On October 19, 2016 Kite Pharma, Inc. (Nasdaq:KITE) reported updates on its advancing pipeline of chimeric antigen receptor (CAR) and T cell receptor (TCR) product candidates and KTE-C19 launch readiness at its Investor Day in New York on October 18, 2016 (Press release, Kite Pharma, OCT 19, 2016, View Source [SID1234515917]).

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"At Kite, our goal is to cure cancer. With KTE-C19, we may have the opportunity to transform the treatment of aggressive non-Hodgkin lymphoma (NHL)," said Arie Belldegrun, M.D., FACS, Chairman, President and Chief Executive Officer of Kite. "While we prepare to manufacture and commercialize KTE-C19 upon approval, we believe this is just the beginning. The breadth of the pipeline we unveiled today, combined with our innovative T cells 2.0 programming, has the potential to deliver hope for a cure to thousands of people across 15 hematological and solid cancer indications."

Kite detailed four new near-term clinical development programs, including timelines for planned Investigational New Drug (IND) applications:

KITE-796: IND in 2018
Directed against the most promising target for acute myeloid leukemia (AML)
single-chain variable fragment (scFv) from human anti-CLL-1 monoclonal antibody (mAb) to minimize immunogenicity
"Control CAR" to incorporate dynamic switch technology
First Kite product candidate from Amgen collaboration
KITE-585: IND in 2017
Directed against the best and a validated target for multiple myeloma (MM)
scFv from human anti-BCMA mAb to minimize immunogenicity
Will leverage Kite’s clinical development and manufacturing expertise for program acceleration
KITE-718: IND in 2016
Directed against next generation MAGE A3/A6, a cancer testis antigen and validated target for TCR therapy for non-small cell lung cancer and bladder cancer
Built on National Cancer Institute (NCI) proof of concept with improved T cell manufacturing technologies
KITE-439: IND in 2018
Directed against HPV-16 E7, a viral oncoprotein target for TCR therapy for cervical cancer and head and neck cancer
Internal expertise to select best-in-class TCR candidates without affinity enhancement
T cells 2.0 next generation cell programming is in development to design engineered T cells that increase safety, potency and effectiveness:

Safety: Dynamic control switch technology ("Control CAR") that may regulate and allow the ability to dial up and dial down engineered T-cell expansion
Potency: Transmembrane Immunomodulatory Proteins (TIPs) for solid tumors that may function at the immune synapse thereby limiting immune-activation to engineered T cells
Effectiveness: T-cell differentiation technology that may enable a reliable and renewable cell source to advance the clinical application of universal allogeneic T-cell therapy
Kite is advancing its KTE-C19 pipeline with ongoing and expanded ZUMA studies to evaluate six additional indications:

ZUMA-2: Mantle cell lymphoma (MCL), with initial Phase 2 data expected in 2017
ZUMA-3: Adult acute lymphoblastic leukemia (Adult ALL), with initial Phase 1 data expected in 2016
ZUMA-4: Pediatric acute lymphoblastic leukemia (Pediatric ALL), with initial Phase 1 data expected in 2016
ZUMA-5: Indolent NHL, with first patient enrolled expected in the first quarter of 2017
ZUMA-7: 2nd line DLBCL, with first patient enrolled expected in 2017
ZUMA-8: Chronic lymphocytic leukemia (CLL), with first patient enrolled expected in 2017
Kite reviewed its proven clinical cell manufacturing capability, preparations to produce and deliver KTE-C19 at commercial scale following U.S. regulatory approval, and ongoing activities to automate next generation manufacturing:

Efficient and consistent manufacturing process
High clinical manufacturing success rate – 99 percent manufacturing of KTE-C19 for patients enrolled in ZUMA-1
Estimated capacity for 4,000+ patient treatments per year and ability to expand quickly
Next generation automation planned to enter feasibility testing in 2017 through collaboration with GE Research
Kite discussed its ongoing activities to build scientific awareness and to commercialize KTE-C19 following U.S. regulatory approval:

Early market research substantiates awareness of CAR-T therapy and potential for adoption
Medical Science Liaison team ready for deployment in the fourth quarter of 2016
Proactive Market Access strategy and engagement with payers
Controlled launch approach lays groundwork for expansion, understanding of therapy, patient management, and reimbursement
A replay of the audio webcast will be available for approximately 30 days and can be accessed through the Events and Presentations section under the Investors tab of Kite’s website at www.kitepharma.com.

About KTE-C19

Kite Pharma’s lead product candidate, KTE-C19, is an investigational therapy in which a patient’s T cells are engineered to express a CAR to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias, and redirect the T cells to kill cancer cells. KTE-C19 has been granted Breakthrough Therapy Designation status for diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma (TFL), and primary mediastinal B-cell lymphoma (PMBCL) by the U.S. Food and Drug Administration and Priority Medicines (PRIME) regulatory support for DLBCL in the EU.

On October 19, 2016 Eli Lilly and Company (NYSE: LLY) reported that the U.S. Food and Drug Administration (FDA) has granted approval of LARTRUVO (olaratumab injection, 10 mg/mL), in combination with doxorubicin, for the treatment of adults with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery (Press release, Eli Lilly, OCT 19, 2016, View Source [SID1234515915]). LARTRUVO’s indication is approved under Accelerated Approval, and is based on data from the Phase 2 portion of the pivotal JGDG trial. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. LARTRUVO, in combination with doxorubicin, is the first FDA-approved front-line therapy for STS in four decades. The confirmatory Phase 3 trial, ANNOUNCE, is fully enrolled.

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"LARTRUVO represents an important step forward in soft tissue sarcoma treatment," said William D. Tap, M.D., chief of the sarcoma medical oncology services at Memorial Sloan Kettering Cancer Center in New York and the principal investigator of the JGDG registration trial. "We are pleased with this approval, which will provide patients with a treatment option that offers new hope in their battle against this difficult disease."

Soft tissue sarcoma is a complex disease with multiple subtypes, making it hard to diagnose and difficult to treat. For decades, there have been no first-line therapeutic advancements for STS that have improved overall survival (OS). According to the American Cancer Society, in 2015, there were an estimated 12,000 new STS cases diagnosed and nearly 5,000 deaths in the U.S. alone, representing an unmet medical need.

LARTRUVO is the first monoclonal antibody approved to treat STS. It also received Fast Track, Orphan Drug and Breakthrough Therapy designations from the FDA for this indication, and was reviewed and approved under the FDA’s Accelerated Approval program. This program allows for earlier approval of drugs that treat serious conditions and that fill an unmet medical need.

"The approval of LARTRUVO is based on an encouraging and positive study for patients, and represents progress in soft tissue sarcoma treatment. For the first time in four decades, we now have a combination regimen – LARTRUVO and doxorubicin – that offers progress over doxorubicin alone in the front-line setting, by improving overall survival for people with soft tissue sarcoma," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "This continues our commitment to discovering new ways to treat cancer, including for people who have rare types of cancer."

"The entire sarcoma patient community is excited to have an innovative medicine approved for the treatment of advanced soft tissue sarcoma," said Bert E. Thomas IV, PhD, MBA, CEO of the Sarcoma Foundation of America. "We are confident that the approval of LARTRUVO may help these patients live longer."

The approval of LARTRUVO is based on the results of JGDG, an open-label, randomized, active-controlled study of 133 patients, which compared LARTRUVO, in combination with doxorubicin chemotherapy, to doxorubicin alone in patients with STS with a histologic subtype for which an anthracycline-containing regimen was appropriate and which is not amenable to curative treatment with surgery or radiotherapy. The efficacy outcome measures were OS, progression-free survival (PFS), and objective response rate (ORR).

Median OS was improved by 11.8 months in patients randomized to receive LARTRUVO plus doxorubicin compared to patients randomized to doxorubicin alone, and was statistically significant. Median OS was 26.5 months (95% CI: 20.9, 31.7) on the LARTRUVO-doxorubicin arm compared to 14.7 months (95% CI: 9.2, 17.1) on the doxorubicin-only arm (stratified hazard ratio [HR], 0.52; 95% CI: 0.34, 0.79, < 0.05). The study met its prespecified protocol-defined endpoint for PFS. Patients treated on the LARTRUVO and doxorubicin arm achieved 8.2 months (95% CI: 5.5, 9.8) of median PFS compared to 4.4 months (95% CI: 3.1, 7.4) on the doxorubicin-only arm (stratified hazard ratio [HR], 0.74; 95% CI: 0.46, 1.19), based on independent review. The number of events at the time of analysis was 37 (56%) on the LARTRUVO-doxorubicin arm and 34 (51%) on the doxorubicin-only arm. The number of deaths at the time of analysis was 39 (59%) on the LARTRUVO-doxorubicin arm and 52 (78%) on the doxorubicin-only arm. Objective response rate (ORR), based on independent review and defined as complete response (CR) plus partial response (PR), was also assessed with an ORR of 18.2 percent (95% CI: 9.8, 29.6) (CR, 4.5%; PR, 13.6%) on the LARTRUVO-doxorubicin arm and 7.5 percent (95% CI: 2.5, 16.6) (CR, 1.5%; PR, 6%) on the doxorubicin-only arm.

The labeling for LARTRUVO contains Warnings and Precautions for infusion-related reactions and embryo-fetal toxicity. The most commonly reported adverse reactions (all grades) occurring in ≥20 percent of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%), fatigue (69% vs 69%), musculoskeletal pain (64% vs 25%), mucositis (53% vs 35%), vomiting (45% vs 19%), diarrhea (34% vs 23%) and headache (20% vs 9%). The most common laboratory abnormalities (all grades) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%), neutropenia (65% vs 63%), thrombocytopenia (63% vs 44%), hyperglycemia (52% vs 28%), elevated aPTT (33% vs 13%), hypokalemia (21% vs 15%) and hypophosphatemia (21% vs 7%). Febrile neutropenia was reported in 13% of LARTRUVO plus doxorubicin-treated patients versus 12% of doxorubicin-treated patients.

Adverse reactions resulting in permanent discontinuation of LARTRUVO occurred in 8% (5/64) of patients. The most common adverse reaction leading to LARTRUVO discontinuation was infusion-related reaction (3%). Dose reductions of LARTRUVO for adverse reactions occurred in 25% (16/64) of patients; the most common adverse reaction leading to dose reduction was Grade 3 or 4 neutropenia (20%). Dose delays of LARTRUVO for adverse reactions occurred in 52% (33/64) of patients; the most common adverse reactions resulting in dose delays were neutropenia (33%), thrombocytopenia (8%) and anemia (5%). See the full Important Safety Information at the end of this press release and the Prescribing Information.

Lilly is committed to helping patients access LARTRUVO and offers support programs for qualified uninsured, underinsured and insured patients who receive LARTRUVO for its FDA-approved indication and who may need assistance with their out-of-pocket prescription medication costs, including a co-pay program where qualified patients pay no more than $25 per infusion. Patients and healthcare professionals with questions about LARTRUVO should contact The Lilly Answers Center at 1-800-LillyRx (1-800-545-5979) or visit www.lilly.com.

About LARTRUVO (olaratumab)

LARTRUVO is a platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody that specifically binds PDGFR-α and prevents receptor activation. LARTRUVO exhibits in vitro and in vivo anti-tumor activity against selected sarcoma cell lines and disrupted the PDGFR-α signaling pathway in in vivo tumor implant models. Information about additional clinical trials for LARTRUVO in sarcoma can be found at ClinicalTrials.gov (in the search box on the home page, type in "olaratumab").

A Phase 3 trial of LARTRUVO and doxorubicin in advanced STS is fully enrolled (ClinicalTrials.gov Identifier: NCT02451943).

About the JGDG Trial

JGDG was an open-label, randomized, active-controlled study that compared LARTRUVO, in combination with doxorubicin chemotherapy, to doxorubicin alone in patients with unresectable, soft tissue sarcoma (STS).

The study enrolled 133 doxorubicin-naïve patients with STS with a histologic subtype for which an anthracycline-containing regimen was appropriate and which is not amenable to curative treatment with surgery or radiotherapy. Sixty-six patients with an ECOG performance status of 0 – 2 were randomized to the LARTRUVO-doxorubicin arm and 67 to the doxorubicin-only arm.

Patients were randomized to receive LARTRUVO at 15 mg/kg as an intravenous infusion on day one of each 21-day cycle in combination with 75 mg/m2 doxorubicin, and LARTRUVO only on day eight. Doxorubicin was administered following LARTRUVO infusion on day one of each 21-day cycle for up to eight cycles. After doxorubicin was discontinued, patients on the LARTRUVO plus doxorubicin arm without evidence of disease progression or unacceptable toxicity could continue to receive LARTRUVO monotherapy until disease progression. All patients received the cardioprotectant dexrazoxane prior to doxorubicin in cycles five to eight.

About Sarcomas

Sarcomas are a diverse and relatively rare type of cancer that usually develop in the connective tissue of the body, which include fat, blood vessels, nerves, bones, muscles, deep skin tissues and cartilage. Soft tissue sarcoma is a complex disease with multiple subtypes, making it very hard to diagnose and difficult to treat. For decades, there have been no front-line therapeutic advancements for STS that have improved overall survival. According to the American Cancer Society, in 2015, there were an estimated 12,000 new STS cases diagnosed and nearly 5,000 deaths in the U.S. alone.

INDICATION

LARTRUVO is indicated, in combination with doxorubicin, for the treatment of adult patients with soft tissue sarcoma (STS) with a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

This indication is approved under Accelerated Approval. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

IMPORTANT SAFETY INFORMATION FOR LARTRUVO

Warnings and Precautions

Infusion-Related Reactions

Infusion-related reactions (IRR) occurred in 70 (14%) of 485 patients who received at least one dose of LARTRUVO across clinical trials. For 68 of these 70 patients (97%), the first occurrence of IRR was in the first or second cycle. Grade ≥3 IRR occurred in 11 (2.3%) of 485 patients, with one (0.2%) fatality. Symptoms of IRR included flushing, shortness of breath, bronchospasm, or fever/chills, and in severe cases symptoms manifested as severe hypotension, anaphylactic shock, or cardiac arrest. Infusion-related reactions required permanent discontinuation in 2.3% of patients and interruption of infusion in 10% of patients. All 59 patients with Grade 1 or 2 IRR resumed LARTRUVO; 12 (20%) of these patients had a Grade 1 or 2 IRR with rechallenge. The incidence of IRR in the overall safety database (N = 485) was similar (18% versus 12%) between those who did (56%) and those who did not (44%) receive premedication. Monitor patients during and following LARTRUVO infusion for signs and symptoms of IRR in a setting with available resuscitation equipment. Immediately and permanently discontinue LARTRUVO for Grade 3 or 4 IRR.
Embryo-Fetal Toxicity

Based on animal data and its mechanism of action, LARTRUVO can cause fetal harm when administered to a pregnant woman. Animal knockout models link disruption of platelet-derived growth factor receptor alpha (PDGFR-α) signaling to adverse effects on embryo-fetal development. Administration of an anti-murine PDGFR-α antibody to pregnant mice during organogenesis caused malformations and skeletal variations. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LARTRUVO and for 3 months after the last dose.
Most Common Adverse Reactions/Lab Abnormalities

The most commonly reported adverse reactions (all grades; grade 3-4) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were nausea (73% vs 52%; 2% vs 3%), fatigue (69% vs 69%; 9% vs 3%), musculoskeletal pain (64% vs 25%; 8% vs 2%), mucositis (53% vs 35%; 3% vs 5%), alopecia (52% vs 40%; 0% vs 0%), vomiting (45% vs 19%; 0% vs 0%), diarrhea (34% vs 23%; 3% vs 0%) decreased appetite (31% vs 20%; 2% vs 0%), abdominal pain (23% vs 14%; 3% vs 0%), neuropathy (22% vs 11%; 0% vs 0%), and headache (20% vs 9%; 0% vs 0%).
The most common laboratory abnormalities (all grades; grade 3-4) occurring in ≥20% of patients receiving LARTRUVO plus doxorubicin versus doxorubicin alone were lymphopenia (77% vs 73%; 44% vs 37%), neutropenia (65% vs 63%; 48% vs 38%) and thrombocytopenia (63% vs 44%; 6% vs 11%), hyperglycemia (52% vs 28%; 2% vs 3%), elevated aPTT (33% vs 13%; 5% vs 0%), hypokalemia (21% vs 15%; 8% vs 3%), and hypophosphatemia (21% vs 7%; 5% vs 3%).
Use in Specific Populations

Lactation: Because of the potential risk for serious adverse reactions in breastfeeding infants, advise women not to breastfeed during treatment with LARTRUVO and for at least 3 months following the last dose.
For more information about LARTRUVO, please see full Prescribing Information at View Source

On October 19, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the U.S. Food and Drug Administration (FDA) approved TECENTRIQ (atezolizumab) for the treatment of people with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumour has EGFR or ALK gene abnormalities (Press release, Hoffmann-La Roche , OCT 19, 2016, View Source [SID1234515914]). This approval is based on results from the randomised Phase III OAK and Phase II POPLAR studies. The largest study, OAK, 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 = 0.74, 95% CI: 0.63, 0.87). The study enrolled people regardless of their PD-L1 status and included both squamous and non-squamous disease types.

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"TECENTRIQ is a new option to help people with this type of previously treated metastatic lung cancer, regardless of PD-L1 expression, live longer than chemotherapy" said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "TECENTRIQ is the first and only approved cancer immunotherapy designed to target the PD-L1 protein, which may play an important role in the way the medicine works."

The TECENTRIQ development programme includes more than 15 clinical trials in lung cancer, including seven phase III studies in previously untreated (first-line) lung cancer. These studies are evaluating the use of TECENTRIQ alone or in combination with other medicines.

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 in 1,225 people with locally advanced or metastatic NSCLC whose disease had progressed following previous treatment with platinum-containing chemotherapy, with the primary analysis consisting of the first 850 randomised patients. Patients with both squamous and non-squamous disease were randomised (1:1) to receive either TECENTRIQ administered intravenously at 1200 mg every 3 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks. The co-primary endpoints were overall survival (OS) in all randomised patients (ITT population) and in a PD-L1-selected subgroup in the primary analysis population.

About the POPLAR study
POPLAR is a multicentre, open-label, randomised, Phase II study evaluating the efficacy and safety of TECENTRIQ compared with chemotherapy (docetaxel) in people with previously treated recurrent locally advanced or metastatic NSCLC. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.

A summary of the efficacy data from the OAK and POPLAR studies that supports this approval is included below.

The most common side effects (≥ 20%) in patients with metastatic non-small cell lung cancer were fatigue, decreased appetite, dyspnea (shortness of breath), cough, nausea, musculoskeletal pain, and constipation. Nine patients (6.3%) who were treated with TECENTRIQ experienced either pulmonary embolism (2), pneumonia (lung infection) (2), pneumothorax, ulcer hemorrhage (bleeding ulcer), cachexia secondary to dysphagia, myocardial infarction (heart attack), or large intestinal perforation which led to death. TECENTRIQ was discontinued for adverse reactions in 4 percent (6) of the 142 patients.

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 TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to target and bind to a protein called PD-L1 (programmed death ligand-1), which is expressed on tumour cells and tumour-infiltrating immune cells. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells. By blocking this interaction, TECENTRIQ may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells. TECENTRIQ is currently only approved in the US.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

About personalised cancer immunotherapy (PCI)
The aim of personalised cancer immunotherapy (PCI) is to provide patients and physicians with treatment options tailored to the specific immune biology associated with a person’s individual tumour. The purpose is to inform treatment strategies which provide the greatest number of people with a chance for transformative benefit. In the case of TECENTRIQ, the goal of PD-L1 as a biomarker is to explore PD-L1 expression on tumour cells and tumour infiltrating immune cells and how that correlates with clinical benefit either as a monotherapy or in combination, and across a broad range of tumour types. The Roche PCI research and development programme comprises more than 20 investigational candidates, ten of which are in clinical trials.

PCI is an essential component of how Roche delivers on the broader commitment to personalised healthcare. To learn more about the Roche approach to cancer immunotherapy please follow this link:
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