On July 24, 2017 Pfizer Inc. (NYSE:PFE) reported that the REFLECTIONS B7391003 study, a comparative, confirmatory safety and efficacy study of PF-06439535 versus Avastin (bevacizumab), met its primary objective (Press release, Pfizer, JUL 24, 2017, View Source [SID1234519866]). PF-06439535 is being developed by Pfizer as a potential biosimilar to Avastin.

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The trial demonstrated equivalence in the primary endpoint of objective response rate (ORR) of PF-06439535 versus Avastin, taken in combination with carboplatin/paclitaxel, for the first line treatment of patients with advanced non-squamous non-small cell lung cancer (NSCLC).

"We are encouraged by this data, and its importance in helping to advance physician confidence in, and understanding of, the potential value of biosimilar medicines for cancer patients around the world," said Salomon Azoulay, MD, Senior Vice President, Chief Medical Officer, Pfizer Essential Health. "As Pfizer’s second proposed oncology monoclonal antibody biosimilar to achieve positive top line data results, we continue to focus on and commit to advancing our pipeline of proposed biosimilars, with the goal of expanding patient access to these important therapeutic options."

This latest data announcement represents Pfizer’s second proposed oncology biosimilar and the fourth proposed biosimilar pipeline molecule to report positive top-line results within the past year. The Pfizer biosimilars pipeline consists of eight distinct biosimilar molecules in mid to late stage development, and several others in early stage development.

About the REFLECTIONS B7391003 Study
REFLECTIONS B7391003 is a comparative, randomized, double blind, clinical trial [N=719] evaluating the efficacy, safety, pharmacokinetics (PK) and immunogenicity of PF-06439535 (a potential biosimilar to Avastin [bevacizumab]) in combination with carboplatin/paclitaxel versus Avastin in combination with carboplatin/paclitaxel for the first line treatment of patients with advanced non-squamous non-small cell lung cancer (NSCLC). The primary endpoint is objective response rate (ORR) which is defined as the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time.

More information about the PF-06439535 REFLECTIONS B7391003 study studies can be found at www.clinicaltrials.gov.

About PF-06439535
PF-06439535 is a monoclonal antibody (mAb) that is in development as a potential biosimilar to Avastin (bevacizumab). Avastin is approved in the U.S., EU and other regions for the treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous lung cancer (NSCLC) in addition to metastatic carcinoma of the colon or rectum; metastatic renal cell carcinoma; and other region-specific indications.

PF-06439535 is an investigational compound and has not received regulatory approval in any country. Biosimilarity has not yet been established by regulatory authorities and is not yet claimed.

On July 24, 2017 Epizyme, Inc. (NASDAQ:EPZM), a clinical-stage biopharmaceutical company creating novel epigenetic therapies, reported that the National Cancer Institute (NCI), part of the National Institutes of Health, has initiated its NCI-COG Pediatric MATCH study, which includes a phase 2 evaluation of tazemetostat as one of its treatment arms. Conducted under Epizyme’s Cooperative Research and Development Agreement (CRADA) executed with NCI in 2016, this multi-institutional study will evaluate tazemetostat as a monotherapy for pediatric patients with advanced solid tumors, including CNS tumors, non-Hodgkin lymphoma or histiocytic disorders that harbor gain of function mutations in EZH2, or loss of function mutations in the SWI/SNF complex subunits SMARCB1 or SMARCA4. The Pediatric MATCH study, which will be operationalized by the Children’s Oncology Group (COG), aims to match targeted agents, such as tazemetostat, with specific molecular changes identified through genomic sequencing of refractory/recurrent tumors from children and adolescents with cancer.

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"We are very pleased to be participating in the Pediatric MATCH trial as it will allow us to extend our exploration of tazemetostat’s potential clinical utility in the treatment of molecularly targeted tumors," said Peter Ho, M.D., Ph.D., chief medical officer of Epizyme. "We look forward to working with the NCI and COG investigators to advance our understanding of tazemetostat’s potential against these devastating cancers in children and adolescents."

"This trial would not have been possible without the enthusiastic support of the partnering pharmaceutical companies, as evidenced by their willingness to provide targeted agents for this trial," said NCI study co-chair Nita Seibel, M.D., of NCI’s Division of Cancer Treatment and Diagnosis.

As part of the CRADA executed between Epizyme and NCI in 2016, NCI has agreed to collaborate with Epizyme on clinical trials to evaluate the safety and efficacy of tazemetostat in both adult and pediatric patients with hematologic malignancies and solid tumors. As part of the agreement, NCI will fund and sponsor all clinical trials conducted under this collaboration.

About the Tazemetostat Clinical Trial Program
Tazemetostat, a first-in-class EZH2 inhibitor, is currently being studied in ongoing Phase 2 programs in both follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) forms of non-Hodgkin lymphoma; certain molecularly defined solid tumors, including epithelioid sarcoma and other INI1-negative tumors; and mesothelioma, as well as in combination studies in DLBCL. Tazemetostat has been granted Fast Track designation by the U.S. Food and Drug Administration for follicular lymphoma regardless of EZH2 mutation and for DLBCL with EZH2-activating mutations, as well as Orphan Drug designation for soft tissue sarcoma and malignant rhabdoid tumors.

About the NCI-COG Pediatric MATCH Trial1
Pediatric MATCH is a precision medicine cancer treatment clinical trial that analyzes patients’ tumors to determine whether they contain genetic abnormalities for which a targeted drug exists (that is, "actionable mutations") and assigns treatment based on the abnormality. This trial seeks to determine whether treating cancers according to their molecular abnormalities will show evidence of effectiveness.

On July 24, 2017 Bristol-Myers Squibb Company (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) accepted its supplemental Biologics License Applications (sBLAs) to update Opdivo (nivolumab) dosing to include 480 mg infused over 30 minutes every four weeks (Q4W) for all currently approved monotherapy indications (Press release, Bristol-Myers Squibb, JUL 24, 2017, View Source [SID1234519861]).

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"Filing for four week dosing infused over 30 minutes across approved Opdivo monotherapy indications supports our commitment to address cancer care from all angles. Driving innovation and making treatment more convenient for healthcare providers, caregivers and patients living with this disease is a priority for BMS," said Murdo Gordon, executive vice president and chief commercial officer, Bristol-Myers Squibb.

The applications are under review with an action date of March 5, 2018.
Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research
At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines for hard-to-treat cancers that could potentially improve outcomes for these patients.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational compounds and approved agents. Our differentiated clinical development program is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs position us to advance the I-O/I-O, I-O/chemotherapy, I-O/targeted therapies and I-O radiation therapies across multiple tumors and potentially deliver the next wave of therapies with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumor biology can be used as a guide for treatment decisions throughout their journey.

We understand making the promise of I-O a reality for the many patients who may benefit from these therapies requires not only innovation on our part but also close collaboration with leading experts in the field. Our partnerships with academia, government, advocacy and biotech companies support our collective goal of providing new treatment options to advance the standards of clinical practice.

About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 60 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO
OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with BRAF V600 wild-type unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

IMPORTANT SAFETY INFORMATION
WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS
YERVOY can result in severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs), adrenocorticotropic hormone (ACTH) level, and thyroid function tests at baseline and before each dose.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Immune-Mediated Pneumonitis
OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis
OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients.

In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis
OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal
hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies
In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies
OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients.

Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients. All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. 6 of the 9 patients were hospitalized for severe
endocrinopathies.

Immune-Mediated Nephritis and Renal Dysfunction
OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis
OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis
OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

Other Immune-Mediated Adverse Reactions
Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions
OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic HSCT after OPDIVO
Complications, including fatal events, occurred in patients who received allogeneic HSCT after OPDIVO. Outcomes were evaluated in 17 patients from Checkmate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic HSCT and died of GVHD and multi-organ failure. Other cases of hepatic VOD after reduced-intensity conditioned allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor blocking antibody before transplantation. Cases of fatal hyperacute GVHD have also been reported. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Embryo-Fetal Toxicity
Based on their mechanisms of action, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with an OPDIVO- or YERVOY- containing regimen and for at least 5 months after the last dose of OPDIVO.

Lactation
It is not known whether OPDIVO or YERVOY is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from an OPDIVO-containing regimen, advise women to discontinue breastfeeding during treatment. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Serious Adverse Reactions
In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO.

The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266).

Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration.

Common Adverse Reactions
In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥ 20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%).

In a separate Phase 3 study of YERVOY 3 mg/kg, the most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

Checkmate Trials and Patient Populations
Checkmate 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck; Checkmate 275 – urothelial carcinoma.

Please see U.S. Full Prescribing Information for OPDIVO and YERVOY, including Boxed WARNING regarding immune-mediated adverse reactions for YERVOY.

On July 24, 2017 Seattle Genetics, Inc. (Nasdaq: SGEN), a global biotechnology company, reported a clinical collaboration agreement with Genentech, a member of the Roche Group, for the evaluation of its investigational antibody-drug conjugate (ADC) SGN-LIV1A in combination with atezolizumab (TECENTRIQ) in patients with metastatic triple-negative breast cancer (TNBC) (Press release, Seattle Genetics, JUL 24, 2017, View Source [SID1234519859]). SGN-LIV1A, one of four clinical-stage treatments under development by Seattle Genetics for solid tumors, consists of a LIV-1 targeted monoclonal antibody linked to the potent cell-killing agent monomethyl auristatin E (MMAE). Breast cancer is the most common cancer among women worldwide, with an estimated 1.7 million new cases per year. About 15 to 20 percent of breast cancers are triple negative, which means they lack expression of three breast cancer-associated proteins that serve as key therapeutic targets.

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"A key challenge in triple-negative breast cancer, or TNBC, is the lack of available novel targeted treatments. People with this disease generally have poor prognoses. Moreover, current therapies are not curative and only delay disease progression," said Robert Lechleider, M.D., Senior Vice President, Clinical Development of Seattle Genetics. "We have phase 1 data showing that SGN-LIV1A is active as monotherapy in patients with heavily pretreated, metastatic TNBC. Now, under this new collaboration, we will evaluate the potential to expand therapeutic benefit to these patients through combination therapy with atezolizumab."

SGN-LIV1A administered in combination with atezolizumab will be evaluated in a phase 1b/2 clinical study as second-line therapy in patients with metastatic TNBC who have not been previously treated with immunotherapy. This randomized, controlled study is anticipated to enroll up to 45 patients in the treatment arm. Seattle Genetics and Genentech will test the experimental combination in MORPHEUS, Roche’s Novel Cancer Immunotherapy Development Platform. MORPHEUS is a phase 1b/2 adaptive platform to develop combinations of cancer immunotherapies rapidly and efficiently.

Under the terms of the collaboration agreement, Genentech will manage the study operations for the phase 1b/2 trial. Seattle Genetics will retain global development and commercialization rights to SGN-LIV1A.

About SGN-LIV1A
SGN-LIV1A is a novel investigational ADC targeted to LIV-1 protein utilizing Seattle Genetics’ proprietary ADC technology. LIV-1 is expressed by most metastatic breast cancers. It has also been detected in a number of other cancers, including melanoma, prostate, ovarian, and cervical cancer. SGN-LIV1A consists of a LIV-1-targeted monoclonal antibody linked to a potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker, using the same technology as ADCETRIS (brentuximab vedotin). It is designed to bind to LIV-1 on cancer cells and release the cell-killing agent into target cells upon internalization. SGN-LIV1A may also cause antitumor activity through other mechanisms, including activation of an immune response.

TECENTRIQ (atezolizumab) is a registered trademark of Genentech, a member of the Roche Group.

On July 24, 2017 OncoCyte Corporation (NYSE MKT:OCX), a developer of novel, non-invasive blood-based liquid biopsy tests to assist in the early detection of cancer, reported that it has successfully completed the Analytical Validation study of its liquid biopsy lung cancer diagnostic test (Press release, BioTime, JUL 24, 2017, View Source [SID1234519858]). The results are consistent with the data reported in May at the American Thoracic Society 2017 International Conference (ATS), which demonstrated sensitivity of 95%, specificity of 73%, and Area Under the Curve (AUC) of 0.92. (An AUC of .92 means that 92% of samples were correctly identified.) The final development step before the commercial launch of the lung cancer diagnostic test will be Clinical Validation, which has commenced with a planned completion in the fourth quarter of this year. If Clinical Validation is successful and OncoCyte’s clinical laboratory receives CLIA certification, then the lung cancer test will be the only commercially available product in what the Company estimates is an up to $4.7 billion annual market opportunity in the U.S.

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Analytical Validation
The studies required for Analytical Validation have been established in the CLSI (Clinical Lab Standards Institute) Guidelines. These guidelines cover the testing for such matters as limits of quantitation, precision, reproducibility, and interfering substances. OncoCyte has completed all of these studies successfully.

The new Analytical Validation data supports expectations that the test’s performance will continue to be robust. The completion of the study establishes the performance characteristics of OncoCyte’s lung cancer diagnostic test and, if the Clinical Validation studies are successful, will allow for industrial scale operations under real world conditions. The Company has submitted an abstract to present the data at a scientific conference this year.

"The data seen in this study ensure reliable and actionable liquid biopsy test results that physicians can use in clinical practice to help patients make more informed treatment decisions," stated Lyndal Hesterberg, Ph.D., Senior Vice President, Research and Development. "The successful completion of the Analytical Validation study is an important milestone as we progress toward commercialization of the test in the second half of 2017 following CLIA certification of the Company’s laboratory and completion of the Clinical Validation stage."

"We estimate that our lung cancer confirmatory diagnostic could result in a substantial reduction in the number of unnecessary, expensive lung biopsies performed annually in the U.S., thereby representing a fundamental advancement in the more accurate diagnosis of suspicious lung nodules by allowing physicians to determine which patients need biopsies versus those who may only need follow-up imaging," said William Annett, President and Chief Executive Officer. "We estimate that approximately 1.4 million patients annually in the U.S. could benefit from the test. Depending on market penetration and reimbursable pricing, we believe this could translate into a market opportunity of up to $4.7 billion annually."

Clinical Validation Stage Underway
The final stage of development following the now completed Analytical Validation Study is Clinical Validation. This stage consists of two distinct sets of studies that will be carried out in OncoCyte’s new clinical laboratory. The first step is CLIA Lab Validation. In this study, OncoCyte will assay approximately 120 samples previously tested in the 299-patient study presented at the ATS meeting, with the goal of demonstrating that OncoCyte’s new clinical laboratory provides the same results on clinical samples as those obtained in OncoCyte’s R&D lab. This study has now begun.
On completion of the CLIA Lab Validation study the second step will be two CLIA Lab Clinical Validation studies. In these studies, OncoCyte will perform assays on blinded prospectively collected samples to assess the performance of the full diagnostic system against clinically confirmed diagnoses. OncoCyte will perform Clinical Validation on two sets of samples. The first study will consist of approximately 300 samples, and if the results of the study are consistent with results to date OncoCyte will launch its liquid biopsy lung cancer diagnostic test. All of the samples required for this first study have now been collected.

The second study will be conducted post-launch and on approximately 200 additional samples to provide additional data to increase the likelihood that physicians will adopt the test and that insurance companies and Medicare will provide reimbursement coverage for the test.

CLIA Certification
OncoCyte’s clinical laboratory must receive Clinical Laboratory Improvement Amendment (CLIA) certification from the state of California. The Company’s complete application for CLIA certification was submitted in March 2017 to the California Department of Public Health and is now under active review. The Company expects to receive CLIA certification during the second half of 2017.

Diagnostic Test Accuracy
Sensitivity and specificity are statistical measures of test performance, with sensitivity measuring the percentage of malignant nodules that are identified correctly by the test and specificity measuring the percentage of benign nodules correctly identified. The AUC of a test is a measure of overall global accuracy that combines sensitivity and specificity, with 1.0 being perfect accuracy and 0.50 being a random result. The score of 0.92 reported at the recent ATS meeting means that 92% of samples were correctly identified.