On March 26, 2018 Bristol-Myers Squibb Company (NYSE:BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended approval of an every four-week (Q4W) Opdivo (nivolumab) dosing schedule of 480 mg infused over 60 minutes as an option for patients with advanced melanoma and previously treated renal cell carcinoma (Press release, Bristol-Myers Squibb, MAR 26, 2018, View Source [SID1234525466]). The CHMP also recommended approval of a two-week (Q2W) Opdivo dosing option of 240 mg infused over 30 minutes to replace weight-based dosing for all six approved monotherapy indications in the EU. The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU).

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"BMS is committed to improving cancer care by, among other things, addressing scheduling and convenience concerns of patients with a range of dosing options for an Immuno-Oncology agent that allows for enhanced flexibility," said Fouad Namouni, M.D., head of development, Oncology, Bristol-Myers Squibb. "This positive CHMP opinion reinforces our commitment and we look forward to hearing from the European Commission. Once approved, the Opdivo four-week dosing infused over 60 minutes would enable BMS to deliver on our promise to explore potentially more flexible and convenient dosing options for patients, caregivers and healthcare providers alike."

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.

INDICATIONS

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.

OPDIVO (nivolumab) is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. 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 hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (10 mg/mL) is an injection for intravenous (IV) use.

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. For patients without HCC, withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4. For patients with HCC, withhold OPDIVO and administer corticosteroids if AST/ALT is within normal limits at baseline and increases to >3 and up to 5 times the upper limit of normal (ULN), if AST/ALT is >1 and up to 3 times ULN at baseline and increases to >5 and up to 10 times the ULN, and if AST/ALT is >3 and up to 5 times ULN at baseline and increases to >8 and up to 10 times the ULN. Permanently discontinue OPDIVO and administer corticosteroids if AST or ALT increases to >10 times the ULN or total bilirubin increases >3 times the ULN. 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 Checkmate 040, immune-mediated hepatitis requiring systemic corticosteroids occurred in 5% (8/154) of patients receiving OPDIVO.

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 the adverse reaction, permanently discontinue or withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Across clinical trials of OPDIVO monotherapy or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, 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), motor dysfunction, vasculitis, and myasthenic syndrome.

If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

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 as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate study in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In patients receiving OPDIVO as a 60-minute infusion prior to the infusion of 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 (n=236). 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. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in at least 2% of patients were pyrexia, ascites, back pain, general physical health deterioration, abdominal pain, and pneumonia. In Checkmate 238, Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in at least 2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. Serious adverse reactions occurred in 18% of OPDIVO-treated patients.

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 (n=236) 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 Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=154) were fatigue (38%), musculoskeletal pain (36%), abdominal pain (34%), pruritus (27%), diarrhea (27%), rash (26%), cough (23%), and decreased appetite (22%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). The most common adverse reactions (≥20%) in patients who received OPDIVO as a single agent were fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, arthralgia, upper respiratory tract infection, pyrexia, headache, and abdominal pain.

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 067–advanced melanoma alone or in combination with YERVOY (ipilimumab); 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; Checkmate 040–hepatocellular carcinoma; Checkmate 238–adjuvant treatment of melanoma

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

About the Bristol-Myers Squibb and Ono Pharmaceutical Co., Ltd. Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Ltd (Ono), Bristol-Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Bristol-Myers Squibb and Ono further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

On March 26, 2018 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that the Phase III IMpower150 study met its co-primary endpoint of overall survival (OS) at this interim analysis and showed that initial (first-line) treatment with the combination of TECENTRIQ (atezolizumab) and Avastin (bevacizumab) plus carboplatin and paclitaxel (chemotherapy) helped people with advanced non-squamous non-small cell lung cancer (NSCLC) live significantly longer compared with Avastin plus carboplatin and paclitaxel (Press release, Hoffmann-La Roche, MAR 26, 2018, View Source [SID1234525397]). A survival benefit was observed across key subgroups, including those with varying levels of PD-L1 expression. Safety for the TECENTRIQ and Avastin plus carboplatin and paclitaxel combination appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combinations. These data will be presented at an upcoming oncology congress.

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Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"We are pleased that the IMpower150 study demonstrated a clinically meaningful survival benefit for people receiving their initial treatment for this type of advanced lung cancer," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "These results add to the growing body of evidence supporting the role of combining TECENTRIQ with Avastin. We will submit these additional data to global health authorities and hope to bring this potential treatment option to patients as soon as possible."

At this interim analysis, the study found that substituting Avastin with TECENTRIQ in the combination with carboplatin and paclitaxel did not show a statistically significant OS benefit in people with advanced NSCLC compared to a combination of Avastin plus carboplatin and paclitaxel. The study will continue as planned to the final analysis. Safety in the TECENTRIQ plus carboplatin and paclitaxel arm appeared consistent with the known safety profile of the individual medicines, and no new safety signals were identified with the combination.
Previously reported results from the IMpower150 study showed that the combination of TECENTRIQ and Avastin plus carboplatin and paclitaxel reduced the risk of disease worsening or death (progression-free survival; PFS), a co-primary endpoint, by 38 percent (HR=0.62; p<0.0001, 95 percent CI: 0.52-0.74) compared to Avastin plus carboplatin and paclitaxel in the first-line treatment of people with advanced non-squamous NSCLC. This PFS benefit was observed across key subgroups, including those with varying levels of PD-L1 expression.
IMpower150 is one of eight Phase III lung cancer studies underway, evaluating TECENTRIQ alone or in combination with other medicines. Following the positive IMpower150 and IMpower131 studies, three more Phase III lung cancer studies are expected to report this year.

About the IMpower150 study
IMpower150 is a multicenter, open-label, randomised, controlled Phase III study evaluating the efficacy and safety of TECENTRIQ in combination with carboplatin and paclitaxel with or without Avastin in people with stage IV non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease. It enrolled 1,202 people, of which those with ALK and EGFR mutations were excluded from the primary intention-to-treat (ITT) analysis. People were randomised (1:1:1) to receive:
TECENTRIQ plus carboplatin and paclitaxel (Arm A), or
TECENTRIQ and Avastin plus carboplatin and paclitaxel (Arm B), or
Avastin plus carboplatin and paclitaxel (Arm C, control arm)

During the treatment-induction phase, people in Arm A received TECENTRIQ administered intravenously at 1200 mg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, people received maintenance treatment with TECENTRIQ (1200 mg every 3 weeks) until loss of clinical benefit or disease progression.
People in Arm B received induction treatment with TECENTRIQ (1200 mg) and Avastin administered intravenously at 15 mg/kg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. People then received maintenance treatment with the TECENTRIQ and Avastin regimen until disease progression (Avastin) or loss of clinical benefit/disease progression (TECENTRIQ).
People in Arm C received induction treatment with Avastin administered intravenously at 15 mg/kg plus intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. This was followed by maintenance treatment with Avastin alone until disease progression.
The co-primary endpoints were PFS and OS, as determined by the investigator using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1). The co-primary OS endpoint in IMpower150 was assessed in all randomised people without an ALK or EGFR genetic mutation (intention-to-treat wild-type). Key secondary endpoints included investigator-assessed PFS and OS, safety in the ITT population and in EGFR and ALK mutation subgroups.
The primary analysis of the co-primary PFS endpoint in IMpower150 was assessed in two populations: all randomised people without an ALK or EGFR genetic mutation (intention-to-treat wild-type) and in a subgroup of people who had a specific biomarker (T-effector "Teff" gene signature expression ). IMpower150 met its PFS co-primary endpoint per study protocol for both populations assessed.

About NSCLC
Lung cancer is the leading cause of cancer death globally.1 Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.2 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.2 NSCLC comprises non-squamous and squamous-cell lung cancer, the squamous form of which is characterised by flat cells covering the airway surface when viewed under a microscope.
About TECENTRIQ (atezolizumab)
TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has eight Phase III lung cancer studies underway, evaluating TECENTRIQ alone or in combination with other medicines.
TECENTRIQ is already approved in the European Union, United States and more than 60 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.
About Avastin (bevacizumab)
Avastin is a biologic cancer treatment approved in combination with chemotherapy for the first-line treatment of advanced NSCLC and, to-date, has helped over 500,000 patients lead longer lives. Avastin is considered a standard of care for the first-line treatment of advanced NSCLC and has been proven to significantly extend overall survival (OS). Avastin is currently approved in combination with any platinum-based chemotherapy in Europe, and with paclitaxel/carboplatin in the US, in first-line non-squamous NSCLC, based on results of the pivotal Phase III E4599 study. Avastin was the first medicine to help people with previously untreated advanced, non-squamous NSCLC live longer (OS) than one year when added to chemotherapy.
About the TECENTRIQ (atezolizumab) and Avastin (bevacizumab) combination
There is a strong scientific rationale to support combining TECENTRIQ and Avastin. The TECENTRIQ and Avastin regimen may enhance the potential of the immune system to combat a broad range of cancers, including first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance TECENTRIQ’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.
About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.
By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with TECENTRIQ to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.
To learn more about the Roche approach to cancer immunotherapy please follow this link:
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On March 26, 2018 PharmaCyte Biotech, Inc. (OTCQB: PMCB), a clinical stage biotechnology company focused on developing targeted cellular therapies for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that it has filed a U.S. patent application with the United States Patent and Trademark Office (USPTO) to protect its therapy to treat cancerous tumors, including the therapy that will be used in its upcoming clinical trial in locally advanced, non-metastatic, inoperable pancreatic cancer (LAPC) (Press release, PharmaCyte Biotech, MAR 26, 2018, View Source [SID1234525389]). PharmaCyte has also filed a Patent Cooperation Treaty (PCT) application, which includes protection of its technology in about 150 different countries outside the United States. Both the U.S. and PCT applications claim a priority date from a U.S. provisional patent application PharmaCyte filed in March of last year.

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The patent applications specifically include methods of treating many types of solid cancerous tumors, such as those of the pancreas, liver, breast and colon, using the live-cell encapsulation of genetically modified human cells that overexpress a form of the cytochrome P450 enzyme system normally found in the liver. These cells are encapsulated using the Cell-in-a-Box technology. Together with low doses of oxazaphosphorines, such as ifosfamide, the encapsulated cells comprise PharmaCyte’s therapy for cancerous tumors. The patent application also includes using PharmaCyte’s platform technology with cyclophosphamide, another chemotherapy drug that must be activated by the cytochrome P450 enzyme system. PharmaCyte believes these technologies will be beneficial to patients who no longer respond to standard chemotherapies, such as gemcitabine and Abraxane.

These new applications, if granted, will provide protection for PharmaCyte’s technology for 20 years – until March 2038. "By filing these patent applications, we are continuing the process of pursuing patent protection for 20 years to protect our therapy for all forms of solid malignant tumors. This is particularly important to the company as we are taking steps to embark upon a clinical trial in LAPC," said PharmaCyte’s Chief Executive Officer, Kenneth L. Waggoner.
PharmaCyte’s pancreatic cancer therapy was designated an orphan drug and listed in the official registry of medicinal products for rare diseases by the U.S. Food and Drug Administration (FDA) on December 17, 2014. Orphan drug exclusivity would provide marketing exclusivity for PharmaCyte’s pancreatic cancer therapy in the U.S. for 7 years after market approval by the FDA. Similarly, PharmaCyte has orphan drug status in the European Union (EU) for its pancreatic cancer therapy, which provides 10 years of marketing exclusivity in all countries in the EU following approval by the European Medicines Agency (EMA).

In addition, the Biologics Price Competition and Innovation Act (BPCIA), which was enacted as part of the Affordable Care Act in 2010, establishes a period of 12 years of "data exclusivity" for reference products to preserve incentives for future innovation. Under this framework, data exclusivity protects the data in the innovator’s regulatory application by prohibiting others, for a period of 12 years, from gaining FDA approval based in part on reliance on or reference to the innovator’s data in a biosimilar application. PharmaCyte’s 12-year exclusivity will begin as soon as the FDA approves the company’s first Cell-in-a-Box-based therapy.

Mr. Waggoner concluded by stating, "While these patent applications should make our investors feel assured about the protection of our pancreatic cancer therapy, they should understand that if our therapy receives FDA approval, the orphan drug designation in the U.S. and the EU, together with the BPCIA data exclusivity that may be awarded, will give us substantial marketing exclusivity for our pancreatic cancer therapy. These patent applications should be viewed as an opportunity to dramatically broaden PharmaCyte’s ability to protect its unique therapy for all malignant solid tumors for the next 20 years

On March 26, 2018 Seattle Genetics, Inc. (NASDAQ: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to enfortumab vedotin, an antibody-drug conjugate (ADC), for patients with locally advanced or metastatic urothelial cancer who were previously treated with checkpoint inhibitors (CPI) (Press release, Seattle Genetics, MAR 26, 2018, View Source;p=RssLanding&cat=news&id=2339635 [SID1234525388]).

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This press release features multimedia. View the full release here: View Source
Breakthrough Therapy Designation is a process designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. It is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
"The FDA Breakthrough Therapy Designation underscores the potential of enfortumab vedotin as a meaningful treatment for patients with locally advanced or metastatic urothelial cancer. Further, it supports our rapid development plans for this ADC, including the ongoing pivotal study in this patient population," said Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics. "Seattle Genetics is an emerging multi-product oncology company, advancing a robust pipeline with the goal of improving outcomes for cancer patients. Enfortumab vedotin is at the forefront of our late-stage clinical pipeline, and we are working closely with our partner and the FDA to bring this potential new treatment to patients as quickly as possible."

"Achieving Breakthrough Therapy Designation for enfortumab vedotin is another step forward in our goal to bring an additional treatment option to patients who need it most," said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development at Astellas. "With the enfortumab vedotin registrational phase 2 trial and CPI-combination trial actively underway, Astellas looks forward to expanding development of enfortumab vedotin and its oncology pipeline, including treatments that would target some of the hardest-to-treat cancers."
The Breakthrough Therapy Designation was granted based on interim results from the phase 1 study examining enfortumab vedotin as monotherapy treatment for patients with metastatic urothelial cancer who were previously treated with CPIs. Enfortumab vedotin is being studied in a pivotal clinical trial, EV-201 (NCT03219333), as monotherapy in this patient setting and in an early-phase clinical trial in combination with CPI therapy, EV-103 (NCT03288545). The companies are also evaluating enfortumab vedotin in other solid tumors, including ovarian and non-small cell lung carcinoma.

More information about the ongoing trials can be found at www.clinicaltrials.gov.
About Enfortumab Vedotin
Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary linker technology. Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.

About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at View Source

Seattle Genetics and Astellas Receive FDA Breakthrough Therapy Designation for Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer
BOTHELL, Wash. & TOKYO–(BUSINESS WIRE)–Mar. 26, 2018– Seattle Genetics, Inc. (NASDAQ: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Yoshihiko Hatanaka, "Astellas") reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to enfortumab vedotin, an antibody-drug conjugate (ADC), for patients with locally advanced or metastatic urothelial cancer who were previously treated with checkpoint inhibitors (CPI).
This press release features multimedia. View the full release here: View Source
Breakthrough Therapy Designation is a process designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. It is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
"The FDA Breakthrough Therapy Designation underscores the potential of enfortumab vedotin as a meaningful treatment for patients with locally advanced or metastatic urothelial cancer. Further, it supports our rapid development plans for this ADC, including the ongoing pivotal study in this patient population," said Robert Lechleider, M.D., Senior Vice President, Clinical Development at Seattle Genetics. "Seattle Genetics is an emerging multi-product oncology company, advancing a robust pipeline with the goal of improving outcomes for cancer patients. Enfortumab vedotin is at the forefront of our late-stage clinical pipeline, and we are working closely with our partner and the FDA to bring this potential new treatment to patients as quickly as possible."
"Achieving Breakthrough Therapy Designation for enfortumab vedotin is another step forward in our goal to bring an additional treatment option to patients who need it most," said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development at Astellas. "With the enfortumab vedotin registrational phase 2 trial and CPI-combination trial actively underway, Astellas looks forward to expanding development of enfortumab vedotin and its oncology pipeline, including treatments that would target some of the hardest-to-treat cancers."
The Breakthrough Therapy Designation was granted based on interim results from the phase 1 study examining enfortumab vedotin as monotherapy treatment for patients with metastatic urothelial cancer who were previously treated with CPIs. Enfortumab vedotin is being studied in a pivotal clinical trial, EV-201 (NCT03219333), as monotherapy in this patient setting and in an early-phase clinical trial in combination with CPI therapy, EV-103 (NCT03288545). The companies are also evaluating enfortumab vedotin in other solid tumors, including ovarian and non-small cell lung carcinoma.
More information about the ongoing trials can be found at www.clinicaltrials.gov.
About Enfortumab Vedotin
Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary linker technology. Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.
About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. We focus on Urology, Oncology, Immunology, Nephrology and Neuroscience as prioritized therapeutic areas while advancing new therapeutic areas and discovery research leveraging new technologies/modalities. We are also creating new value by combining internal capabilities and external expertise in the medical/healthcare business. Astellas is on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at View Source

About Seattle Genetics
Seattle Genetics is an innovative biotechnology company dedicated to improving the lives of people with cancer through targeted therapies. The company’s industry-leading antibody-drug conjugate (ADC) technology harnesses the targeting ability of antibodies to deliver cell-killing agents directly to cancer cells. Seattle Genetics commercializes ADCETRIS (brentuximab vedotin) for the treatment of several types of CD30-expressing lymphomas. The company is also advancing a robust pipeline of novel therapies for solid tumors and blood-related cancers designed to address significant unmet medical needs and improve treatment outcomes for patients. More information can be found at www.seattlegenetics.com and follow @SeattleGenetics on Twitter.

On March 26, 2018 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company announced the presentation of maturing data from the TOPACIO trial of niraparib in combination with an anti-PD-1 monoclonal antibody, KEYTRUDA during a plenary session today at the 2018 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in New Orleans, Louisiana. In addition, retrospective data analyses of the Phase 3 ENGOT-OV16/NOVA study that could potentially reduce Grade 3/4 thrombocytopenia in niraparib treated patients was presented in the plenary session on Sunday, March 25 (Press release, TESARO, MAR 26, 2018, View Source [SID1234525015]).

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"Patients with platinum-resistant or platinum-refractory ovarian cancer have limited treatment options available to them. Approximately 10,000 women in each of the US and EU begin treatment for platinum-resistant or refractory ovarian cancer each year," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "Preliminary results from TOPACIO suggest the combination of niraparib and an anti-PD-1 antibody could provide meaningful clinical benefit to these patients, regardless of biomarker status. Planning of a registration study is underway to support approval of ZEJULA and TSR-042 combination therapy for these patients. TSR-042 is TESARO’s anti-PD-1 antibody, which is currently in a registration study for MSI-H tumors."

"These data provide a compelling initial step in our ovarian cancer development strategy which is progressing from monotherapy ZEJULA utilized in PRIMA, NOVA and QUADRA to doublet and triplet combination approaches with anti-PD-1 antibodies and bevacizumab," said Marty Huber, M.D., Senior Vice President and Chief Medical Officer of TESARO. "Our ultimate goal is to maximize the benefit to women across the full spectrum of ovarian cancer"

Phase 2 TOPACIO Data Demonstrate Activity in Platinum-Resistant and Platinum-Refractory Ovarian Cancer Patients, Regardless of Biomarker Status
TOPACIO is a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of niraparib plus KEYTRUDA (pembrolizumab) in patients with recurrent, platinum-resistant ovarian cancer or triple negative breast cancer. Niraparib administered orally, once-daily, at a dose of 200 milligrams is being evaluated in combination with 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle in two patient cohorts; platinum-resistant/refractory ovarian cancer and triple-negative breast cancer. Endpoints include RECIST response rate, duration of response, disease control rate, progression-free survival and overall survival. Data presented at SGO were from the group of patients with ovarian cancer.

At the time of data cutoff, of the 62 patients enrolled, 60 were evaluable; 45% had been treated with 3 or more prior lines of chemotherapy, 97% with prior taxane, 63% received prior bevacizumab, and 29% were platinum refractory. The majority (73%) did not have a BRCA mutation. Data indicate an overall response rate (ORR; including CR and PR) of 25% and a disease control rate (DCR; CR+PR+SD) of 68%; ORR was 24% in the platinum refractory population. Response rates were not dependent on biomarker status; ORR was 26% (9/34) in patients without a tumor BRCA mutation (tBRCAwt), and 29% (7/24) in patients with HRD-negative tumors. Duration of response was immature, with 9 of 15 (60%) of responders remaining on treatment, and over one-half of patients with disease control continuing on treatment or having already received treatment for over 6 months.

For patients with platinum-resistant ovarian cancer, response to chemotherapy is 5-18%, including the most commonly prescribed regimen in the U.S., bevacizumab plus pegylated liposomal doxorubicin1. Platinum refractory patients typically have even lower response rates and NCCN treatment guidelines recommend clinical trials for these patients2. Historical response to PARP inhibitors is 5-10% in patients without BRCA mutations who have platinum resistant disease3 and 0-14% in those with BRCA mutations and platinum refractory disease4. Response rates of 10-15% have been reported with anti-PD-1 antibodies in this ovarian cancer population5.

The combination of niraparib with pembrolizumab was well tolerated with an incidence of Grade 3/4 thrombocytopenia of 9%. In addition to thrombocytopenia, the other most commonly observed Grade ≥3 adverse events included anemia (19%) and neutropenia (6%).

Abstracts containing additional data from the TOPACIO trial, including results from patients with platinum-resistant ovarian cancer and patients with triple-negative breast cancer, have been submitted to the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. The TOPACIO trial is being conducted in collaboration with Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc., which is providing support for the trial.

A Retrospective Analysis of Phase 3 ENGOT-OV16/NOVA Trial Identified Predictors of Early Dose Modification for Niraparib
A retrospective analysis of the Phase 3 NOVA trial identified two baseline characteristics, patient body weight less than 170 pounds (77 kilograms) or platelet count of <150,000/µL to be significant factors for Grade 3 or 4 thrombocytopenia. The incidence of thrombocytopenia in the first month in this population was 35% in the NOVA study vs 12% in those with higher weight and platelet counts. By month 4, of the patients who remained on treatment, 83% with body weight < 170lbs or platelet count of <150,000/µL at baseline were receiving a dose of niraparib <300 milligrams. With dose interruptions, this group’s average daily dose was 207 milligrams in the first two months of niraparib therapy in NOVA. Regardless, efficacy was uncompromised (HR: 1.01 (95%CI: 0.69, 1.48)) in patients receiving a 200 milligram versus 300 milligram dose of niraparib. Of note, in TOPACIO, where starting dose is 200 milligrams, a 9% incidence of Grade 3 or 4 thrombocytopenia was reported.

"This analysis provides physicians with new information to help quickly identify the most appropriate dose for each of their patients," said Dr. Mansoor Raza Mirza, M.D., Medical Director of the Nordic Society of Gynecologic Oncology (NSGO) and principal investigator on the ENGOT-OV16/NOVA trial. "This information is particularly important as we move towards combination treatment approaches with niraparib, which are currently being studied in multiple ongoing clinical trials."

About ZEJULA (Niraparib)
Niraparib is marketed in the United States and Europe under trade name ZEJULA. ZEJULA (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in some clinical studies. Discontinue ZEJULA if MDS/AML is confirmed. Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

About TSR-042

TSR-042 is a monoclonal antibody targeting PD-1 and was developed as part of the collaboration between TESARO and AnaptysBio, Inc. This collaboration was initiated in March of 2014, and is focused on the development of monospecific antibody drugs targeting PD-1, TIM-3 (TSR-022), and LAG-3 (TSR-033), in addition to a bi-specific antibody drug candidate targeting PD-1/LAG-3 (TSR-075).