On September 28, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported results from Part 1 of the Phase 3 CheckMate -227 trial evaluating Opdivo (nivolumab) plus low-dose Yervoy (ipilimumab) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC). Opdivo plus low-dose Yervoy met the independent co-primary endpoint of overall survival, demonstrating superior benefit compared to chemotherapy in patients whose tumors expressed PD-L1 ≥1% (Hazard Ratio (HR) 0.79; 97.72% Confidence Interval (CI): 0.65 to 0.96). Additionally, in an exploratory analysis, results showed improved overall survival for patients treated with the combination of Opdivo plus low-dose Yervoy with PD-L1 <1% (HR 0.62; 95% CI: 0.48 to 0.78). The two-year survival rate for patients treated with the combination regimen was 40% for both patients whose tumors expressed PD-L1 ≥1% and patients whose tumors expressed PD-L1 <1%. In the chemotherapy control arm, two-year survival rates were 33% and 23%, respectively.

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These results represent the first and only time a dual Immuno-Oncology (I-O) therapy has demonstrated superior overall survival versus chemotherapy in the first-line NSCLC setting and will be featured in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain (Presentation #LBA4_PR, Saturday, September 28, 4:30-6:20 PM CEST).

The safety profile of Opdivo plus low-dose Yervoy was consistent with previously reported studies in NSCLC and no new safety signals were observed.

With a minimum follow-up of 29.3 months, patients treated with Opdivo plus low-dose Yervoy, regardless of PD-L1 expression level, experienced a nearly four times longer duration of response compared to patients treated with chemotherapy. In patients with PD-L1 ≥1%, the objective response rate was 35.9% (95% CI, 31.1 to 40.8) with Opdivo plus low-dose Yervoy (5.8% complete responses) versus 30.0% (95% CI, 25.5 to 34.7) with chemotherapy (1.8% complete responses). The median duration of response (DoR) for the combination therapy arm was 23.2 months versus 6.2 months in the chemotherapy arm. In patients with PD-L1 <1%, the objective response rate was 27.3% (95% CI, 30.7 to 45.4) with Opdivo plus low-dose Yervoy (2.1% complete responses) versus 23.1% (95% CI, 17.3 to 29.8) with chemotherapy (1.1% complete responses), with a median DoR of 18 months for the combination therapy arm versus 4.8 months in the chemotherapy arm.

"These positive results validate the immunologic rationale for the dual inhibition of PD-1 and CTLA-4 in the treatment of lung cancer," said Martin Reck, M.D., Ph.D., CheckMate -227 study investigator, Lung Clinic Grosshansdorf, German Center of Lung Research. "These data show that dual Immuno-Oncology therapy has the potential to deliver deep and durable responses, with a clear survival benefit, in first-line non-small cell lung cancer, without the need for chemotherapy."

"The Part 1 data from CheckMate -227 make Opdivo and Yervoy the first and only dual Immuno-Oncology therapy to demonstrate superior overall survival over chemotherapy in first-line non-small cell lung cancer," said Fouad Namouni, M.D., head, Oncology Development, Bristol-Myers Squibb. "These results build upon the long-term clinical data in first-line melanoma and renal cell carcinoma demonstrating the benefit of combining Yervoy and Opdivo compared to standard of care. We look forward to sharing these data with regulatory authorities and through continued research, expanding our understanding of the value of this unique combination for patients with cancer."

About CheckMate -227

CheckMate -227 is a multi-part open-label Phase 3 trial evaluating Opdivo-based regimens versus platinum-doublet chemotherapy in patients with first-line advanced non-small cell lung cancer across non-squamous and squamous tumor histologies:

Part 1:
Part 1a: Opdivo plus low-dose Yervoy or Opdivo monotherapy versus chemotherapy in patients whose tumors express PD-L1
Part 1b: Opdivo plus low-dose Yervoy or Opdivo plus chemotherapy versus chemotherapy in patients whose tumors do not express PD-L1
Part 2: Opdivo plus chemotherapy versus chemotherapy, regardless of PD-L1
There are two co-primary endpoints in Part 1 for Opdivo plus Yervoy (versus chemotherapy): overall survival (OS) in patients whose tumors express PD-L1 (assessed in patients enrolled in Part 1a) and progression-free survival (PFS) in patients with TMB ≥10 mut/Mb across the PD-L1 spectrum (assessed in patients enrolled across Parts 1a and 1b). Part 1 met both its co-primary endpoints of PFS with the Opdivo plus Yervoy combination versus chemotherapy in patients whose tumors have high (≥10 mutations/megabase, mut/mb) TMB, regardless of PD-L1 expression, and OS demonstrating a superior benefit for Opdivo plus low-dose Yervoy or Opdivo versus chemotherapy in first-line NSCLC patients whose tumors express PD-L1 ≥1%. Part 2 did not meet its primary endpoint for OS for Opdivo plus chemotherapy versus chemotherapy alone, in patients with non-squamous NSCLC.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is one of the most common types of lung cancer and accounts for up to 85% of diagnoses. Survival rates vary depending on the stage and type of the cancer when diagnosed. For patients diagnosed with metastatic lung cancer, the five-year survival rate is approximately 5%.

Bristol-Myers Squibb: Advancing Oncology Research

At Bristol-Myers Squibb, patients are at the center of everything we do. The focus of our research is to increase quality, long-term survival for patients and make cure a possibility. Through a unique multidisciplinary approach powered by translational science, we harness our deep scientific experience in oncology and Immuno-Oncology (I-O) research to identify novel treatments tailored to individual patient needs. Our researchers are developing a diverse, purposefully built pipeline designed to target different immune system pathways and address the complex and specific interactions between the tumor, its microenvironment and the immune system. We source innovation internally, and in collaboration with academia, government, advocacy groups and biotechnology companies, to help make the promise of transformational medicines, like I-O, a reality for patients.

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 treated more than 35,000 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 65 countries, including the United States, the European Union, Japan and China. 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 60 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 unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with unresectable or metastatic melanoma.

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 metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy. 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 advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of patients with intermediate or poor risk, previously untreated advanced renal cell carcinoma (RCC).

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), as a single agent, 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), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older 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.

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated pneumonitis occurred in 6% (25/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated pneumonitis occurred in 1.7% (2/119) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 10% (52/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated colitis occurred in 7% (8/119) of patients.

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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated hepatitis occurred in 13% (51/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 7% (38/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hepatitis occurred in 8% (10/119) 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 1 mg/kg with YERVOY 3 mg/kg, hypophysitis occurred in 9% (36/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypophysitis occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated hypophysitis occurred in 3.4% (4/119) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, adrenal insufficiency occurred in 5% (21/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 7% (41/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, adrenal insufficiency occurred in 5.9% (7/119) 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 1 mg/kg with YERVOY 3 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving this dose of OPDIVO with YERVOY. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Hyperthyroidism occurred in 12% (66/547) of patients receiving this dose of OPDIVO with YERVOY. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 15% (18/119) of patients. Hyperthyroidism occurred in 12% (14/119) of patients. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg, diabetes occurred in 1.5% (6/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, diabetes occurred in 2.7% (15/547) 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. Six 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated nephritis and renal dysfunction occurred in 1.7% (2/119) 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 1 mg/kg with YERVOY 3 mg/kg, immune-mediated rash occurred in 22.6% (92/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 16.6% (91/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, immune-mediated rash occurred in 14% (17/119) 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 1 mg/kg with YERVOY 3 mg/kg (0.2%) after 1.7 months of exposure. Encephalitis occurred in one RCC patient receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg (0.2%) after approximately 4 months of exposure. Encephalitis occurred in one MSI-H/dMMR mCRC patient (0.8%) receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg after 15 days 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, aplastic anemia, pericarditis, 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 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg, infusion-related reactions occurred in 4.2% (5/119) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1 receptor blocking antibody prior to or after an allogeneic HSCT.

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.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

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 breastfeeding 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 (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) 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 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). 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 ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 032, serious adverse reactions occurred in 45% of patients receiving OPDIVO (n=245). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, pneumonitis, pleural effusions, and dehydration. 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 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY and in 43% of patients receiving sunitinib. The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis; in patients treated with sunitinib, they were pneumonia, pleural effusion, and dyspnea. 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 ≥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 ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 49% of patients (n=154). The most frequent serious adverse reactions reported in ≥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 ≥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 (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). 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 032, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=245) were fatigue (45%), decreased appetite (27%), musculoskeletal pain (25%), dyspnea (22%), nausea (22%), diarrhea (21%), constipation (20%), and cough (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (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 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) vs sunitinib (n=535) were fatigue (58% vs 69%), rash (39% vs 25%), diarrhea (38% vs 58%), musculoskeletal pain (37% vs 40%), pruritus (33% vs 11%), nausea (30% vs 43%), cough (28% vs 25%), pyrexia (25% vs 17%), arthralgia (23% vs 16%), decreased appetite (21% vs 29%), dyspnea (20% vs 21%), and vomiting (20% vs 28%). 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 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent, the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY, the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). 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%).

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%).

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

Checkmate Trials and Patient Populations

Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second-line treatment of metastatic squamous non-small cell lung cancer; Checkmate 057–second-line treatment of metastatic non-squamous non-small cell lung cancer; Checkmate 032–small cell lung cancer; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 205/039–classical Hodgkin lymphoma; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 275–urothelial carcinoma; Checkmate 142–MSI-H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 040–hepatocellular carcinoma; Checkmate 238–adjuvant treatment of melanoma.

About the Bristol-Myers Squibb and Ono Pharmaceutical Collaboration

In 2011, through a collaboration agreement with Ono Pharmaceutical Co., 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, Ono and Bristol-Myers Squibb 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 September 28, 2019 AstraZeneca reported detailed overall survival (OS) results from the Phase III FLAURA trial of Tagrisso (osimertinib) in the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 28, 2019, View Source [SID1234539870]).

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Results showed a statistically significant and clinically meaningful improvement in OS, a key secondary endpoint for Tagrisso versus gefitinib or erlotinib, both of which were previous standard-of-care (SoC) treatments in this setting (HR 0.799 [95% CI, 0.641-0.997], p=0.0462).

Tagrisso delivered a median OS of 38.6 months versus 31.8 months for the comparator arm. At three years, 28% of patients in the Tagrisso arm and 9% of patients in the comparator arm remained on 1st-line study treatment. Tagrisso also showed a statistically significant and clinically meaningful 52% reduction in the risk of central nervous system (CNS) disease progression, increasing the time patients with CNS metastases lived without CNS disease progression or death (HR 0.48 [95% CI, 0.26-0.86], p=0.014).1

The results were presented at the Presidential Symposium of the ESMO (Free ESMO Whitepaper) (European Society for Medical Oncology) 2019 Congress in Barcelona, Spain (Abstract #LBA5_PR).

José Baselga, Executive Vice President, Oncology R&D said: "Tagrisso has set a new benchmark in EGFR-mutated non-small cell lung cancer by demonstrating a median overall survival of more than three years. We have not before seen survival benefits of this magnitude in any global Phase III trial with any such therapy. The ground-breaking data reaffirm the benefit of using Tagrisso first and further support its use as the 1st-line standard of care in this setting."

Dr Suresh S. Ramalingam, Principal Investigator of the FLAURA trial from Winship Cancer Institute of Emory University, Atlanta, US, said: "The results of the FLAURA trial provide further evidence to support the role of osimertinib as the preferred 1st-line therapy option for patients with EGFR-mutated non-small cell lung cancer. It is highly noteworthy that 28% of patients are still being treated with 1st-line osimertinib at three years versus 9% on either gefitinib or erlotinib."

Summary of FLAURA results

Tagrisso

(n=279)

EGFR-tyrosine kinase inhibitors (TKI)

(gefitinib or erlotinib)

(n=277)

Progression-free survival (PFS) (primary endpoint)i

Median in months

(95% CI)

18.9

(15.2, 21.4)

10.2 months

(9.6, 11.1)

Hazard ratio

(95% CI)

0.46

(0.37, 0.57)

p-value

p < 0.0001

OS (secondary endpoint)i

Hazard ratio

(95% CI)

0.799

(0.641-0.997)

p-value

p = 0.0462ii

Median in months

(95% CI)

38.6

(34.5-41.8)

31.8

(26.6-36.0)

Survival at 12 months

(95% CI)

89.1%

(84.8-92.2)

82.5%

(77.4-86.6)

Survival at 24 months

(95% CI)

74.2%

(68.6-79.0)

58.9%

(52.7-64.6)

Survival at 36 months

(95% CI)

53.7%

(47.5-59.5)

44.1%

(38.0-50.1)

CNS PFS (secondary endpoint)i,1

Hazard ratio

(95% CI)

0.48

(0.26-0.86)

p-value

p = 0.014

Median in months

(95% CI)

Not reached

(16.5-NC)iii

13.9

(8.3-NC)iii

Time to first subsequent therapy or death (TFST) (exploratory endpoint)i

Hazard ratio

(95% CI)

0.48

(0.39-0.58)

Number (%) of patients with events

69.5%

87.4%

Median in months

(95% CI)

25.5

(22.0, 29.1)

13.7

(12.3, 15.7)

Time to second subsequent therapy or death (TSST) (exploratory endpoint)i

Hazard ratio

(95% CI)

0.69

(0.56-0.84)

Number (%) of patients with events

64.5%

73.3%

Median in months

(95% CI)

31.1

(28.8, 35.9)

23.4

(20.0, 25.6)

Patients remaining on initial study treatment

12 months

69.5%

47.3%

24 months

42.3%

16.2%

36 months

28.0%

9.4%

I The data cut-off date was 25 June 2019 (OS, TFST, TSST) and 12 June 2017 (PFS, CNS PFS)

ii Criteria for statistical significance at the final analysis of OS was a p-value of less than 0.0495 (determined by O’Brien- Fleming approach)

iii NC=Not Calculable

In the FLAURA trial, the safety and tolerability of Tagrisso was consistent with its established profile. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 42% of patients taking Tagrisso versus 47% in the comparator arm. The most common AEs in patients treated with Tagrisso were diarrhoea (60%), rash (59%), nail toxicity (39%), dry skin (38%), stomatitis (29%), fatigue (21%) and decreased appetite (20%). Despite almost twice the length of therapy, fewer patients experienced a grade 3 or higher AE (42% vs. 47%) or discontinued due to AEs (15% vs. 18%).

The FLAURA trial met its primary endpoint in July 2017, showing a statistically significant and clinically meaningful improvement in PFS, increasing the time patients lived without disease progression or death from any cause.

Tagrisso is currently approved in 78 countries, including the US, Japan, China and the EU, for 1st-line EGFR-mutated (EGFRm) metastatic NSCLC.

About lung cancer

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined.2 Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC.3 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.4-6 These patients are particularly sensitive to treatment with EGFR-TKIs which block the cell-signalling pathways that drive the growth of tumour cells. Approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.7 The presence of brain metastases often reduces median survival to less than eight months.8

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have now received approval in more than 75 countries, including the US, Japan, China and the EU, for 1st-line EGFRm advanced NSCLC, and in more than 85 countries, including the US, Japan, China and the EU, for 2nd-line use in patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being developed in the adjuvant setting (ADAURA trial), in the locally-advanced unresectable setting (LAURA), in combination with chemotherapy (FLAURA2) in the metastatic setting, and with potential new medicines to address resistance to EGFR-TKIs (SAVANNAH, ORCHARD).

About FLAURA

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg orally once daily versus comparator EGFR-TKIs (either gefitinib [250mg orally, once daily] or erlotinib [150mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa (gefitinib) and Tagrisso, and ongoing Phase III trials ADAURA, LAURA and FLAURA2 as well as the Phase II combination trials SAVANNAH and ORCHARD.4-6

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a targetable genetic mutation which represents approximately three-quarters of all patients with lung cancer.9 Imfinzi (durvalumab), an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON, PEARL, and CASPIAN) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, PACIFIC-2, ADRIATIC, ADJUVANT BR.31, PACIFIC-4, and PACIFIC-5) both as monotherapy and in combination with tremelimumab and/or chemotherapy.

About AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On September 28, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed positive results from the Phase III PAOLA-1 trial, showing Lynparza (olaparib) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer (Press release, AstraZeneca, SEP 28, 2019, View Source [SID1234539869]).

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The trial compared Lynparza when added to standard-of-care (SoC) bevacizumab vs. bevacizumab alone in women in the 1st-line maintenance setting, irrespective of their genetic biomarker status or outcome from previous surgery. Investigator-assessed results showed Lynparza added to bevacizumab reduced the risk of disease progression or death by 41% (equal to a hazard ratio of 0.59) and improved PFS to a median of 22.1 months vs. 16.6 months for those treated with bevacizumab alone. At two years since trial initiation, 46% of women treated with Lynparza added to bevacizumab showed no disease progression vs. 28% of women receiving bevacizumab alone.

The sensitivity analysis of blinded independent central review (BICR) of PFS was consistent, showing a similar improvement with a median of 26.1 months for Lynparza added to bevacizumab vs. 18.3 months for bevacizumab alone. The safety and tolerability profile of Lynparza and bevacizumab were consistent with those known from previous trials for each medicine, and with no detriment to quality of life.

The results were presented during the Presidential Symposium of the 2019 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) congress in Barcelona, Spain (Abstract #LBA2_PR).

The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations, which showed treatment with Lynparza added to bevacizumab demonstrated greater benefit vs. bevacizumab alone. In the BRCAm-positive sub-group, Lynparza added to bevacizumab reduced the risk of disease progression or death by 69% (equal to a hazard ratio of 0.31). In the broader HRD-positive sub-group, which represents approximately half of women with newly-diagnosed advanced ovarian cancer and includes BRCAm, Lynparza added to bevacizumab reduced the risk of disease progression or death by 67% (equal to a hazard ratio of 0.33).

José Baselga, Executive Vice President, Oncology R&D, said: "This trial was designed to reflect everyday clinical practice using a global standard-of-care treatment with Lynparza. The results showed at two years nearly half of women with advanced ovarian cancer were progression-free with Lynparza added to bevacizumab as a 1st-line maintenance treatment, regardless of their biomarker status or surgical outcome. We are working with regulatory authorities to bring Lynparza to these patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "PAOLA-1 is the second positive Phase III trial involving Lynparza in the 1st-line maintenance setting for advanced ovarian cancer. Following the positive SOLO-1 trial, we are encouraged by the PAOLA-1 results which reaffirm AstraZeneca and MSD’s ongoing commitment to explore potential treatment options for more women with ovarian cancer."

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Centre Léon Bérard and President of the GINECO group, said: "The goal of 1st-line, including maintenance, treatment for women with newly-diagnosed advanced ovarian cancer is to delay relapse. Unfortunately, the risk of relapsing is high, as two out of three women relapse within three years of initial diagnosis. In PAOLA-1, the results of Lynparza added to bevacizumab were significant and have the potential to change clinical practice in how women with advanced ovarian cancer are treated in the 1st-line maintenance setting."

Summary of PFS in overall population

Median in months

Hazard Ratio

(95% CI)

Lynparza +

bevacizumab

bevacizumab alone

PFS (investigator assessed)

(n=806)

22.1

16.6

0.59 (0.49-0.72)

p<0.0001

PFS (BICR)

26.1

18.3

0.63 (0.51-0.77)

p<0.0001

Summary of PFS in exploratory subgroup analyses

Median in months

Hazard Ratio

(95% CI)

Lynparza +

bevacizumab

bevacizumab alone

PFS by BRCAm status

BRCAm (n=237)

37.2 i

21.7

0.31 (0.20-0.47)

Non-BRCAm (n=569)

18.9

16.0

0.71 (0.58-0.88)

PFS by HRD status

HRD-positive (n=387)

37.2 i

17.7

0.33 (0.25-0.45)

HRD-positive, non-BRCAm (n=152)

28.1 i

16.6

0.43 (0.28-0.66)

HRD-negative/unknown (n=419)

16.9

16.0

0.92 (0.72-1.17)

i The median PFS estimate is immature at this time (below 50% maturity) and will evolve with additional follow up

Overall Grade 3 or above adverse events (AEs) were 57% for Lynparza added to bevacizumab and 51% for bevacizumab alone. The most common AEs ≥20% were nausea (53%), fatigue (53%), hypertension (46%), anaemia (41%), lymphopenia (24%), vomiting (22%) and arthralgia (22%). Grade 3 or above AEs were hypertension (19%), anaemia (17%), lymphopenia (7%), neutropenia (6%), fatigue (5%), nausea (2%), diarrhoea (2%), leukopenia (2%) vomiting (1%) and abdominal pain (1%). AEs led to dose interruption in 54% of patients on Lynparza while 20% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for the treatment of advanced ovarian cancer and metastatic breast cancer and has been used to treat over 25,000 patients worldwide. It is the only PARP inhibitor with positive Phase III trials in four different cancer types (ovarian, breast, pancreatic and prostate).

About PAOLA-1

PAOLA-1 is a double-blind Phase III trial testing the efficacy and safety of Lynparza added to SoC bevacizumab vs. bevacizumab alone, as a 1st-line maintenance treatment for newly-diagnosed advanced FIGO Stage III-IV high grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab.

PAOLA-1 is an ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group specialising in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).

About ovarian cancer

Ovarian cancer is the eighth most common cause of death from cancer in women worldwide. In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.1 Most women are diagnosed with advanced (Stage III or IV) ovarian cancer and have a five-year survival rate of approximately 30%.2 For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission or cure.3,4,5,6

About homologous recombination deficiency

Homologous recombination deficiencies (HRDs) encompass a wide range of genetic abnormalities, including BRCA mutations, that can be detected using tests. As the BRCA gene drives DNA repair via homologous recombination, mutation of this gene leads to HR deficiency thereby interfering with normal cell DNA repair mechanisms. BRCA mutations are just one of many HRDs which are found in up to half of all newly diagnosed advanced ovarian cancer patients and confer sensitivity to PARP inhibitors including Lynparza.

About Lynparza

Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair, such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR pathway.

Lynparza is currently approved in 64 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer, regardless of BRCA status. It is approved in the US, the EU, Japan and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 43 countries, including the US and Japan, for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally-advanced breast cancer. Regulatory reviews are underway in other jurisdictions for ovarian, breast and pancreatic cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for the treatment of advanced ovarian cancer and metastatic breast cancer and has been used to treat over 25,000 patients worldwide. Lynparza has the broadest and most advanced clinical-trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About GINECO

GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) is the French Cooperative Group in Oncology labelled by INCA (Institut National du Cancer, or French NCI) developing and conducting gynaecological and metastatic breast cancer clinical trials at the national and international level. Founded in 1993, the GINECO group is a member of international consortia such as ENGOT and GCIG.

About ENGOT

ENGOT (European Network for Gynaecological Oncological Trial groups) is a research network of the European Society of Gynaecological Oncology (ESGO). Founded in 2007, ENGOT includes 21 cooperative groups from 25 European countries.

About GCIG

The GCIG (Gynecological Cancer InterGroup) aims to promote and facilitate high quality clinical trials in order to improve outcomes for women with gynaecological cancer. Founded in 1998, GCIG includes 23 cooperative groups from 28 countries worldwide.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

On September 28, 2019 Seattle Genetics, Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported initial results from the phase 1 clinical trial EV-103. Forty-five patients were evaluated for safety with the combination of the investigational agent enfortumab vedotin and the immune therapy pembrolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy (Press release, Astellas, SEP 28, 2019, View Source [SID1234539868]). The study met outcome measures for safety and exhibited encouraging clinical activity for this platinum-free combination in a first-line setting. The data will be presented during an oral session today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain (Abstract #901O).

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Enfortumab vedotin is a first-in-class antibody drug conjugate (ADC) that targets Nectin-4, a protein present on almost all urothelial tumor cells and associated with cancer formation.1

"Advanced urothelial cancer is an aggressive disease for which more options are needed, especially for patients who are ineligible for first-line treatment with cisplatin," said Dr. Christopher J. Hoimes, Director, Genitourinary Oncology, Case Comprehensive Cancer Center at University Hospitals Seidman Cancer Center, Cleveland, Ohio. "This study tests the combination of the investigational agent enfortumab vedotin with the PD-1 inhibitor pembrolizumab, in a biomarker unselected population. Initial results provide support for further development of enfortumab vedotin combinations in this and other settings of urothelial cancer."

Fifty-one percent of patients (23/45) had an adverse event greater than or equal to Grade 3. Among these events, an increase in lipase was the most frequent (13 percent; 6/45). Four patients (9 percent) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. There was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndrome.

Treatment-related adverse events of clinical interest that were greater than or equal to Grade 3 were rash (11 percent; 5/45), hyperglycemia (7 percent; 3/45) and peripheral neuropathy (4 percent; 2/45); these rates were similar to those observed with enfortumab vedotin monotherapy.2 Eleven percent (5/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (one event each of pneumonitis, dermatitis bullous, hyperglycemia, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were Grade 5 events.

The data demonstrated the combination of enfortumab vedotin plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate (ORR) of 71 percent (32/45; 95% Confidence Interval (CI): 55.7, 83.6). The complete response (CR) rate was 13 percent (6/45). Fifty-eight percent (26/45) of patients had a partial response and 22 percent (10/45) had stable disease. Ninety-one percent of responses were observed at the first assessment.

"These data are encouraging and support further exploration of a potential platinum-free combination of pembrolizumab and the investigational agent enfortumab vedotin," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

"We are motivated by these results, and we will continue to study enfortumab vedotin alone and in combination with other agents in different stages of urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.

Enfortumab vedotin is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in a neoadjuvant/adjuvant, locally advanced or metastatic setting.

About the EV-103 Trial
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1 trial of enfortumab vedotin alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.

The dose escalation-cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts included in this analysis is safety. The analysis of these first cohorts included several of the study’s secondary objectives. Key secondary objectives related to efficacy include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and overall survival (OS). DOR and OS were not mature at the time of analysis and will be included in a future analysis.

Additional cohorts in the EV-103 study will evaluate enfortumab vedotin:

with cisplatin or carboplatin in a first-line setting for metastatic disease;
in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease;
as a monotherapy or in combination with pembrolizumab in muscle invasive disease;
with pembrolizumab in second-line metastatic disease; and
with gemcitabine in first- or second-line metastatic disease.3
More information about enfortumab vedotin clinical trials can be found at clinicaltrials.gov.

About Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90 percent of cases).4 In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide.5

The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.6

About Enfortumab Vedotin
Enfortumab vedotin is an investigational antibody-drug conjugate (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 that is expressed on many solid tumors, and that has been identified as an ADC target by Astellas.

The safety and efficacy of enfortumab vedotin are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval or become commercially available for the uses being investigated.

On September 27, 2019, Rigel Pharmaceuticals, Inc., a Delaware corporation (the "Company") reported that it entered into a Credit and Security Agreement, dated as of September 27, 2019 (the "Closing Date") by and among the Company, the lenders party thereto from time to time and MidCap Financial Trust, as administrative agent and collateral agent ("Agent") (the "Term Loan Credit Agreement"), which provides for a $60 million term loan facility (Filing, 8-K, Rigel, SEP 27, 2019, View Source [SID1234552181]). The Term Loan Credit Agreement provides for (i) on the Closing Date, $10.0 million aggregate principal amount of term loans, (ii) at the Company’s option, until December 31, 2020, an additional $10.0 million term loan facility, (iii) at the Company’s option, until March 31, 2021, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche Three") and (iv) at the Company’s option, until March 31, 2022, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche 4") (collectively, the "Term Loans"). The Company used the proceeds of the Term Loans for general corporate purposes

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The obligations under the Term Loan Credit Agreement are secured by a perfected security interest in all of the Company’s assets except for intellectual property and certain other customary excluded property pursuant to the terms of the Term Loan Credit Agreement.

The Term Loans are subject to an origination fee of 0.25% of each funded tranche of Term Loans. The Company will pay the Agent an annual administrative fee of 0.25% of the amount borrowed under the Term Loans, payable annually. The Term Loans may be prepaid in full or in part through September 27, 2020 with payment of a 2.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2021 with payment of a 1.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2022 with payment of a 1.0% prepayment premium, after which they may be prepaid in full or in part with no prepayment premium. An additional 2.5% of the amount of Terms Loans advanced by the lenders will be due upon prepayment or repayment of the Term Loans in full.

The interest rate applicable to the Term Loans is LIBOR plus 5.65%, subject to a LIBOR floor of 1.50%. Commencing October 1, 2019, the Company initially will make interest-only payments for 24 months, followed by 36 months of amortization payments. The interest-only period will be extended to 36 months and again to 48 months upon the satisfaction of certain conditions set forth in the Term Loan Credit Agreement. All unpaid principal and accrued interest is due and payable in full no later than September 1, 2024.

The Term Loan Credit Agreement requires that the Company (i) upon both of (x) the draw of Tranche 3 or Tranche 4 and (y) cash falling below 1.25x Term Loans outstanding, maintain U.S. Tavalisse Net Revenue (as defined in the Term Loan Credit Agreement) in amounts set forth in the Term Loan Credit Agreement and (ii) upon the draw of Tranche 3 or Tranche 4, maintain cash and cash equivalents of at least $10.0 million. The Term Loan Credit Agreement also contains customary representations and warranties and customary affirmative and negative covenants, including, among other things, restrictions on indebtedness, liens, investments, mergers, dispositions, prepayment of other indebtedness and dividends and other distributions.

Events of default under the Term Loan Credit Agreement include: (i) failure by the Company to timely make payments due under the Term Loan Credit Agreement; (ii) material misrepresentations or misstatements in any representation or warranty by the Company when made; (iii) failure by the Company or its subsidiaries to comply with the covenants under the Term Loan Credit Agreement and other related agreements; (iv) certain defaults under a specified amount of other indebtedness of the Company or its subsidiaries; (v) insolvency or bankruptcy-related events with respect to the Company or any of its subsidiaries; (vi) certain undischarged judgments against the Company or its subsidiaries; (vii) certain ERISA-related events with respect to the Company or its subsidiaries above a specified amount; (viii) certain security interests or liens under the loan documents ceasing to be, or being asserted by the Company not to be, in full force and effect; (ix) the institution of criminal proceedings against the Company; (x) an event of default under the guarantee of the obligations under the Term Loan Credit Agreement; (xi) the prepayment of any subordinated debt other than as specifically permitted by the terms of such subordination; (xii) the occurrence of a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiii) certain adverse actions by the FDA or DEA with respect to certain products or which could be reasonably expected to result in a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiv) a default or material breach under certain specified material contracts and (xv) any loan document ceasing to be, or any challenge or assertion by the Company that such loan document is not, in full force and effect. If one or more events of default occurs and continues beyond any applicable cure period, the Agent may, with the consent of the lenders holding a majority of the loans and commitments under the facilities, or will, at the request of such lenders, terminate the commitments of the lenders to make further loans and declare all of the obligations of the Company under the Term Loan Credit Agreement to be immediately due and payable.