On June 5, 2017 Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, reported updated clinical and biomarker data for its lead immuno-oncology product candidates, CMB305 and G100 (Press release, Immune Design, JUN 5, 2017, View Source [SID1234519373]). The data are being presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting in Chicago.

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CMB305 Monotherapy in Soft Tissue Sarcoma Patients: Clinical Benefit, Safety and Patient Selection

Data in an oral presentation last Friday by Neeta Somaiah, M.D., Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, highlight the results of 25 soft tissue sarcoma (STS) patients with recurrent disease treated with CMB305:

Patient characteristics: 92% metastatic, 56% progressing upon trial entry, and 52% with ≥2 prior lines of chemotherapy
Survival: median overall survival (mOS) has still not yet been reached.
• The overall survival rate at 12 and 18 months was 83% and 76%, respectively.
• These new data compare favorably to mOS for approved second line and later sarcoma agents, which is only 12.4-13.5 months, as well as a published mOS of 11.7 months for synovial sarcoma patients specifically; the largest patient population enrolled in this trial.
Disease control: a disease control rate (CDR) of 64% (16/25) was observed, including durable tumor growth arrest in patients who had evidence of disease progression at study entry.
Safety: CMB305 was well tolerated, with only one related Grade 3 adverse event (AE).
Immune response: CMB305 generated a strong and broad anti-NY-ESO-1 immune response in >50% of the patients, with 32% patients experiencing an integrated response (T cells and antibodies).
Antigen spreading: induction of an immune response against other tumor antigens not targeted by CMB305 was detected in 33% of evaluable patients following CMB305 therapy.
In a related presentation today, Seth M. Pollack, M.D. of the Fred Hutchinson Cancer Research Institute, will present data examining the relationship between immune response against NY-ESO-1 and clinical benefit in a combined set of CMB305 and LV305 patients (n=64) with various tumor types. LV305 is the vector only, "prime" component of CMB305, and was the subject of a separate Phase 1 study:

NY-ESO-1 specific "public" T cell receptor (pTCR): three NY-ESO-1-specific T-cell receptor sequences isolated from a patient responding to therapy were found to be shared by approximately 50% of all study patients, as well as healthy blood donors, tested. These pTCR sequences indicate a low level of pre-existing anti-NY-ESO-1 immunity which appear to be expanded by CMB305.
Immune response: the induction of an integrated anti-NY-ESO-1 immune response (antibodies and T-cells) was observed in more than 30% of the patients who received therapy.
Biomarker (immune response) vs. Survival: the induction of an anti-NY-ESO-1 immune response by these agents is associated with improved patient survival, particularly in patients with pre-existing anti-NY-ESO-1 immunity.
Patient selection: these immune biomarkers, including novel bio-markers derived from pTCRs, may guide regulatory strategy via the selection of patients more likely to have survival benefit on CMB305 therapy.
G100 Monotherapy in Follicular NHL (FL) Patients: Clinical Benefit, Safety and Changes to the Tumor Microenvironment (TME)

In a poster presentation today, Christopher Flowers, M.D., Department of Hematology and Medical Oncology, Emory University School of Medicine, will present results of 9 patients with FL treated with escalating doses of G100 monotherapy (with local radiation (XRT)).

Patient characteristics: of the 9 FL patients enrolled, 45% were treatment-naïve and 56% were relapsed/refractory, and most had Stage III and IV disease (56% and 33%, respectively). Additionally, 55% of patients had received at least two prior therapies and 78% had progressive disease upon study entry.
Disease control:
• Objective responses were observed at all three dose levels tested.
• 44% of the patients achieved a partial response (PR) based on WHO criteria (at least a 50% tumor reduction).
• Some patients had tumor shrinkage over a prolonged period, e.g., continuing up to 8+ months, and a duration of response exceeding 4 months in some patients.
• DCR of 100% of patients (44% PR, 56% SD).
• 50% of evaluable patients experienced shrinkage of untreated distal (abscopal) lesion.
Safety: G100 was well tolerated, with no related Grade 3/4 AEs in all three dose levels tested.
Tumor microenvironment: G100 resulted in favorable tumor microenvironment changes
• Tumor biopsies showed increased inflammatory responses and T cell infiltrates in abscopal, non-treated tumors.
"These data demonstrate that both CMB305 and G100, our lead cancer immunotherapy product candidates, are capable of activating patients’ immune systems in ways that have a direct effect on patients’ tumor growth, whether it is tumor-growth arrest on CMB305 therapy and subsequent survival benefit, or ORR and systemic tumor shrinkage after local therapy with G100," said Sergey Yurasov, MD, PhD, Senior Vice President and Chief Medical Officer at Immune Design. "Also, importantly, we are evaluating immune biomarkers that may identify patients who are likely to benefit the most from CMB305 therapy. We plan to present these clinical data to regulatory agencies in planning for a pivotal trial that may lead to subsequent regulatory approval, and enable us to bring these novel, safe immunotherapies to cancer patients."

ASCO Presentation Details

ORAL PRESENTATION

Immune response, safety, and survival impact from CMB305 in NY-ESO-1+ recurrent soft tissue sarcomas (STS)

Abstract # 11006
Session Title: Sarcoma
Date: Friday, June 2, 2017
Time: 3 p.m. — 6 p.m. CT (oral session)
Location: S100bc
Presenter: Neeta Somaiah, M.D., Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center
POSTER PRESENTATIONS

The Association of CMB305 or LV305-induced and baseline anti-NY-ESO-1 immunity with survival in recurrent cancer patients

Abstract # 3090
Session Title: Developmental Therapeutics—Immunotherapy
Date: Monday, June 5, 2017
Time: 8 a.m. — 11:30 a.m. CT
Location: Hall A
Presenter: Seth M. Pollack, M.D., Fred Hutchinson Cancer Research Center
Intratumoral G100 to induce systemic immune responses and abscopal tumor regression in patients with follicular lymphoma

Abstract # 7537
Session Title: Hematologic Malignancies — Lymphoma and Chronic Lymphocytic Leukemia
Date: Monday, June 5, 2017
Time: 8 a.m. — 11:30 a.m. CT
Location: Hall A
Presenter: Christopher Flowers, M.D., Department of Hematology and Medical Oncology, Emory University School of Medicine
About CMB305

CMB305 is a prime-boost vaccine approach against NY-ESO-1-expressing tumors, designed to generate an integrated, anti-NY-ESO-1 immune response in vivo via a targeted, specific interaction with dendritic cells, a mechanism of action Immune Design believes differs from traditional cancer vaccines. CMB305 is being evaluated in STS patients in ongoing Phase 1 monotherapy and 2 combination studies with the anti-PD-L1 antibody, Tecentriq (atezolizumab), pursuant to a collaboration with Genentech. Immune Design has received Orphan Drug Designation for CMB305 from the U.S. Food and Drug Administration (FDA) for the treatment of soft tissue sarcoma, as well as from the FDA and European Medicines Agency for each of the components of CMB305 for the treatment of soft tissue sarcoma.

About G100

G100 contains a potent synthetic small molecule toll-like receptor-4 (TLR-4) agonist, Glucopyranosyl Lipid A (GLA), and is the lead product candidate in Immune Design’s Antigen Agnostic approach. It leverages the activation of both innate and adaptive immunity, including dendritic cells, in the tumor microenvironment to create an immune response against the tumor’s preexisting diverse set of antigens. G100 is being evaluated as both a monotherapy (with XRT) and in combination with Merck’s anti-PD-1 agent, Keytruda (pembrolizumab), pursuant to a clinical collaboration with Merck, in a randomized Phase 1/2 trial in patients with follicular non-Hodgkin’s lymphoma. The FDA has granted Orphan Drug Designation for G100 for the treatment of follicular non-Hodgkin’s lymphoma.

On June 5, 2017 Fortress Biotech, Inc. (NASDAQ: FBIO) ("Fortress"), a biopharmaceutical company dedicated to acquiring, developing and commercializing novel pharmaceutical and biotechnology products, reported that Mustang Bio, Inc. ("Mustang"), a subsidiary of Fortress, has entered into exclusive, worldwide licensing agreements with City of Hope ("COH") for the use of three novel CAR T therapies in the development of cancer treatments (Press release, Fortress Biotech, JUN 5, 2017, View Source [SID1234519371]). 

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The CAR T therapies covered under the agreements include: human epidermal growth factor receptor 2 (HER2) CAR T technology (HER2 Technology), which will initially be applied in the treatment of glioblastoma multiforme; CS1‐specific CAR T technology (CS1 Technology) to be directed against multiple myeloma; and prostate stem cell antigen (PSCA) CAR T technology (PSCA Technology) to be used in the treatment of prostate cancer. All three technologies were developed in the laboratory of Stephen J. Forman, M.D., director of COH’s T cell Immunotherapy Research Laboratory.  

Dr. Manuel Litchman, President and Chief Executive Officer of Mustang, said, "We believe the in‐licensing of this COH technology will enable us to expand our CAR T portfolio through the application of novel product candidates and new indications. We look forward to our continued partnership with Dr. Forman and his team at COH, as we work together to advance cutting‐edge treatment options for cancer patients."

This announcement builds upon established exclusive patent license agreements that Mustang has entered into with COH related to Mustang’s lead CAR T therapies, MB‐101 (IL13Rα2‐specific CAR) and MB‐102 (CD123 CAR), spacer technology to be used in the development of CAR T treatments, and intraventricular and intracerebroventricular methods of delivering T cells that express CARs.

On June 5, 2017 Abbvie reported Long-term follow-up results from the pivotal Phase 3 RESONATE trial (PCYC-1112) showed continued survival rates in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) treated with IMBRUVICA (ibrutinib) up to four years, according to new data presented today at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (poster session: 8:00 a.m. – 11:30 a.m. CDT; poster discussion: 1:15 p.m. – 2:30 p.m. CDT) (Press release, AbbVie, JUN 5, 2017, View Source [SID1234519369]). The data regarding IMBRUVICA, a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor and the first chemotherapy-free treatment for patients with CLL, were announced by AbbVie (NYSE: ABBV), a global biopharmaceutical company. IMBRUVICA is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

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According to the study results, IMBRUVICA was associated with significantly longer progression free survival (PFS; 59 percent) in R/R CLL/SLL with median follow-up of 44 months, including in patient subgroups with genomic abnormalities that are traditionally considered high-risk for poor outcomes. In addition, 3-year overall survival (OS; 74 percent) was longer in IMBRUVICA-treated patients. Further, the overall response rate (ORR) was 91 percent with complete response (CR) rates increasing over time (9 percent) (abstract #7510).1

"These results suggest ibrutinib continues to provide persistent responses over the long-term in patients with chronic lymphocytic leukemia, including those who are difficult to treat," said John C. Byrd, MD, Distinguished University Professor at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute and lead investigator of the study.* "As a clinician who has treated patients with CLL for more than 20 years, I’m pleased to see the potential for efficacy and safety responses to continue over an extended period of time."

CLL, the most common form of leukemia in adults, is a type of cancer that starts from cells that become certain white blood cells (called lymphocytes) in the bone marrow. The cancer (leukemia) cells start in the bone marrow but then spread into the blood. There are more than 20,000 newly diagnosed CLL patients every year.2 CLL is predominately a disease of the elderly, with a median age of 71 at diagnosis.2 SLL is similar to CLL and affects the same lymphocytes; the only difference between the two is the location where the cancer primarily occurs.3 To-date, more than 25,000 CLL patients have been treated in the U.S. with IMBRUVICA since approval in 2014.

"The first pivotal RESONATE data on IMBRUVICA were presented three years ago at ASCO (Free ASCO Whitepaper) and represented the promise of a new standard of care in blood cancer treatment. We are pleased to continue to see very favorable responses and survival outcomes to IMBRUVICA in relapsed and refractory CLL patients now into the fourth year of study," said Danelle James, M.D., M.S., Head of Clinical Science, Pharmacyclics LLC, an AbbVie company. "We believe in the potential of IMBRUVICA across a range of blood cancers and other serious diseases, and are continuing to explore its potential as part of our robust clinical research program."

About the Study

Abstract #7510: Long-term efficacy and safety with ibrutinib (ibr) in previously treated chronic lymphocytic leukemia (CLL): Up to four years follow-up of the RESONATE study (Poster Board: #272)

Poster Session on Monday, June 5, 2017, 8:00 a.m. – 11:30 a.m. CDT at Hall A
Poster Discussion on Monday, June 5, 2017, 1:15 p.m. – 2:30 p.m. CDT at E354b
At up to 4 years of follow up, PFS was significantly longer for IMBRUVICA than ofatumumab (median NR versus 8 months, [HR 0.133; P<0.0001]; 3-year PFS 59 percent versus 3 percent). Significant benefit was observed across patient subgroups with genomic abnormalities that are traditionally considered high-risk for poor outcomes. Specifically, the high-risk genomic abnormalities were deletion 11q (del 11q), deletion 17p (del 17p), complex karyotype (CK), unmutated immunoglobulin heavy-chain variable-region (IGHV), NOTCH1 mutation, TP53 mutation, SF3B1 mutation, BIRC3 mutation and XP01 mutation. Patients with del 11q trended to have the most favorable outcome; however, PFS was not statistically different for patients with del 17p or del 11q or without these FISH abnormalities. At analysis, with the majority of patients (68 percent) randomized to ofatumumab crossing over to IMBRUVICA, OS was longer for IMBRUVICA versus ofatumumab (median OS not reached for either arm). The OS rate for IMBRUVICA at 3 years was 74 percent, and ORR was 91 percent, with CR and incomplete bone marrow recovery (CRi) increasing over time (now 9 percent).1

RESONATE is a Pharmacyclics-sponsored, randomized, multi-center, open-label, international Phase 3 study, which enrolled 391 patients with R/R CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (median age 67). Patients were administered either 420 mg oral IMBRUVICA (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300 mg followed by 11 doses at 2,000 mg per dose and schedule consistent with local labeling). The study met its primary endpoint, demonstrating improved PFS.1

The adverse event (AE) profile of IMBRUVICA was consistent with previous reports. Major hemorrhage, Grade ≥3 atrial fibrillation, and Grade ≥3 hypertension occurred in 6 percent, 6 percent, and 8 percent of patients, respectively, over a follow-up of up to 4 years. The incidence of most Grade ≥3 AEs decreased from year 1 versus year 2-3: neutropenia (18 percent versus 8 percent); pneumonia (11 percent versus 4 percent); atrial fibrillation (4 percent versus 2 percent), respectively. Discontinuations were most frequently due to progressive disease (27 percent) and AEs (12 percent). At analysis, 90 IMBRUVICA patients (46 percent) continue on therapy in the study.1

About IMBRUVICA
IMBRUVICA (ibrutinib) is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton’s tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling complex that plays an important role in the survival and spread of malignant B cells.4,5 IMBRUVICA blocks signals that tell malignant B cells to multiply and spread uncontrollably.4

IMBRUVICA is FDA-approved in five distinct patient populations: CLL, SLL, Waldenström’s macroglobulinemia (WM), along with previously-treated mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL).4

IMBRUVICA was first approved for patients with MCL who have received at least one prior therapy in November 2013.
Soon after, IMBRUVICA was initially approved in CLL patients who have received at least one prior therapy in February 2014. By July 2014, the therapy received approval for CLL patients with 17p deletion, and by March 2016, the therapy was approved as a frontline CLL treatment.
IMBRUVICA was approved for patients with WM in January 2015.
In May 2016, IMBRUVICA was approved in combination with bendamustine and rituximab (BR) for CLL/SLL patients.
In January 2017, IMBRUVICA was approved for patients with MZL who require systemic therapy and have received at least one prior anti-CD20-based therapy.
Accelerated approval was granted for the MCL and MZL indications based on overall response rate. Continued approval for MCL and MZL may be contingent upon verification and description of clinical benefit in confirmatory trials.4

IMBRUVICA was one of the first medicines to receive U.S. FDA approval via the new Breakthrough Therapy Designation pathway. This designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases. IMBRUVICA has been granted four Breakthrough Therapy Designations from the FDA, spanning CLL/SLL, WM, MCL and chronic graft-versus-host-disease (cGVHD). In addition, IMBRUVICA is the first standard therapy specifically approved for patients with previously-treated MZL and WM.

IMBRUVICA is being studied alone and in combination with other treatments in several blood and solid tumor cancers and other serious illnesses. IMBRUVICA has one of the most robust clinical oncology development programs for a single molecule in the industry, with approximately 130 ongoing clinical trials. There are a total of 30 ongoing company-sponsored trials, 14 of which are in Phase 3, and approximately 100 investigator-sponsored trials and external collaborations that are active around the world. To date, 70,000 patients around the world have been treated with IMBRUVICA in clinical practice and clinical trials.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre- and postsurgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and nonfatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Evaluate patients for fever and infections and treat appropriately.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13% to 29%), thrombocytopenia (range, 5% to 17%), and anemia (range, 0% to 13%) based on laboratory measurements occurred in patients treated with single agent IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6% to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. Atrial fibrillation should be managed appropriately and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines.

Hypertension – Hypertension (range, 6% to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new-onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing antihypertensive medications and/or initiate antihypertensive treatment as appropriate.

Second Primary Malignancies – Other malignancies (range, 3% to 16%) including non-skin carcinomas (range, 1% to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2% to 13%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (eg, high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS

The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia** (61%), thrombocytopenia** (62%), diarrhea (43%), anemia** (41%), musculoskeletal pain (30%), rash (30%), nausea (29%), bruising (30%), fatigue (29%), hemorrhage (22%), and pyrexia (21%).

** Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).

The most common Grade 3 or 4 non-hematologic adverse reactions (≥5%) in MZL patients were pneumonia (10%), fatigue (6%), diarrhea (5%), rash (5%), and hypertension (5%).

Approximately 6% (CLL/SLL), 14% (MCL), 11% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4%-10% (CLL/SLL), 9% (MCL), and 9% (WM [6%] and MZL [13%]) of patients discontinued due to adverse reactions. Most common adverse reactions leading to discontinuation were pneumonia, hemorrhage, atrial fibrillation, rash, and neutropenia (1% each) in CLL/SLL patients and subdural hematoma (1.8%) in MCL patients. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea, and rash (1.6% each) in WM and MZL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid coadministration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see Full Prescribing Information: View Source

On June 5, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY), the Breast International Group (BIG), Breast European Adjuvant Study Team (BrEAST) and Frontier Science Foundation (FS) reported the Phase III APHINITY study showed adjuvant (after surgery) treatment with the combination of Perjeta (pertuzumab), Herceptin (trastuzumab) and chemotherapy (the Perjeta-based regimen) significantly reduced the risk of breast cancer recurrence or death (invasive disease-free survival; iDFS) by 19% in people with HER2-positive early breast cancer (eBC) compared to Herceptin and chemotherapy alone (HR=0.81; 95% CI 0.66-1.00, p=0.045) (Press release, Hoffmann-La Roche, JUN 5, 2017, View Source [SID1234519367]).

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At three years, 94.1% of people treated with the Perjeta-based regimen did not have their breast cancer return compared to 93.2% treated with Herceptin and chemotherapy.1 The safety profile of the Perjeta-based regimen was consistent with that seen in previous studies, with a low incidence of cardiac events and no new safety signals.1,2
Based on data available at the time of the primary analysis, an estimate of iDFS at four years showed that 92.3% of people treated with the Perjeta-based regimen did not have their breast cancer return compared to 90.6% treated with Herceptin and chemotherapy, suggesting that further analyses with longer follow-up will be important to provide additional insights on these treatments.1

"The goal of adjuvant treatment is to help each person with cancer have the best chance of a cure, and we come closer to this goal with each advance," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "In the APHINITY study, the Perjeta-based regimen improved upon the high bar set by Herceptin in people with HER2-positive early breast cancer. We look forward to working with global health authorities to bring this treatment option to patients."

Gunter von Minckwitz, M.D., study coordinator from the BIG and academic study partners, President of the German Breast Group, added, "APHINITY provides yet another example of the importance of industry-academic collaborations and their value in advancing cancer care for people affected by this challenging disease. The median follow-up at the primary analysis was 45.4 months, and these early data are very encouraging. As we continue to follow patients up to 10 years, we hope that future analyses will provide additional insights on the role of a pertuzumab-based regimen in HER2-positive early breast cancer."

At the time of the primary analysis, with median follow-up of 45.4 months, the reduction in risk of invasive breast cancer recurrence with the Perjeta-based regimen was greatest in people with lymph node-positive (HR=0.77; 95% CI 0.62-0.96, p=0.019) or hormone receptor-negative disease (HR=0.76; 95% CI 0.56-1.04, p=0.085).1 At three years, among people with node-positive disease, 92.0% of people treated with the Perjeta-based regimen did not have their breast cancer return compared to 90.2% treated with Herceptin and chemotherapy, and iDFS rates in the hormone receptor-negative disease subgroup were 92.8% in the Perjeta-based arm and 91.2% in the Herceptin and chemotherapy arm.1 The number of events in both treatment arms was low in people with node-negative disease, where no benefit with the Perjeta-based regimen was detected at this time.1

HER2-positive breast cancer is an aggressive form of the disease that affects approximately one in five people with breast cancer.3 Despite advancements in the treatment of HER2-positive eBC, one in four people treated with Herceptin and chemotherapy will eventually see their cancer return in the long-term.4,5 Treating breast cancer early, before it has spread, may help prevent the disease from returning and potentially reaching an incurable stage.6

Adjuvant therapy is given after surgery and is aimed at killing any remaining cancer cells to help reduce the risk of the cancer returning.6

Full results of the primary analysis will be presented in an oral session today at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago by Gunter von Minckwitz, M.D., study coordinator from the BIG and academic study partners (Abstract #LBA500), and will be featured in ASCO (Free ASCO Whitepaper)’s official press programme. Results from the APHINITY trial will also be published today in the New England Journal of Medicine.

About APHINITY7
APHINITY (Adjuvant Pertuzumab and Herceptin IN Initial TherapY in Breast Cancer, NCT01358877/ BO25126/ BIG 4-11) is an international, Phase III, randomised, double-blind, placebo-controlled, two-arm study evaluating the efficacy and safety of Perjeta plus Herceptin and chemotherapy compared to Herceptin and chemotherapy as adjuvant therapy in 4,805 people with operable HER2-positive eBC.

People enrolled in the study underwent surgery and were randomised to one of two arms (1:1) to receive either:
Six to eight cycles of chemotherapy (anthracycline or non-anthracycline-containing regimen) with Perjeta and Herceptin, followed by Perjeta and Herceptin every three weeks for a total of one year (52 weeks) of treatment.
Six to eight cycles of chemotherapy (anthracycline or non-anthracycline-containing regimen) with placebo and Herceptin, followed by placebo and Herceptin every three weeks for a total of one year (52 weeks) of treatment.
Radiotherapy and/or endocrine therapy could be initiated at the end of adjuvant chemotherapy. For people with hormone receptor-positive disease enrolled in the APHINITY trial, it was recommended that endocrine therapy be administered for at least five years after completing adjuvant chemotherapy. The APHINITY study allowed for a range of standard chemotherapy regimens to be used and participants with both node-positive and node-negative disease were eligible for enrolment. The primary efficacy endpoint of the APHINITY study is iDFS, which in this study is defined as the time a patient lives without return of invasive breast cancer at any site or death from any cause after adjuvant treatment. Secondary endpoints include cardiac and overall safety, overall survival, disease-free survival and health-related quality of life.


* iDFS at four years was calculated based on data available at the time of primary analysis with median follow-up of 45.4 months
** Primary cardiac events included heart failure New York Heart Association (NYHA) class III or IV with left ventricular ejection fraction (LVEF) drop ≥10 points from baseline and to below 50%, and cardiac death
About Perjeta
Perjeta is a medicine that targets the HER2 receptor, a protein found on the outside of many normal cells and in high quantities on the outside of cancer cells in HER2-positive cancers.8,9 Perjeta is designed specifically to prevent the HER2 receptor from pairing (or ‘dimerising’) with other HER receptors (EGFR/HER1, HER3 and HER4) on the surface of cells, a process that is believed to play a role in tumour growth and survival. Binding of Perjeta to HER2 may also signal the body’s immune system to destroy the cancer cells. The mechanisms of action of Perjeta and Herceptin are believed to complement each other, as both bind to the HER2 receptor, but to different places. The combination of Perjeta and Herceptin is thought to provide a more comprehensive, dual blockade of HER signalling pathways, thus preventing tumour cell growth and survival.10,11

On June 5, 2017 Celsion Corporation (NASDAQ:CLSN), an oncology drug development company, reported an update on its OVATION Study, a Phase Ib dose escalating clinical trial combining GEN-1, the Company’s DNA-based immunotherapy, with the standard of care for the treatment of newly-diagnosed patients with advanced (stage III/IV) ovarian cancer who will undergo neoadjuvant chemotherapy followed by interval debulking surgery. GEN-1 is an IL-12 DNA plasmid vector formulated as a nanoparticle in a non-viral delivery system to cause the sustained local production and secretion of the Interleukin-12 (IL-12) protein loco-regionally at the tumor site.

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The Company announced the latest clinical and translational data from the OVATION Study in a poster presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2017 Annual Meeting at McCormick Place in Chicago, IL. The poster presentation, entitled "Phase 1 study of the safety and activity of formulated IL-12 plasmid administered intraperitoneally in combination with neoadjuvant chemotherapy in patients with newly diagnosed advanced stage ovarian cancer," was presented on Saturday, June 3rd from 1:15 PM to 4:45 PM by Dr. Premal H. Thaker, Associate Professor, Obstetrics and Gynecology Division of Gynecologic Oncology, Washington University in St. Louis School of Medicine. The presentation summarized clinical findings and available translational data from all fourteen patients treated in the trial to-date.

"The OVATION study has accrued patients from four major research cancer centers. We have seen highly promising clinical findings including a patient with a complete pathological response along with a very high rate of R0 at time of debulking surgery. The translational research data in the poster presentation demonstrates that GEN-1 is producing beneficial cytokines and positively impacting T-cells in the tumor," said Dr. Premal Thaker. "This is strong early data and we believe that GEN-1 may be stimulating the immune system to improve tumor control in these patients. I am looking forward to continuing our clinical evaluation of GEN-1 in subsequent ovarian cancer studies."

Celsion reported encouraging clinical data from the first fourteen patients who have completed treatment in the OVATION Study. GEN-1 plus standard chemotherapy produced positive results, with no dose limiting toxicities and promising dose dependent efficacy signals which appear to correlate well with successful surgical outcomes as summarized below:
Of the fourteen patients treated to date in the entire study, two (2) patients demonstrated a complete response, ten (10) patients demonstrated a partial response and two (2) patients demonstrated stable disease, as measured by RECIST criteria. This translates to a 100% disease control rate ("DCR") and an 86% objective response rate ("ORR"). Of the five patients treated in the highest dose cohort, there was a 100% objective response rate with one (1) complete response and four (4) partial responses.

Fourteen patients had successful resections of their tumors, with nine (9) patients (64%) having an R0 resection, which indicates a microscopically margin-negative resection in which no gross or microscopic tumor remains in the tumor bed. Of the five patients treated at the highest dose cohort, all five patients (100%) experienced a R0 surgical resection.

One patient demonstrated a pathological complete response (pCR). pCRs are typically seen in less than 7% of patients receiving neoadjuvant chemotherapy followed by surgical resection, and have been associated with a median overall survival (OS) of 72 months, which is more than three years longer than those who do not experience a pCR.

All patients experienced a clinically significant decrease in their CA-125 protein levels as of their most recent study visit. CA-125 is used to monitor certain cancers during and after treatment. CA-125 is present in greater concentrations in ovarian cancer cells than in other cells.

Celsion also reported supportive translational research data from the first four patient cohorts who have completed treatment in the OVATION Study. The translational data provides further insight into GEN-1’s mechanism of action through the evaluation of dose-related changes in the tumor and peritoneal immune cell population, as well as through the peritoneal cytokine levels.

Treatment-Related Changes in IL-12 and Cytokine Levels in Peritoneal Fluid
The analysis of peritoneal fluid and blood samples collected immediately before and 24 hours after IP administration of multiple doses of GEN-1 (36, 47, 61, 79 mg/m2) and standard NACT (carboplatin every 21 days and Taxol weekly) shows clear evidence of IL-12 gene transfer and biological response following GEN-1 treatment on a dose-dependent basis.

The translational data also demonstrated significant increases in IFN-gamma and decreases in VEGF levels. The treatment-related changes in immune activating cytokines and pro-tumor VEGF levels followed a dose-dependent trend and were predominantly in the peritoneal fluid compartment with little to no changes observed in the patients’ systemic blood stream.

Treatment-Related Changes in the Density of Various T-cells in Tumors
The immuno-histochemical (IHC) analysis of tumor tissue collected before treatment (laparoscopy) and after completion of eight GEN-1 weekly treatments showed increased infiltration of CD3+, CD4+ CD8+ T-cells into tumor tissue of several patients. The most pronounced effects observed in the IHC analysis were decreases in the density of immunosuppressive T-cell signals (FoxP3+, PD-1+, PDL-1+, IDO-1+) in the tumor microenvironment. The ratio of CD8+ cells to immunosuppressive T-cells was increased in 60-80% of patients suggesting an overall shift in the immune environment to pro-immune stimulatory following treatment with GEN-1.

An intriguing effect of the treatment on tumor microenvironment is a substantial reduction in the immunosuppressive T-cell subsets and an overall shift in the T-cell environment to favoring immune stimulation.

"Now having completed enrollment, per protocol, of our OVATION Study, we are impressed with GEN-1’s apparent activity in combination with standard chemotherapy in newly diagnosed patients with stage III and IV ovarian cancer. These data appear to correlate with the notable, unexpected surgical outcomes among all patients completing the prescribed eight weekly treatments and reinforce our confidence in the promise of GEN-1’s ability to work safely and effectively in advanced ovarian cancer," said Michael H. Tardugno, Celsion’s chairman, president and CEO. "Given these encouraging findings, in addition to our plans to evaluate GEN-1 in combination with Avastin in 2 nd line, the Company will consider continuing our clinical trials in the underserved newly diagnosed patient population."

OVATION Study Design
The Phase Ib trial evaluated weekly intraperitoneal dosing of GEN-1 in combination with neoadjuvant chemotherapy, the standard of care for patients newly diagnosed with ovarian cancer. Concurrently with neoadjuvant chemotherapy, enrolled patients received escalating weekly doses of GEN-1, from levels beginning at 36mg/m², to 47mg/m², 61mg/m² and 79mg/m² weekly for 8 treatments in total, followed by interval debulking surgery. The regimen is primarily being evaluated for its safety and tolerability.

About GEN-1 Immunotherapy
GEN-1, designed using Celsion’s proprietary TheraPlas platform technology, is an IL-12 DNA plasmid vector encased in a nanoparticle delivery system, which enables cell transfection followed by persistent, local secretion of the IL-12 protein. IL-12 is one of the most active cytokines for the induction of potent anti-cancer immunity acting through the induction of T-lymphocyte and natural killer (NK) cell proliferation. The Company has previously reported positive safety and encouraging Phase I results with GEN-1 given as monotherapy in patients with peritoneally metastasized ovarian cancer, and recently completed a Phase Ib trial of GEN-1 in combination with PEGylated doxorubicin in patients with platinum-resistant ovarian cancer.