On October 24, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA (pembrolizumab), the company’s anti-PD-1 (programmed death receptor-1) therapy, for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (tumor proportion score [TPS] of 50 percent or more) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations (Press release, Merck & Co, OCT 24, 2016, View Source [SID1234515978]).

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With this new indication, KEYTRUDA is now the only anti-PD-1 therapy to be approved in the first-line treatment setting for these patients. In addition, the FDA approved a labeling update to include data from KEYNOTE-010 in the second-line or greater treatment setting for patients with metastatic NSCLC whose tumors express PD-L1 (TPS of one percent or more) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. In metastatic NSCLC, KEYTRUDA is approved for use at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA (pembrolizumab) should be withheld or discontinued and corticosteroids administered when appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Monitor patients for signs and symptoms of infusion-related reactions and for Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Female patients of reproductive potential should be advised of the potential hazard to a fetus. For more information regarding immune-mediated and infusion-related adverse reactions and use in pregnancy, see "Selected Important Safety Information" below.

"KEYTRUDA improved survival, compared to traditional chemotherapy, in patients with non-small cell lung cancer whose tumors express high levels of PD-L1," said Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laboratories. "The approval of KEYTRUDA for the first-line treatment of metastatic non-small cell lung cancer has the potential to change the treatment landscape for these patients."

"With this new indication, KEYTRUDA can now be a first treatment option instead of chemotherapy for patients with metastatic non-small cell lung cancer whose tumors express high levels of PD-L1," said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. "These data reaffirm the importance of testing for PD-L1 expression in non-small cell lung cancer in order to identify those patients who are most likely to benefit from treatment with KEYTRUDA."

Data Supporting First-Line Approval

The approval was based on data from KEYNOTE-024, a randomized, open-label, phase 3 study evaluating KEYTRUDA monotherapy compared to standard of care (SOC) platinum-containing chemotherapy for the treatment of patients with both squamous (18%) and non-squamous (82%) metastatic NSCLC. The study enrolled patients who had not received prior systemic chemotherapy treatment for their metastatic disease and whose tumors had high PD-L1 expression (TPS of 50 percent or more) and with no EGFR or ALK aberrations. The study randomized 305 patients to receive KEYTRUDA (200 mg every three weeks) or investigator-choice SOC platinum-based chemotherapy (pemetrexed+carboplatin, pemetrexed+cisplatin, gemcitabine+cisplatin, gemcitabine+carboplatin, or paclitaxel+carboplatin). Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. The primary endpoint was progression-free survival (PFS); additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR).

Based on an interim analysis demonstrating KEYTRUDA (pembrolizumab) was superior compared to chemotherapy for both the primary endpoint of PFS and the secondary endpoint of OS, the trial was stopped early in June 2016 to give patients still on chemotherapy the opportunity to receive KEYTRUDA.

Findings demonstrated that KEYTRUDA reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37, 0.68]; p<0.001). Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of death compared to chemotherapy (HR, 0.60 [95% CI, 0.41, 0.89]; p=0.005).


Efficacy Results from KEYNOTE-024

Endpoint KEYTRUDA
200 mg every 3 weeks
(n=154)
Chemotherapy

(n=151)
PFS
Number (%) of patients with event 73 (47%) 116 (77%)
Median in months (95% CI) 10.3 (6.7, NR) 6.0 (4.2, 6.2)
Hazard ratio* (95% CI) 0.50 (0.37, 0.68)
p-Value (stratified log-rank) <0.001
OS
Number (%) of patients with event 44 (29%) 64 (42%)
Median in months (95% CI) NR
(NR, NR)
NR
(9.4, NR)
Hazard ratio* (95% CI) 0.60 (0.41, 0.89)
p-Value (stratified log-rank) 0.005†
Objective Response Rate
ORR % (95% CI) 45% (37, 53) 28% (21, 36)
Complete response % 4% 1%
Partial response % 41% 27%
p-Value (Miettenen-Nurminen) 0.001
Median duration of response
in months (range)

NR
(1.9+, 14.5+)

6.3
(2.1+, 12.6+)
* Based on the stratified Cox proportional hazard model
† P-value is compared with 0.0118 of the allocated alpha for this interim analysis
NR = not reached

"The approval of KEYTRUDA in the first-line setting adds to the momentum of progress that has been made to treat lung cancer, particularly in the area of immunotherapy," said Laurie Fenton Ambrose, president and CEO, Lung Cancer Alliance. "Patients now have an option beyond chemotherapy at initial diagnosis. This approval reinforces the need for biomarker testing so care can be personalized and most effective."

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis. See additional "Selected Important Safety Information" below.

Data Supporting Second-Line Labeling Update

KEYNOTE-010 is a randomized, open-label, phase 2/3 trial evaluating KEYTRUDA (2 mg/kg [n=344] or 10 mg/kg [n=346] every three weeks) compared to SOC chemotherapy (docetaxel, 75 mg/m2 every three weeks [n=343]) in 1,033 patients with squamous (21%) and non-squamous (70%) metastatic NSCLC with all levels of PD-L1 expression (TPS of one percent or more) who had progressed following platinum-containing chemotherapy and, if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Additionally, results were reported in a subset of patients who had high PD-L1 expression (TPS of 50 percent or more) in the KEYTRUDA 2 mg/kg (n=139), KEYTRUDA 10 mg/kg (n=151), and chemotherapy cohorts (n=152). The primary endpoints were OS and PFS. Additional efficacy measures included ORR and response duration.

KEYTRUDA demonstrated superior OS versus docetaxel in patients with all levels of PD-L1 expression. Based on exploratory analyses, higher OS was associated with higher PD-L1 expression level.

Efficacy Results from KEYNOTE-010: Subgroup of Patients with TPS of 50 Percent or More
Endpoint KEYTRUDA
2 mg/kg every
3 weeks
n=139
KEYTRUDA
10 mg/kg every
3 weeks
n=151
Docetaxel
75 mg/m 2 every
3 weeks
n=152
OS
Deaths (%) 58 (42%) 60 (40%) 86 (57%)
Median in months (95% CI) 14.9 (10.4, NR) 17.3 (11.8, NR) 8.2 (6.4, 10.7)
Hazard ratio* (95% CI) 0.54 (0.38, 0.77) 0.50 (0.36, 0.70) —
p-Value (stratified log-rank) <0.001 <0.001 —
PFS
Events (%) 89 (64%) 97 (64%) 118 (78%)
Median in months (95% CI) 5.2 (4.0, 6.5) 5.2 (4.1, 8.1) 4.1 (3.6, 4.3)
Hazard ratio* (95% CI) 0.58 (0.43, 0.77) 0.59 (0.45, 0.78) —
p-Value (stratified log-rank) <0.001 <0.001 —
Objective Response Rate
ORR† (95% CI) 30% (23, 39) 29% (22, 37) 8% (4, 13)
p-Value (Miettenen-Nurminen) <0.001 <0.001 —
Median duration of response in
months (range)
NR
(0.7+, 16.8+) NR
(2.1+, 17.8+) 8.1
(2.1+, 8.8+)
* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
† All responses were partial responses
NR = not reached

Efficacy Results from KEYNOTE-010: All Randomized Patients with TPS of One Percent or More
Endpoint KEYTRUDA
2 mg/kg every
3 weeks
n=344
KEYTRUDA
10 mg/kg every
3 weeks
n=346
Docetaxel
75 mg/m 2 every
3 weeks
n=343
OS
Deaths (%) 172 (50%) 156 (45%) 193 (56%)
Median in months (95% CI) 10.4 (9.4, 11.9) 12.7 (10.0, 17.3) 8.5 (7.5, 9.8)
Hazard ratio* (95% CI) 0.71 (0.58, 0.88) 0.61 (0.49, 0.75) —
p-Value (stratified log-rank) <0.001 <0.001 —
PFS
Events (%) 266 (77%) 255 (74%) 257 (75%)
Median in months (95% CI) 3.9 (3.1, 4.1) 4.0 (2.6, 4.3) 4.0 (3.1, 4.2)
Hazard ratio* (95% CI) 0.88 (0.73, 1.04) 0.79 (0.66, 0.94) —
p-Value (stratified log-rank) 0.068 0.005 —
Objective Response Rate
ORR† (95% CI) 18% (14, 23) 19% (15, 23) 9% (7, 13)
p-Value (Miettenen-Nurminen) <0.001 <0.001 —
Median duration of response in
months (range)
NR
(0.7+, 20.1+) NR
(2.1+, 17.8+) 6.2
(1.4+, 8.8+)
* Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
† All responses were partial responses
NR = not reached

In KEYNOTE-010, treatment was discontinued for adverse reactions in eight percent of the 682 patients receiving KEYTRUDA (pembrolizumab) across both doses. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA (pembrolizumab) occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most frequent adverse reactions (reported in at least 10% of KEYTRUDA patients and occurring at the same or higher incidence than in the docetaxel arm) were decreased appetite (25% for KEYTRUDA vs. 23% for docetaxel), dyspnea (23% vs. 20%), nausea (20% vs. 18%), cough (19% vs. 14%), rash (17% vs. 8%), constipation (15% vs. 12%), vomiting (13% vs. 10%), arthralgia (11% vs. 9%), back pain (11% vs. 8%), and pruritus (11% vs. 3%). Other clinically important adverse reactions occurring in patients receiving KEYTRUDA were fatigue (25%), diarrhea (14%), asthenia (11%), and pyrexia (11%).

PD-L1 Companion Diagnostic for Patients with Metastatic NSCLC

The PD-L1 IHC 22C3 PharmDx kit made by Dako North America, Inc., an Agilent Technologies Company, was approved in 2015 by the FDA for use in detecting PD-L1, an immune-related biomarker expressed on some tumor cells. The diagnostic is intended to aid in identifying appropriate patients for treatment with KEYTRUDA, including previously treated patients whose tumors have any level of PD-L1 expression (TPS of one percent or more) and previously untreated patients whose tumors have high levels of PD-L1 expression (TPS of 50 percent or more). Tumors with a TPS of less than one percent are considered to have no PD-L1 expression.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA (pembrolizumab) is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression (TPS ≥50%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab) (continued)

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA (pembrolizumab), including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA (pembrolizumab) can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than docetaxel) were decreased appetite (25% vs. 23%), dyspnea (23% vs. 20%), and nausea (20% vs. 18%).

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 360 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

On October 24, 2016 Oasmia Pharmaceutical and Karo Pharma reported that they have entered into an agreement concerning Karo Pharma’s cancer project KB9520, which has shown promising results in pre-clinical models for a number of different types of cancer (Press release, Oasmia, OCT 24, 2016, View Source [SID1234515976]).

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Oasmia acquires the project and strengthens its oncology project portfolio. Karo Pharma receives 3,080,000 newly issued shares as a down payment corresponding to a value of MSEK 25. Additionally, Oasmia will pay Karo Pharma 20% of all future revenues generated by the project for Oasmia.

Oasmia will continue the development process and will be responsible for all project expenses.

"This is a solid industrial solution where the companies can focus within their respective areas. Oasmia, which has several cancer projects in both early and late developmental phase, strengthens its already unique product portfolio. The collaboration is based on a separation of focus that will work well and I am personally committed to making this a successful collaboration for both companies" says Anders Lönner, Executive Chairman in Karo Pharma.

"This is a very exciting acquisition for Oasmia as the project will complement the company’s current product portfolio with novel innovative candidates within our focus area. A prerequisite in this transaction from our side has been to get access to Anders Lönners unique track record in developing companies and his international business experience. Since we are looking forward to several registrations of new pharmaceutical products, his expertise will be very valuable. Anders Lönner is proposed to be part of Oasmia’s Board of Directors and will also be proposed as chairman at an extraordinary shareholders meeting." says Julian Aleksov, largest shareholder in Oasmia Pharmaceutical.

Stockholm Corporate Finance has been advising Oasmia in this transaction.

On October 24, 2016 Inovio Pharmaceuticals, Inc. (NASDAQ:INO) reported that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on its proposed phase III clinical program for VGX-3100 (Press release, Inovio, OCT 24, 2016, View Source [SID1234515974]). A clinical hold is a notification issued by the FDA to a trial sponsor to delay a proposed clinical trial or suspend an ongoing clinical trial. This study has not yet been initiated and has not enrolled or dosed subjects. Additionally, the hold does not pertain to any of Inovio’s other ongoing clinical studies.

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Inovio anticipates receiving a formal letter with complete information from the FDA within 30 days. In its initial communication, the FDA has requested additional data to support the shelf-life of the newly designed and manufactured disposable parts of the CELLECTRA 5PSP immunotherapy delivery device. Inovio is working diligently with the FDA to address its concerns and anticipates that the requested data will be available before the end of this year. Inovio estimates that the start of the phase III clinical program will be delayed until the first half of 2017 pending resolution of the FDA’s requests.

On October 24, 2016 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company committed to improving patient lives by manufacturing high quality products for biotechnology and pharmaceutical companies and advancing its proprietary R&D pipeline, reported the presentation of preclinical study data demonstrating that phosphatidylserine (PS)-targeting antibodies similar to bavituximab are able to enhance the anti-tumor activity of anti-PD-L1 therapy in a model of triple negative breast cancer (TNBC) (Press release, Peregrine Pharmaceuticals, OCT 24, 2016, View Source [SID1234515967]). Data showed that a combination of anti-PS and anti-PD-L1 therapies, with or without paclitaxel, led to greater anti-tumor responses than any of the treatments administered as single agents or dual treatment combinations with paclitaxel, in the well-characterized E0771 murine model of TNBC. Study results were presented by researchers from Duke University Medical Center at the American Association for Cancer Research (AACR) (Free AACR Whitepaper)’s Tumor Immunology and Immunotherapy Conference held October 20-23, 2016 in Boston, MA.

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In addition to evaluating the anti-tumor activity of the various treatment combinations, researchers also examined the impact of various traditional cancer therapies on PS expression in cancer cells. Study results confirmed that levels of PS expression were upregulated in E0771 and 4T1 TNBC cells following treatment with chemotherapy, radiation or photodynamic therapy. Photodynamic therapy also was shown to increase PS expression on tumor cells.

"These study results provide the latest support for the belief that PS-targeting therapies can enhance the anti-tumor activity of checkpoint inhibitors such as anti-PD-L1 therapy in the treatment of TNBC. Just last month, we announced results from another preclinical study in TNBC demonstrating that 80% of animals receiving the triple combination of anti-PS, anti-PD-1 and anti-LAG3 therapies experienced complete tumor regressions, whereas there were no animals in the anti-PD-1 and anti-LAG3 combination treatment arm that had a complete regression," said Jeff T. Hutchins, Ph.D., Peregrine’s vice president, preclinical research. "Additionally, these latest study findings related to increased PS expression on the surface of tumor cells following traditional cancer treatments demonstrate important activity within the tumor microenvironment that offers rationale for the potential of anti-PS agents in combatting cancer. We plan to continue to work with our collaborators at Duke University Medical Center to further study the therapeutic potential of PS-targeting agents in combination with checkpoint inhibitors like anti-PD-L1 and conventional therapies that augment immunotherapy mechanisms."

Bavituximab is an investigational monoclonal antibody that targets PS. Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. Previous studies demonstrated PS-targeting antibodies shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor responses. Peregrine evaluates the preclinical equivalent of bavituximab, ch1N11, in animal model studies to guide clinical development.

Peregrine’s clinical development strategy for bavituximab currently focuses on small, early-stage, proof-of-concept trials evaluating the drug in combination with other cancer treatments. This approach includes the recently announced grants by the National Comprehensive Cancer Network (NCCN) to support three different clinical trials of bavituximab treatment combinations. Those trials will evaluate novel bavituximab combinations in glioblastoma, head and neck cancer, and hepatocellular carcinoma including an immunotherapy combination. Additionally, Peregrine continues to advance its pre-clinical collaboration with Memorial Sloan Kettering Cancer Center with the goal of evaluating combinations of bavituximab with other checkpoint inhibitors and immune stimulatory agents. The intent behind this strategy is to focus our research and development spending to further validate bavituximab’s combination potential as we seek to advance the program though a pharmaceutical or biotechnology partner.

On October 24, 2016 Advaxis, Inc. (NASDAQ:ADXS), a clinical stage biotechnology company developing cancer immunotherapies, reported topline results from the early closure of stage 2 of the Phase 2 GOG-0265 trial, conducted by the Gynecologic Oncology Group (GOG, now part of NRG Oncology) and supported by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) (Press release, Advaxis, OCT 24, 2016, View Source [SID1234515966]).

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GOG-0265 is a single-arm, open-label Phase 2 multicenter study (NCT01266460) designed to evaluate the safety and activity of axalimogene filolisbac in patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) in a standard Simon two-stage design. The first stage of the study included a six-patient safety run-in and enrolled 26 patients. The first stage of the study was previously completed, meeting the predetermined safety and efficacy criteria required to proceed into the second stage of patient enrollment. The second stage enrolled 24 patients prior to the clinical hold that affected Advaxis’ clinical development programs last year. The second stage was not completed as designed due to the clinical hold.

A preliminary analysis of 12-month overall survival data from 24 patients enrolled in the second stage prior to the clinical hold showed that treatment with axalimogene filolisbac resulted in a 37.5 percent 12-month overall survival rate. These preliminary findings are consistent with earlier data that showed a 38.5 percent 12-month overall survival rate in 26 patients enrolled in the first stage of the study, despite modest differences in dosing schedules between the two stages.

Based on protocol defined prognostic factors of patients who enrolled in the study (n=50), a 12-month survival rate of 25 percent would have been expected. Comparing this 25 percent 12-month overall survival rate to the 38 percent 12-month overall survival rate actually observed across the total study population, treatment with axalimogene filolisbac resulted in a 52 percent increase in the expected 12-month overall survival rate.

"These data demonstrate a meaningful improvement in 12-month overall survival rate compared to historical GOG studies," said Warner K. Huh, M.D., division director of Gynecologic Oncology at the University of Alabama at Birmingham, and lead investigator of the study. "Historical survival rates for patients with PRmCC underscore the need for additional treatment options for patients and these results illustrate the promising therapeutic potential for axalimogene filolisbac in women with this rare cancer."

In the second stage of the study, 15 out of 24 patients experienced a Grade 1 or Grade 2 treatment-related adverse event (TRAE). The most common Grade 1 or Grade 2 TRAEs were hypotension and symptoms related to cytokine release (e.g., nausea, chills, fever). Nine out of 24 patients experienced a Grade 3 TRAE and two out of 24 patients experienced a Grade 4 TRAE, which were hypotension and symptoms related to cytokine release.

"We are very encouraged by these data and look forward to presenting and discussing a more detailed analysis of the trial results at an upcoming medical society meeting," said Daniel J. O’Connor, president and chief executive officer of Advaxis. "We believe that a more than 50 percent increase in 12-month overall survival rate is clinically meaningful, and Advaxis plans to pursue registrational opportunities in Europe in 2017."

Axalimogene filolisbac was recently classified as an advance therapy medicinal product (ATMP) in the EU, has received U.S. Food and Drug Administration (FDA) Fast Track Designation as an adjuvant therapy for treating high risk, locally advanced cervical cancer (HRLACC), and has been granted U.S. orphan drug designation for the treatment of invasive cervical cancer.

About Cervical Cancer

Cervical cancer is the fourth most common cancer in women worldwide.2 An estimated 13,000 new cases will be diagnosed in the United States in 2016, and 4,100 people will die of the disease, according to the National Cancer Institute. Persistent HPV infection is the most important factor in the development of cervical cancer, research shows.3,4 According to the ICO Information Centre on HPV and Cervical Cancer, about 4.4 percent of women in the United States are estimated to harbor high-risk cervical HPV infection at a given time, and about 72 percent of cervical cancers are attributed to high-risk HPV strains.5 The prognosis for women with advanced and recurrent cervical cancer remains poor, with survival of only 4 to 7 months following failure of first-line treatment, research has shown.6. According to the American Cancer Society, the 5-year mortality rate for metastatic disease is at just 17 percent, with the area continuing to be a high unmet medical need.7

About The GOG Foundation, Inc.

The GOG Foundation, Inc. (GOG), now part of NRG Oncology, is a non-profit international organization with the purpose of promoting excellence in the quality and integrity of clinical and basic scientific research in the field of gynecologic malignancies. The GOG is committed to maintaining the highest standards in clinical trials development, execution, analysis and distribution of results. Continuous evaluation of its processes is utilized in order to constantly improve the quality of patient care. The GOG conducts clinical trials for patients with a variety of gynecologic malignancies, including cancers that arise from the ovaries, uterus, cervix, vagina and vulva. General information on many of these trials for medical professionals and the lay public can be obtained from ClinicalTrials.gov.

NRG Oncology is one of four adult US Network groups funded under the newly structured NCI National Clinical Trials Network. NRG Oncology is comprised of three legacy cooperative groups, the National Surgical Adjuvant Breast and Bowel Project (NSABP), the Radiation Therapy Oncology Group (RTOG), and the Gynecologic Oncology Group (GOG).