, JUN 4, 2016, View Source [SID:1234513019]). The companion diagnostic will enable physicians to identify those patients most likely to benefit from AstraZeneca’s first-in-class poly ADP-ribose polymerase (PARP) inhibitor.

Lynparza is an innovative, oral PARP inhibitor that exploits tumor DNA repair pathway deficiencies to preferentially kill cancer cells. This mode of action gives olaparib the potential for activity in a range of tumor types with DNA repair deficiencies. Lynparza is approved in the US for the treatment of patients with germline BRCA-mutated advanced ovarian cancer and in the European Union for patients with platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer.

Under the terms of the agreement, Foundation Medicine will develop and make available a regulatory approved product utilizing the Quality Systems Regulations (QSR)-compliant version of its FoundationOne comprehensive genomic profiling platform. This assay will detect multiple classes of genomic alterations across a range of genes involved in Homologous Recombination Repair (HRR). The assay, based on a scientifically selected panel of genes known to be involved in driving the HRR process, will be developed alongside the clinical program for Lynparza, as part of a coordinated drug-diagnostic regulatory strategy.

Nina Mojas, global medicine lead for Lynparza at AstraZeneca said, "This agreement supports the broad development program for our first-in-class PARP inhibitor, Lynparza. Utilizing Foundation Medicine’s leading capabilities in molecular information will help our work to assess the potential of the medicine to address unmet patient need across a number of cancers driven by DNA repair deficiencies, including and – significantly – beyond the BRCA mutations."

"Following our new master collaboration agreement with AstraZeneca, we are pleased to launch this first strategic initiative to support and advance the development of Lynparza in a number of cancers," stated Steven J. Kafka, Ph.D., president and chief operating officer for Foundation Medicine. "The work we’ve undertaken with AstraZeneca underscores the importance and potential of utilizing our rigorously validated, comprehensive profiling approach to make available to physicians an FDA-approved universal companion diagnostic solution for use with targeted medicines."

FoundationOne® Identifies Patients with Advanced Lung Cancer Likely to Respond or Develop Resistance to Certain RET Inhibitor Therapies

On June 4, 2016 Foundation Medicine, Inc. (NASDAQ:FMI) reported new critical genomics data at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting 2016 demonstrating the clinical significance of comprehensive genomic profiling (CGP) with FoundationOne in identifying patients with advanced lung cancer most likely to respond to RET inhibitor targeted therapies and also to predict those patients likely to develop resistance to targeted therapy (Press release, Foundation Medicine, JUN 4, 2016, View Source [SID:1234513018]).

Key Data Highlights:

The poster titled, "MDM2 amplification (Amp) to mediate cabozantinib resistance in patients (Pts) with advanced RET-rearranged lung cancers," presented by Romel Somwar, Ph.D., senior research scientist, pathology, Memorial Sloan Kettering Cancer Center, analyzes the genomic profiles of patients treated with the RET inhibitor, cabozantinib, to better understand the molecular mechanisms that underlie intrinsic and secondary resistance. Key study findings include:

Comprehensive genomic profiles were performed on 3,842 lung cancer patients, detecting concurrent MDM2 amplification in 20 percent of tumors with RET fusions
In RET-rearranged cell lines and xenografts treated with cabozantinib and the MDM2 inhibitors, AMG232 and RG7388, a combination of cabozantinib and AMG232 proved more effective at suppressing tumor growth than either agent alone
The study shows that MDM2 amplification is a potential mechanism of primary or acquired resistance to cabozantinib, and therefore MDM2 inhibitors might be studied clinically to prevent the development of acquired resistance and enable longer, more durable responses to treatment
The second poster presentation titled, "Significant systemic and CNS activity of RET inhibitor vandetanib combined with mTOR inhibitor everolimus in patients with advanced NSCLC with RET fusion," by Tina Cascone, M.D., Ph.D. and Vivek Subbiah, M.D., from The University of Texas MD Anderson Cancer Center, demonstrates that targeted combination therapy of vandetanib with the mTOR inhibitor, everolimus, was tolerable and demonstrated significant activity in RET rearranged NSCLC. Key study findings include:

Vandetanib and everolimus were administered to 13 stage IV NSCLC patients, including six patients with tumors harboring RET fusions
All six patients with RET fusions experienced a response, including five partial responses and one patient with stable disease
The six patients with RET fusions were identified using CGP with FoundationOne. Notably, two additional patients tested positive for RET fusions using FISH and did not respond to treatment.
The study suggests that combination therapy was superior to monotherapy with RET inhibitors, warranting further studies of this combination. The study further highlights the superior accuracy of CGP for calling fusions over traditional single gene tests, like FISH.
"By helping us better understand the likelihood of response and resistance to certain therapies, CGP is providing information that can help improve physician treatment decisions and ultimately, we believe, lead to better patient outcomes," said Vincent Miller, M.D., chief medical officer, Foundation Medicine. "Additionally, the sensitivity and accuracy of FoundationOne to reliably detect all classes of clinically relevant alterations in non-small cell lung cancer allow us to circumvent the false positives that often arise with single gene and standard hotspot testing. As this study shows, inaccuracies in genomic testing can lead to unnecessary and often unsuccessful treatments, as well as inefficient and costly care delivery."

Genomic alterations in the RET gene are found in several different types of cancer. RET gene fusions occur in 1 percent of non-small cell lung cancers (NSCLC) and are well-established oncogenic drivers. The RET inhibitor agents, vandetanib and cabozantinib, have demonstrated antitumor activity in NSCLC patients harboring RET fusions, although data suggest that objective responses are observed in only a minority of patients, and progression-free survival (PFS) is shorter than with other oncogene targeted therapies in this disease. A portion of tumors may harbor intrinsic resistance to RET inhibitors, while some respond but eventually progress, yielding to the development of secondary resistance. However, molecular mechanisms that underlie resistance to cabozantinib are poorly understood. Taken together, these studies reinforce the critical importance of FoundationOne in identifying patients likely to respond to targeted therapies and to predict those patients likely to develop resistance.

Lung cancer is by far the leading cause of death among both men and women; about 1 out of 4 cancer deaths are from lung cancer1. There are two major types of lung cancer: NSCLC and small cell lung cancer (SCLC). NSCLC is the most common and accounts for approximately 85 percent of all lung cancer cases2. The American Cancer Society estimates there will be about 224,390 new cases of lung cancer in the United States for 2016 and about 158,080 deaths1.

Pfizer Presents Data from Phase 1b Trial Investigating Utomilumab (a 4-1BB agonist) in Combination with a Checkpoint Inhibitor

On June 4, 2016 Pfizer Inc. (NYSE:PFE) reported results from a Phase 1b trial of Pfizer’s investigational immunotherapy agent utomilumab (the proposed non-proprietary name for PF-05082566), a 4-1BB (also called CD137) agonist, in combination with pembrolizumab, a PD-1 inhibitor, in patients with advanced solid tumors (Press release, Pfizer, JUN 4, 2016, View Source [SID:1234513014]). This is the first reported study of a 4-1BB agonist combined with a checkpoint inhibitor. Encouraging safety data from the study were shared today as an oral presentation at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

"While these are early data, the combination of utomilumab with pembrolizumab demonstrates an encouraging safety profile and an early indication of potential anti-tumor activity across solid tumors," said Anthony W. Tolcher, M.D., director of clinical research at South Texas Accelerated Research Therapeutics (START) San Antonio. "We believe these results warrant further investigation to confirm whether combining utomilumab with a checkpoint inhibitor may amplify anti-tumor responses."

Of the 23 patients enrolled in the trial, six had a confirmed complete or partial response. The majority (four of six) of these responses lasted at least six months, with two patients maintaining their response for nearly one year at the time of data cut off. Treatment emergent adverse events were generally mild and did not appear to increase with higher doses of utomilumab, and no dose-limiting toxicity was reported.

"Pfizer believes that bringing the promise of immunotherapies for cancer to more patients will occur through combining agents that work on different pathways within the immune system," said Chris Boshoff, vice president and head of Early Development, Translational and Immuno-Oncology for Pfizer Oncology. "We are exploring numerous utomilumab combinations in order to better understand its potential role in mobilizing the immune system against difficult-to-treat cancers."

Pfizer is investigating utomilumab in both hematologic cancers and solid tumors in several planned and ongoing trials. It is being evaluated as a single agent across multiple tumors, in combination with rituximab in lymphoma,1 and in combination with other immunotherapies (e.g., OX40 agonist [PF-04518600], anti-CCR4 [mogamulizumab] and avelumab, an investigational fully human anti-PD-L1 IgG1 monoclonal antibody being developed through an alliance between Merck KGaA, Darmstadt, Germany, and Pfizer) in various solid tumors and hematological malignancies.2,3,4 The mogamulizumab/utomilumab combination is a collaboration with Kyowa Hakko Kirin, Japan.3

About the Study

This Phase 1b dose-escalation study assessed overall safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of utomilumab in combination with pembrolizumab in 23 patients with advanced solid tumors (non-small cell lung, renal cell carcinoma, head and neck, pancreatic, anaplastic thyroid, small-cell lung, colon, sarcoma, thymoma and melanoma). The primary objective was to estimate the maximum tolerated dose and select the recommended Phase 2 dose. Patients received utomilumab (0.45 to 5.0 mg/kg) and pembrolizumab (2 mg/kg) intravenously on day one of 21-day cycles. The number of cycles patients have received across all doses ranged from two to 19, and five patients remain on treatment (maximum dosing is 32 cycles).

The six confirmed responses included two complete responses in one patient with small cell lung cancer and one patient with renal cell carcinoma; partial responses were observed in one patient each with renal cell carcinoma, non-small cell lung cancer, head and neck cancer and anaplastic thyroid cancer. The most common treatment related adverse events were rash, fatigue, itching, fever, decreased appetite and nausea, with none reported as Grade 3 or 4. No patients discontinued due to treatment related toxicity.

About Utomilumab

Utomilumab (PF-05082566) is a fully human monoclonal antibody (mAb) agonist that selectively binds to 4-1BB (also called CD137), a protein receptor expressed in many cancer-fighting T cells. When a 4-1BB agonist binds to CD137, it has been observed to stimulate and increase the number of T cells, which is believed to accelerate the immune response to attack and kill cancer cells. In preclinical models, utomilumab has shown anti-tumor activity by enhancing T cell mediated immune responses.5,6,7 Utomilumab is being studied in combination with checkpoint inhibitors, which act on another immune signaling pathway and are believed to work by blocking signals from cancer cells which inhibit the host immune system. This signal blockade may allow the host immune system to attack cancer cells.

Learn more about how Pfizer Oncology is applying innovative approaches in an effort to improve the outlook for people living with cancer at View Source

Halozyme Presents Stage One Efficacy And Safety Analysis Of Phase 2 Clinical Study In Metastatic Pancreatic Cancer Patients Treated With PEGPH20

On June 4, 2016 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, repprted results from a final analysis of 135 metastatic pancreatic cancer patients who were treated in Stage One of HALO 109-202, a phase 2 clinical study of its investigational new drug PEGPH20 in combination with ABRAXANE (nab-paclitaxel) and gemcitabine (PAG arm) as compared to ABRAXANE and gemcitabine alone (AG arm) (Press release, Halozyme, JUN 4, 2016, View Source [SID:1234513006]).

This final analysis of secondary and exploratory endpoints was conducted using the Ventana companion diagnostic to retrospectively identify high levels of hyaluronan (HA). The key results based on a February 2016 data cut-off showed in the HA-high patient population:

Median progression-free survival (PFS) was 9.2 months in the PAG arm versus 6.0 months in the AG arm, hazard ratio (HR) with a 95 percent confidence interval (CI): 0.46 (0.15, 1.40);
Overall response rate (ORR) of 50 percent, including one complete response in the PAG arm versus 33 percent and all partial responses in the AG arm;
Median duration of response (DoR) of 8.1 months in the PAG arm versus 3.7 months in the AG arm;
The exploratory analysis of median overall survival (OS) was similar between the treatment arms — 11.8 months vs. 10.9 months in the PAG vs. AG arms respectively. Factors potentially having an impact on these results include less aggressive disease among patients in the AG arm and a greater than 40 percent discontinuation rate of PEGPH20 treatment at the time of the clinical hold, resulting in all patients receiving AG alone in both arms;
The rate of thromboembolic (TE) events reduced from 43 percent to 9 percent in the PAG arm and from 25 percent to 6 percent in the AG arm with the introduction of prophylaxis with low molecular weight heparin (enoxaparin) from Stage One to Stage Two of the study.
"We are encouraged by the positive trends in this final Stage One dataset, even with PEGPH20 treatment being discontinued for more than 40 percent of patients in the PAG arm due to the prior clinical hold," said Dr. Athena Countouriotis, senior vice president and chief medical officer. "The safety profile continues to show the benefit of prophylactic enoxaparin use and the dataset continues to support our ongoing phase 3 study."

Prior interim analyses were based on patient follow up through December 2014. Results announced today include 14 months of additional follow up through February 2016. Stage One of HALO 202 enrolled a total of 146 patients between May 2013 to July 2014. The study was placed on clinical hold from April to July 2014 during which time PEGPH20 was discontinued while patients in both arms continued to receive treatment with ABRAXANE and gemcitabine alone. Stage Two enrolled a total of 133 patients as of February 2016 and Halozyme remains blinded to the overall efficacy. The company projects to report mature PFS and ORR results from Stage Two late in the fourth quarter.

Dr. Andrea Bullock, attending physician in Gastrointestinal Oncology at Beth Israel Deaconess Medical Center and an Instructor in Medicine at Harvard University said: "As one of the highest enrollers in the HALO 202 study, I am encouraged by the final data from Stage One in the HA-high patients. While the sample size remains small, the median PFS and ORR continue to favor the PEGPH20 combination treatment arm compared to the standard of care AG arm. I look forward to the Stage Two results later this year and to participating in the phase 3 global study very soon."

Halozyme’s ongoing phase 3 study, HALO 301, uses the Ventana companion diagnostic to prospectively identify HA-high patients and mirrors the design of the phase 2 study including the current inclusion/exclusion criteria; 2:1 randomization; and dosing regimens. This double-blinded placebo-controlled study plans to enroll a total of 420 patients at approximately 200 centers within 20 countries. The co-primary endpoints are PFS and OS, with a target hazard ratio of 0.59 for PFS, which is well supported by the final results from Stage One of HALO 202.

Halozyme is the only oncology biotech targeting HA, a glycosaminoglycan – or chain of natural sugars throughout the body – that can accumulate around cancer cells inhibiting other therapies. PEGPH20 is designed to degrade HA to improve the access to tumor cells for chemotherapy, monoclonal antibodies and other immuno-therapy agents.

About HALO 301
HALO 301 is a phase 3 global, randomized, double-blind placebo controlled clinical trial evaluating investigational new drug PEGPH20 as a first-line therapy for potential treatment of patients with metastatic pancreatic cancer. The trial will be conducted at approximately 200 sites with two co-primary endpoints of progression free survival and overall survival in patients receiving investigational new drug PEGPH20 in combination with gemcitabine and ABRAXANE (nab-paclitaxel) compared to gemcitabine and nab-paclitaxel alone. Secondary endpoints also include objective response rate and overall survival. More information may be found at clinicaltrials.gov (search HALO 301 or trial identifier NCT02715804) or www.HALO301.com.

About PEGPH20
PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.