On June 3, 2019 Bristol-Myers Squibb Company (NYSE: BMY) reported updated results from studies evaluating Opdivo (nivolumab) and Yervoy (ipilimumab), alone or in combination, in patients with advanced or metastatic melanoma (Press release, Bristol-Myers Squibb, JUN 3, 2019, View Source [SID1234536800]). These analyses (Abstracts #9533, #9568 and #9551) will be featured on Monday, June 3 from 1:15-4:15 PM CDT at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting in Chicago.

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Five-Year Analysis from Phase 1 CA209-004 Study

A five-year analysis of the Phase 1 CA209-004 study, the longest follow-up for the Opdivo plus Yervoy combination in patients with previously treated or untreated advanced melanoma to date, showed that with a median follow-up of 43.1 months (range: 0.9-76.7) in all patients, at four years or longer, overall survival (OS) rates were stable at 57% (95% Confidence Internal [CI]: 47, 67). The three-year OS rate following discontinuation of therapy was 56% (95% CI: 46, 66). The study also showed long-term survival outcomes with Opdivo plus Yervoy, regardless of BRAF or lactate dehydrogenase (LDH) status, with four-year OS rates of 62% (95% CI: 48, 74) versus 49% (95% CI: 32, 65) for patients with normal and elevated LDH, respectively, and four-year OS rates of 54% (95% CI: 41, 65) and 61% (95% CI: 38, 77) for patients with wild-type and mutant BRAF tumors, respectively. The overall safety of the combination was consistent with previously reported studies of these medicines in patients with advanced melanoma.

New Analyses from Phase 3 CheckMate -067 Study

An analysis exploring long-term quality of life (QoL) and symptom burden in the Phase 3 CheckMate -067 study found that QoL was maintained during the treatment-free interval (TFI) – the period where a patient is off study treatment and free of subsequent therapy – in patients with previously untreated unresectable or metastatic melanoma following discontinuation of therapy with Opdivo or Opdivo plus Yervoy. Patient reported outcome (PRO) scores were maintained from last on-treatment visit to follow-up 1 (30 days after the last dose) or follow-up 2 (84 days after follow-up 1) for patients who discontinued treatment. PRO scores remained stable beyond follow-up 2 for the EQ-5D-3L (measures of mobility, self-care, usual activities, pain/discomfort and anxiety/depression), which were collected at survival follow-up visits every three months in the first year and then every six months.

Finally, a four-year analysis from the CheckMate -067 study of Opdivo and Yervoy, alone or in combination, in patients with previously untreated unresectable or metastatic melanoma, showed that patient-reported QoL and symptoms were maintained from baseline during extended treatment. Of 813 patients included in the PRO analysis population, QoL – including an assessment of functioning and symptom burden – was maintained for the duration of treatment and in follow-up, with no sustained clinically meaningful deterioration in any treatment arm.

"These latest results provide further support for the long-term scientific rationale for combining Opdivo and Yervoy for the treatment of advanced melanoma," said Arvin Yang, M.D., Ph.D., development lead, melanoma and genitourinary cancers, Bristol-Myers Squibb. "We will continue to evaluate the combination in these patients, as it also provides us with a wealth of valuable scientific information on the impact of immuno-oncology therapy in this population."

"Given the significant impact of treatment with Opdivo, alone or in combination with Yervoy, we’re able to gain new insights into the quality of life benefits of these immuno-oncology therapies," said John O’Donnell, MPP, Ph.D., Vice President, Worldwide Health Economics and Outcomes Research, Bristol-Myers Squibb. "What we saw in multiple analyses of CheckMate -067 is that quality of life was maintained throughout the course of treatment and follow-up and, as important, these benefits were maintained when the patients were off therapy."

About CA209-004

CA209-004 is a Phase 1b, open-label, multicenter, multidose, dose-finding study of Opdivo in combination with Yervoy in patients with previously treated or untreated advanced malignant melanoma. The trial evaluated different dosing schedules for the Opdivo plus Yervoy regimen, including Opdivo plus Yervoy every three weeks (Q3W) for four doses, followed by Opdivo Q3W for four doses (Cohorts 1, 2, 2a, and 3) (n=53), or Opdivo 1 mg/kg and Yervoy 3 mg/kg Q3W for four doses followed by Opdivo 3 mg/kg every two weeks for up to 96 weeks (Cohort 8) (n=41). Forty percent of patients in Cohorts 1-3 and 51% of patients in Cohort 8 were previously treated. Patients were followed for the primary endpoint of safety (based on adverse event reports and the results of clinical laboratory tests, immune safety tests, physical examinations, vital sign measurements, Eastern Cooperative Oncology Group [ECOG] performance status, and electrocardiogram evaluations) and the secondary endpoints of response and progression-free survival (PFS) for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years.

About CheckMate -067

CheckMate -067 is a Phase 3, double-blind, randomized trial that evaluated the combination of Opdivo plus Yervoy or Opdivo monotherapy versus Yervoy monotherapy in 945 patients with previously untreated advanced melanoma. Patients in the combination group (n=314) received Opdivo 1 mg/kg plus Yervoy 3 mg/kg (Q3W) for four doses followed by Opdivo 3 mg/kg every two weeks (Q2W). Patients in the Opdivo monotherapy group (n=316) received Opdivo 3 mg/kg Q2W plus placebo. Patients in the Yervoy monotherapy group (n=315) received Yervoy 3 mg/kg every three weeks for four doses plus placebo. Patients were treated until progression or unacceptable toxic effects. Overall survival (OS) and progression-free survival (PFS) were co-primary endpoints of the trial. Secondary endpoints included objective response rates (ORR), efficacy by tumor PD-L1 expression level and safety.

About Metastatic Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 91,270 new diagnoses of melanoma and more than 9,320 related deaths are estimated for 2018. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma is mostly curable when treated in its very early stages; however, survival rates are roughly halved if regional lymph nodes are involved. Patients in the United States diagnosed with advanced melanoma classified as Stage IV historically have a five-year survival rate of 15% to 20% and 10-year survival of about 10% to 15%.

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 50 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with 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 June 3, 2019 BerGenBio ASA (OSE:BGBIO) reported data showing significant efficacy in Phase II clinical trials (BGBC003, NCT02488408) evaluating bemcentinib, a first-in-class selective oral AXL inhibitor, in combination with low-dose cytarabine (LDAC) or decitabine as a potential new treatment regimen for acute myeloid leukaemia (AML) patients unable to tolerate intensive therapy (Press release, BerGenBio, JUN 3, 2019, View Source [SID1234536799]). The data will be presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), Chicago, Illinois (31 May – 4 June 2019).

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In total, 33 patients were enrolled into the trial: 16 into the LDAC + bemcentinib group, of which 13 are evaluable for efficacy to date, and 17 into the decitabine + bemcentinib group, of which 12 are evaluable for efficacy to date.

Among the 13 evaluable patients in the LDAC + bemcentinib group, 6 responses have been reported; 4 patients achieved complete remission / complete remission with incomplete hematologic recovery (CR/CRi) and 2 patients’ partial remission (PR). This yields an overall response rate (ORR) of 46%, including 31% CR/CRi among elderly AML patients (>70 years). Furthermore, one patient achieved durable stable disease for more than 3 months. The relapse free survival rate (RFS) for patients with CR/CRi is 6.2 months (0.7 to 9.6 months); data immature.

In the decitabine/bemcentinib group, of the 12 evaluable patients, 3 responses have been reported; 1 patient achieved CR/CRi and 2 patients PR. This yields an ORR of 25%. Furthermore, five patients had durable stable disease for more than 3 months. The RFS for patients with CR/CRi is 5 months; data immature.

The combination treatment of bemcentinib and LDAC or decitabine was overall well-tolerated; the most common adverse events (>15% of patients) included anaemia, neutropenia and diarrhoea. No grade 5 TRAEs were reported and all events were reversible.

Professor Sonja Loges, attending physician and principal investigator, University Medical Centre Hamburg Eppendorf, Germany commented: "These early results are very encouraging, particularly as we have seen responses in a less fit AML patient population with comparatively poor prognosis [having not responded to first-line therapies], or with high risk cytogenetics. These data show that bemcentinib in combination with LDAC resulted in a significantly higher ORR than previously observed/historical benchmarks in single-agent cytarabine. These early results warrant further investigation of bemcentinib in a larger trial addressing AML patients unfit for intensive chemotherapy."

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "A majority of AML patients are unable to tolerate intensive chemotherapy and have limited treatment options, particularly if established first-line therapies fail. These combination trials of bemcentinib with low-dose cytarabine and decitabine show promising results that the addition of our selective AXL inhibitor will improve the outcome of treatment with these much-used agents. Although these are early findings, we are encouraged by the emerging clinical data and focused on advancing our late stage development programme."

– END –

About AML and the BGBC003 trial
Acute myeloid leukaemia (AML) is a rapidly progressing blood cancer. AML is the most common form of acute leukaemia in adults, where malignant AML blasts interfere with the normal functioning of the bone marrow leading to a multitude of complications like anaemia, infections and bleeding. AML is diagnosed in over 20,000 patients in the US annually and is rapidly lethal if left untreated. Successful treatment typically requires intensive therapy or bone marrow transplantation, and relapse and resistance are common. Consequently, there is an urgent need for effective novel therapies in relapsed/refractory patients, particularly those that are ineligible for intensive therapy or bone marrow transplant.

The BGBC003 trial is a phase Ib/II multi-centre open label study of bemcentinib in combination with cytarabine (part B2) and decitabine (part B3) in patients with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing-co-morbidities. Up to 28 patients will be enrolled at centres in the US, Norway, Germany and Italy.

For more information please access trial NCT02488408 at www.clinicaltrials.gov.

About AXL
AXL kinase is a cell membrane receptor and an essential mediator of the biological mechanisms underlying life-threatening diseases. In cancer, AXL suppresses the body’s immune response to tumours and drives cancer treatment failure across many indications. AXL inhibitors, therefore, have potential high value at the centre of cancer combination therapy, addressing significant unmet medical needs and multiple high-value market opportunities. Research has also shown that AXL mediates other aggressive diseases.

On June 3, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported full results from the Phase III SOLO3 trial which compared Lynparza (olaparib) with physician’s choice of chemotherapy in the treatment of patients with germline BRCA1/2-mutated (gBRCAm) advanced ovarian cancer who had received two or more prior lines of chemotherapy (Press release, AstraZeneca, JUN 3, 2019, View Source [SID1234536798]).

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The results from the trial, presented at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US, showed a statistically-significant and clinically-meaningful improvement in objective response rate (ORR) for Lynparza vs. chemotherapy (72.2% vs. 51.4% [95% CI, 1.40-4.58], p=0.002). ORR measures the proportion of patients with reduction in tumour burden of a predefined percentage.

The trial also met the key secondary endpoint of progression-free survival (PFS), demonstrating a statistically-significant and clinically-meaningful improvement in the time patients lived without disease progression for Lynparza (13.4 months) vs. chemotherapy (9.2 months [HR 0.62] p=0.013]).

José Baselga, Executive Vice President, Oncology R&D, said: "Lynparza provides a much-needed alternative and improvement over standard-of-care chemotherapy for patients with BRCA-mutated, advanced ovarian cancer. This is the fourth positive Phase II/III trial in advanced ovarian cancer for Lynparza, across multiple lines of therapy. We look forward to working closely with regulatory authorities to include findings from this trial in the prescribing information for Lynparza."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "Lynparza is the first and only PARP inhibitor to demonstrate efficacy versus chemotherapy in relapsed BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. The positive SOLO3 results reaffirm AstraZeneca and MSD’s ongoing commitment to explore potential treatment options beyond standard of care for BRCA-mutated with advanced stage disease."

Summary of resultsi

Lynparza
(300 mg bd)

Chemotherapy

ORR (primary endpoint)

Number of patients

151

72

Number of patients with response (%)

109 (72.2%)

37 (51.4%)

Odds ratio (95% CI)

2.53 (1.40, 4.58)

p-value

0.002

PFS (key secondary endpoint)i,ii

Number of patients

178

88

Number of patients with event (%)

110 (61.8%)

49 (55.7%)

Hazard ratio (95% CI)

0.62 (0.43, 0.91)

Median in months

13.4

9.2

p-value

0.013

iAssessed by blinded independent central review.

iiAnalysis was done at 59.8% maturity.

The safety and tolerability profile of Lynparza in the SOLO3 trial was consistent with previous trials. The most common adverse events (AEs) ≥ 20% were nausea (65%), fatigue/asthenia (52%), anaemia (51%), vomiting (38%), diarrhoea (28%), neutropenia (23%) and abdominal pain (21%). The most common ≥ Grade 3 AEs were anaemia (21%), neutropenia (10%), fatigue/asthenia (5%) and thrombocytopenia (4%). AEs led to dose interruption in 48% of patients on Lynparza while 7% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for multiple indications in advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide.

About SOLO3

SOLO3 was a Phase III randomised, open-label, controlled, multicentre trial to evaluate the efficacy and safety of Lynparza tablets following two or more prior lines of chemotherapy. The trial randomised 266 patients with a deleterious or suspected deleterious BRCA1 or BRCA2 mutation. Eligible patients were randomised (2:1) to receive Lynparza 300mg tablets twice daily or physician’s choice of single-agent chemotherapy (paclitaxel, topotecan, pegylated liposomal doxorubicin or gemcitabine). The primary endpoint was ORR by blinded independent central review and key secondary endpoints included PFS, time to second disease progression or death and overall survival. The SOLO3 trial addresses a post-approval commitment from the December 2014 accelerated US approval of Lynparza in ovarian cancer.

About ovarian cancer

Ovarian cancer is a leading cause of cancer death in women worldwide, with a five-year survival rate of 19%.1 In 2018, there were over 295,000 new cases diagnosed and around 185,000 deaths.2 Over 70% of women with ovarian cancer have advanced disease at the time of diagnosis, with up to 80% at risk of recurrence after initial treatment.3 Effective treatments are needed in later lines of therapy as patients typically obtain limited benefit after two prior lines of chemotherapy.3

About BRCA mutations

Breast cancer susceptibility genes 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About Lynparza

Lynparza (olaparib) 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 (HRR), 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.

Lynparza is currently approved in over 60 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, Canada and Brazil as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in nearly 40 countries, including the US and Japan, for germline BRCAm 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 both ovarian cancer and breast cancer.

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 the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States 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.

On June 3, 2019 Astellas Pharma Inc. (TSE: 4503) (President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seattle Genetics, Inc. (Nasdaq: SGEN) reported that data from the first cohort of a pivotal phase 2 clinical trial known as EV-201 demonstrated that the investigational agent enfortumab vedotin rapidly shrank tumors in most patients, resulting in an objective response rate (ORR) of 44 percent (55/125; 95% Confidence Interval (CI): 35.1-53.2) (Press release, Astellas, JUN 3, 2019, View Source [SID1234536797]). Complete responses (CR) were observed in 12 percent of patients (15/125). The median duration of tumor response was 7.6 months (range 0.95-11.3+). This cohort was open to patients with locally advanced or metastatic urothelial cancer who had received previous treatment with a platinum-containing chemotherapy and a PD-1/L1 checkpoint inhibitor. Responses were similar in the subgroups of patients analyzed, including those who had the worst prognosis, such as patients who had three or more previous lines of therapy, patients with liver metastases, and those who had not responded to a PD-1/L1 inhibitor. Treatment-related adverse events that occurred in 40 percent or more of patients were fatigue, alopecia, rash, decreased appetite, taste distortion, and peripheral neuropathy.

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The data will be featured today in the official press program of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and be presented as a Late-Breaking oral presentation (Abstract #LBA4505) and have been submitted for publication in a peer-reviewed journal.

Despite recent advances in treatment, approximately 80 percent of people do not respond to PD-1/L1 inhibitors, which are the standard of care after platinum-containing therapy has failed as an initial treatment for advanced disease.[1],[2],[3] These patients have few treatment options and new therapies are urgently needed.

Enfortumab vedotin is an investigational antibody-drug conjugate (ADC) that targets Nectin-4, a protein that is highly expressed in urothelial cancers.[4],[5] Based on the results of the EV-201 trial, the companies plan to submit a Biologics License Application (BLA) for enfortumab vedotin to the U.S. Food and Drug Administration (FDA) this year. Based on preliminary results from the phase 1 EV-101 trial, the FDA granted enfortumab vedotin Breakthrough Therapy designation for people with locally advanced or metastatic urothelial cancer whose disease has progressed during or following checkpoint inhibitor therapy.

"Outcomes for patients diagnosed with locally advanced or metastatic urothelial cancer are generally poor, and treatment options after initial chemotherapy and immunotherapy are very limited," said Daniel P. Petrylak, M.D., Professor of Medicine and of Urology, Yale Cancer Center, New Haven. "These data have the potential to change the treatment course of advanced urothelial cancer, and it is gratifying to see these results for patients."

"Even with the recent introduction of new therapies, there remains a need for continued innovation in the treatment of urothelial cancer, and if approved, we hope to bring this potential treatment to physicians and patients as quickly as possible," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.

"We are encouraged that enfortumab vedotin is the first novel therapy to demonstrate substantial clinical activity in these difficult-to-treat patients who currently have limited treatment options," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

A global, randomized phase 3 confirmatory clinical trial (EV-301) is ongoing and is intended to support global registrations. Another trial (EV-103) is underway to evaluate enfortumab vedotin in earlier lines of treatment for patients with locally advanced or metastatic urothelial cancer, including in combination with pembrolizumab and/or platinum chemotherapy in newly diagnosed patients as well as patients who progressed from earlier-stage disease.

EV-201 Study Results

Efficacy
In the first cohort of the EV-201 study, 125 patients were treated with enfortumab vedotin. The primary endpoint of confirmed objective response rate (ORR) was 44 percent per blinded independent central review (BICR) [(55/125; 95% CI: 35.1-53.2)]. The overall duration of response (DoR), a key secondary endpoint, was 7.6 months (range 0.95-11.3+).

Most responses occurred within the first cycle of treatment, and were observed across all pre-specified patient subgroups irrespective of lines of therapy, response to prior PD-1/L1 inhibitor, or presence of liver metastases:

Three or more prior therapies: 41 percent ORR (26/63)
Non-responders to PD-1/L1 inhibitors: 41 percent ORR (41/100)
Liver metastases: 38 percent ORR (19/50)
Median overall survival (OS) was 11.7 months (95% CI:9.1-not reached), and the median progression-free survival (PFS) was 5.8 months (95% CI:4.9-7.5).

Safety

The most common treatment-related adverse events (AEs) occurring in more than 40 percent of patients were fatigue (50 percent (62/125)); alopecia (49 percent (61/125)); rash (48 percent (60/125)); decreased appetite (44 percent (55/125)); taste distortion (40 percent (50/125)); and peripheral neuropathy (50 percent (63/125)).
Most peripheral neuropathy (94 percent) and rash (75 percent) were less than or equal to Grade 2 in severity. Hyperglycemia occurred in 11 percent of patients (14/125).
The most common severe AEs (defined as greater than or equal to Grade 3) were: neutropenia – experienced by 8 percent of patients (10/125); anemia in 7 percent of patients (9/125); and fatigue in 6 percent of patients (7/125). One death due to interstitial lung disease occurred outside the safety-reporting period and was confounded by prolonged high-dose steroid use and suspected pneumonia.
About the EV-201 Trial
EV-201 is an ongoing single-arm, pivotal phase 2 clinical trial of enfortumab vedotin in patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1/L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy and who are ineligible for cisplatin (cohort 2). EV-201 continues to enroll patients in cohort 2. In cohort 1, 128 patients were enrolled at multiple centers internationally.[6] The primary endpoint is confirmed objective response rate per blinded independent central review. Secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety and tolerability.

More information about enfortumab vedotin clinical trials can be found at clinical trials.gov.

About Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90 percent of cases).[7] In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States.[8] Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide.

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 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 June 3, 2019 Amgen (NASDAQ: AMGN) reported the first clinical results from a Phase 1 study evaluating investigational AMG 510, the first KRASG12C inhibitor to reach the clinical stage (Press release, Amgen, JUN 3, 2019, View Source;p=RssLanding&cat=news&id=2400393 [SID1234536796]). In the trial, there were no dose-limiting toxicities at tested dose levels. AMG 510 showed anti-tumor activity when administered as a monotherapy in patients with locally-advanced or metastatic KRASG12C mutant solid tumors. These data are being presented during an oral session at the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago.

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"KRAS has been a target of active exploration in cancer research since it was identified as one of the first oncogenes more than 30 years ago, but it remained undruggable due to a lack of traditional small molecule binding pockets on the protein. AMG 510 seeks to crack the KRAS code by exploiting a previously hidden groove on the protein surface," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "By irreversibly binding to cysteine 12 on the mutated KRAS protein, AMG 510 is designed to lock it into an inactive state. With high selectivity for KRASG12C, we believe investigational AMG 510 has high potential as both a monotherapy and in combination with other targeted and immune therapies."

The Phase 1, first-in-human, open-label multicenter study enrolled 35 patients with various tumor types (14 non-small cell lung cancer [NSCLC], 19 colorectal cancer [CRC] and two other). Eligible patients were heavily pretreated with at least two or more prior lines of treatment, consistent with their tumor type and stage of disease. The primary endpoint is safety, and key secondary endpoints include pharmacokinetics, objective response rate (assessed every six weeks), duration of response and progression-free survival. Patients were enrolled in four dose cohorts – 180 mg, 360 mg, 720 mg and 960 mg, taken orally once a day.

Five out of 10 evaluable patients with NSCLC experienced a partial response (PR), and another four had stable disease (SD), for a disease control rate (DCR) of 90 percent (9/10).1 All five patients with response to therapy had a treatment duration of 7.3-27.4 weeks at data cutoff and remain active on treatment. One patient with PR improved further to a complete response of the target lesions at week 18, post data cutoff.

In addition, 13 of 18 evaluable patients with CRC achieved SD, with the majority of CRC patients treated at the first two dose levels. Twenty-six patients remain on study and nine have discontinued.

Treatment-related adverse events (AEs) were primarily grade 1 events (approximately 68 percent). Two grade 3 treatment-related AEs were reported (anemia and diarrhea). No grade 4 treatment-related AEs and no serious treatment-related AEs were reported. Enrollment into dose expansion is underway.

"While there’s been significant progress in treating solid tumor cancers overall with targeted therapies, patients with the KRASG12C mutation have not benefited from these advances," said Marwan G. Fakih, M.D., clinical study investigator and co-director of the Gastrointestinal Cancer Program, City of Hope, Duarte, Calif. "In this early Phase 1 trial, investigational AMG 510 showed encouraging anti-tumor activity. We look forward to further investigating AMG 510 with the goal of closing the treatment gap for patients with this type of mutation."

Amgen Webcast Investor Meeting
Amgen will host a webcast investor meeting at ASCO (Free ASCO Whitepaper) 2019 on Monday, June 3 at 6:30 p.m. CT. David M. Reese, M.D., executive vice president of Research and Development at Amgen, along with members of Amgen’s clinical development team and clinical investigators, will participate at the investor meeting to discuss Amgen’s oncology program and data presented at ASCO (Free ASCO Whitepaper) 2019. Live audio of the conference call will be broadcast over the internet simultaneously and will be available to members of the news media, investors and the general public.

The webcast, as with other selected presentations regarding developments in Amgen’s business given at certain investor and medical conferences, can be accessed on Amgen’s website, www.amgen.com, under Investors. Information regarding presentation times, webcast availability and webcast links are noted on Amgen’s Investor Relations Events Calendar. The webcast will be archived and available for replay for at least 90 days after the event.

About KRAS
The subject of more than three decades of research, the RAS gene family are the most frequently mutated oncogenes in human cancers.2,3 Within this family, KRAS is the most prevalent variant and is particularly common in solid tumors.3 A specific mutation known as KRASG12C accounts for approximately 13 percent of non-small cell lung cancers, three to five percent of colorectal cancers and one to two percent of numerous other solid tumors.4 Approximately 30,000 patients are diagnosed each year in the United States with KRASG12C driven cancers.5 Amgen is exploring the potential of KRASG12C inhibition across a broad variety of tumor types.