on June 4, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported updated results from CheckMate -012, a multi-arm, Phase 1b trial evaluating two Immuno-Oncology agents, Opdivo and Yervoy, in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, JUN 4, 2016, View Source [SID:1234512989]). In this study, Opdivo was administered as monotherapy or as part of a combination with other agents, including Yervoy, at different doses and schedules. Data from the Opdivo monotherapy arm and other cohorts were previously reported. These updated results include findings from a pooled analysis of two Opdivo and Yervoy combination regimen cohorts, [3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy either every six (Q6W) or 12 weeks (Q12W) (n=77)] which showed the magnitude of response rate from the combination regimen was enhanced with increased PD-L1 expression. In these combination regimen cohorts, the confirmed objective response rate (ORR) in patients with ≥1% PD-L1 expression was 57% and the confirmed ORR was up to 92% (n=12/13) in patients with ≥50% PD-L1 expression. In patients with <1% PD-L1 expression, the confirmed ORR was 15%. The ORR was 47% and 39% for the Q12W and Q6W, respectively in the overall population which included all patients regardless of PD-L1 expression level.

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In the study, the rate of treatment related Grade 3/4 adverse events (AEs) was 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy cohorts, respectively. The rate of treatment-related Grade 3/4 AEs leading to discontinuation was 5%, 8%, and 10% of patients in the Q12W, Q6W and Opdivo monotherapy arms, respectively. There were no treatment-related deaths.

These data will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) during an oral presentation on Saturday, June 4, from 1:27 PM – 1:39 PM CDT (Abstract #3001).

"The results from this study provide important insight into the combination immunotherapy with Opdivo and Yervoy, and supports the potential for this combination as a first-line treatment option for patients with advanced non-small cell lung cancer," said Matthew D. Hellmann, M.D., Memorial Sloan Kettering Cancer Center. "The frequency, depth, and durability of responses among patients in this study treated with the combination regimen, and particularly among those with increased PD-L1 expression, are promising. We look forward to additional research of this combination in the first-line setting of patients with non-small cell lung cancer."

Results from CheckMate -012 continue to support the dosing schedule selected – 3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy every six weeks – for evaluation in further studies, including the Phase 3 trial, CheckMate -227, comparing Opdivo, the Opdivo and Yervoy combination regimen or Opdivo and platinum-based doublet chemotherapy versus platinum-based doublet chemotherapy in chemotherapy-naïve Stage IV or recurrent NSCLC.

Jean Viallet, M.D., Global Clinical Research Lead, Oncology, Bristol-Myers Squibb, commented, "We find these Opdivo and Yervoy combination regimen results in first-line advanced non-small cell lung cancer compelling. These data reinforce our approach to identify an optimized combination dosing schedule for further study in patients with advanced non-small cell lung cancer. As we continue to advance our Immuno-Oncology clinical research, our goal is to offer patients with first-line lung cancer the potential for improved outcomes."

About CheckMate -012

CheckMate -012 is a multi-arm Phase 1b trial evaluating the safety and tolerability of Opdivo in patients with chemotherapy-naïve advanced non-small cell lung cancer (NSCLC), as either a monotherapy or in combination with other agents including Yervoy, at different doses and schedules. The primary endpoint of the study was safety with secondary endpoints of objective response rate (ORR) and 24-week progression-free survival (PFS). Exploratory endpoints included overall survival (OS) and efficacy by PD-L1 expression. In the study, patients were tested for PD-L1 expression and 68% of patients in the Q12W cohort and 77% of patients in the Q6W cohort expressed PD-L1.

The efficacy and safety results of the three dosing schedules in CheckMate -012 reported at ASCO (Free ASCO Whitepaper) are below.

Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
Confirmed ORR, %
(95% CI)
47
(31, 64) 39
(23, 55) 23*
(13, 37)
Median duration of response, mo (95% CI) NR (11.3, NR) NR (8.4, NR) NR (5.7, NR)
Median length of follow-up, mo (range) 12.9 (0.9–18.0) 11.8 (1.1–18.2) 14.3 (0.2–30.1)
*not randomized

CheckMate -012 also evaluated the efficacy by PD-L1 expression, an exploratory endpoint, of Opdivo as monotherapy (previously reported) and in combination with Yervoy across the Q6W and Q12W dosing schedules. The chart below describes the efficacy results based on PD-L1 expression levels presented today at ASCO (Free ASCO Whitepaper).

Nivo 3 Q2W
+ Ipi 1 Q12W
(n = 38)
Nivo 3 Q2W
+ Ipi 1 Q6W
(n = 39)
Nivo 3 Q2W
(n = 52)
ORR, % (n/N)
<1% PD-L1
≥1% PD-L1
≥50% PD-L1
30 (3/10)
57 (12/21)
100 (6/6)
0 (0/7)
57 (13/23)
86 (6/7)
14 (2/14)
28 (9/32)
50 (6/12)
Median PFS (95% CI), mo
<1% PD-L1
≥1% PD-L1
≥50% PD-L1
4.7 (0.9, NR)
8.1 (5.6, NR)
13.6 (6.4, NR)
2.4 (1.7, 2.9)
10.6 (3.6, NR)
NR (7.8, NR)
6.6 (2.0, 11.2)
3.5 (2.2, 6.6)
8.4 (2.2, NR)
1-year OS rate (95% CI), %
<1% PD-L1
≥1% PD-L1
≥50% PD-L1
NC
90 (66, 97)
NC
NC
83 (60, 93)
100 (100, 100)
69 (50, 82)
79 (47, 93)
83 (48, 96)
The rate of total adverse events in the Q12W (82%) and Q6W (72%) arms were comparable to monotherapy (71%). In the study, Grade 3/4 adverse events (AEs) were 37%, 33%, and 19% for the Q12W, Q6W and Opdivo monotherapy arms, respectively. Treatment-related Grade 3/4 AEs lead to discontinuation in 5% and 8% of patients in the Q12W and Q6W cohorts, respectively and were similar to Opdivo monotherapy. There were no treatment-related deaths. The treatment-related select AEs in patients administered the optimized dosing schedule (3 mg/kg of Opdivo every two weeks plus 1 mg/kg of Yervoy every six weeks) were skin related (36%), gastrointestinal (23%), endocrine (20%), and pulmonary (6%) and there were ≤5% treatment-related Grade 3/4 AEs per category.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Non-small cell lung cancer (NSCLC) is one of the most common types of the disease and accounts for approximately 85% of cases. About 25% to 30% of all lung cancers are squamous cell carcinomas, and non-squamous NSCLC accounts for approximately 50% to 65% of all lung cancer cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47% and 50%; for Stage IV NSCLC, the five-year survival rate drops to 2%.

Bristol-Myers Squibb & Immuno-Oncology: Advancing Oncology Research

At Bristol-Myers Squibb, we have a vision for the future of cancer care that is focused on Immuno-Oncology, now considered a major treatment choice alongside surgery, radiation, chemotherapy and targeted therapies for certain types of cancer.

We have a comprehensive clinical portfolio of investigational and approved Immuno-Oncology agents, many of which were discovered and developed by our scientists. Our ongoing Immuno-Oncology clinical program is looking at broad patient populations, across multiple solid tumors and hematologic malignancies, and lines of therapy and histologies, with the intent of powering our trials for overall survival and other important measures like durability of response. We pioneered the research leading to the first regulatory approval for the combination of two Immuno-Oncology agents, and continue to study the role of combinations in cancer.

We are also investigating other immune system pathways in the treatment of cancer including CTLA-4, CD-137, KIR, SLAMF7, PD-1, GITR, CSF1R, IDO, and LAG-3. These pathways may lead to potential new treatment options – in combination or monotherapy – to help patients fight different types of cancers.

Our collaboration with academia, as well as small and large biotech companies, to research the potential Immuno-Oncology and non-Immuno-Oncology combinations, helps achieve our goal of providing new treatment options in clinical practice.

At Bristol-Myers Squibb, we are committed to changing survival expectations in hard-to-treat cancers and the way patients live with cancer.

About Opdivo

Cancer cells may exploit "regulatory" pathways, such as checkpoint pathways, to hide from the immune system and shield the tumor from immune attack. Opdivo is a PD-1 immune checkpoint inhibitor that binds to the checkpoint receptor PD-1 expressed on activated T-cells, and blocks the binding of PD-L1 and PD-L2, preventing the PD-1 pathway’s suppressive signaling on the immune system, including the interference with an anti-tumor immune response.

Opdivo’s broad global development program is based on Bristol-Myers Squibb’s understanding of the biology behind Immuno-Oncology. Our company is at the forefront of researching the potential of Immuno-Oncology to extend survival in hard-to-treat cancers. This scientific expertise serves as the basis for the Opdivo development program, which includes a broad range of Phase 3 clinical trials evaluating overall survival as the primary endpoint across a variety of tumor types. The Opdivo trials have also contributed toward the clinical and scientific understanding of the role of biomarkers and how patients may benefit from Opdivo across the continuum of PD-L1 expression. To date, the Opdivo clinical development program has enrolled more than 18,000 patients.

Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world in July 2014, and currently has regulatory approval in 51 countries including the United States, Japan, and in the European Union.

U.S. FDA APPROVED INDICATIONS FOR OPDIVO

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

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

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

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

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

OPDIVO (nivolumab) is indicated for the treatment of patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post- transplantation brentuximab vedotin. 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.

Please refer to the end of the Important Safety Information for a brief description of the patient populations studied in the trials.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

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

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

Immune-Mediated Pneumonitis

Immune-mediated pneumonitis, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience with solid tumors, fatal immune-mediated pneumonitis occurred with OPDIVO. In addition, in 069, there were six patients who died without resolution of abnormal respiratory findings. Monitor patients for signs with radiographic imaging and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In 069 and 067, immune-mediated pneumonitis occurred in 6% (25/407) of patients receiving OPDIVO with YERVOY: Fatal (n=1), Grade 3 (n=6), Grade 2 (n=17), and Grade 1 (n=1). In 037, 066, and 067, immune-mediated pneumonitis occurred in 1.8% (14/787) of patients receiving OPDIVO: Grade 3 (n=2) and Grade 2 (n=12). In 057, immune- mediated pneumonitis, including interstitial lung disease, occurred in 3.4% (10/287) of patients: Grade 3 (n=5), Grade 2 (n=2), and Grade 1 (n=3). In 025, pneumonitis, including interstitial lung disease, occurred in 5% (21/406) of patients receiving OPDIVO and 18% (73/397) of patients receiving everolimus. Immune-mediated pneumonitis occurred in 4.4% (18/406) of patients receiving OPDIVO: Grade 4 (n=1), Grade 3 (n=4), Grade 2 (n=12), and Grade 1 (n=1). In 205 and 039, pneumonitis, including interstitial lung disease, occurred in 4.9% (13/263) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 3.4% (9/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 2 (n=8).

Immune-Mediated Colitis

Immune-mediated colitis can occur with OPDIVO treatment. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. As a single agent, withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon restarting OPDIVO. When administered with YERVOY, withhold OPDIVO for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis upon restarting OPDIVO. In 069 and 067, diarrhea or colitis occurred in 56% (228/407) of patients receiving OPDIVO with YERVOY. Immune-mediated colitis occurred in 26% (107/407) of patients: Grade 4 (n=2), Grade 3 (n=60), Grade 2 (n=32), and Grade 1 (n=13). In 037, 066, and 067, diarrhea or colitis occurred in 31% (242/787) of patients receiving OPDIVO. Immune-mediated colitis occurred in 4.1% (32/787) of patients: Grade 3 (n=20), Grade 2 (n=10), and Grade 1 (n=2). In 057, diarrhea or colitis occurred in 17% (50/287) of patients receiving OPDIVO. Immune-mediated colitis occurred in 2.4% (7/287) of patients: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=2). In 025, diarrhea or colitis occurred in 25% (100/406) of patients receiving OPDIVO and 32% (126/397) of patients receiving everolimus. Immune-mediated diarrhea or colitis occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 3 (n=5), Grade 2 (n=7), and Grade 1 (n=1). In 205 and 039, diarrhea or colitis occurred in 30% (80/263) of patients receiving OPDIVO. Immune-mediated diarrhea (Grade 3) occurred in 1.1% (3/263) 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

Immune-mediated hepatitis can occur with OPDIVO treatment. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune- mediated hepatitis. In 069 and 067, immune-mediated hepatitis occurred in 13% (51/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=8), Grade 3 (n=37), Grade 2 (n=5), and Grade 1 (n=1). In 037, 066, and 067, immune-mediated hepatitis occurred in 2.3% (18/787) of patients receiving OPDIVO: Grade 4 (n=3), Grade 3 (n=11), and Grade 2 (n=4). In 057, one patient (0.3%) developed immune-mediated hepatitis. In 025, there was an increased incidence of liver test abnormalities compared to baseline in AST (33% vs 39%), alkaline phosphatase (32% vs 32%), ALT (22% vs 31%), and total bilirubin (9% vs 3.5%) in the OPDIVO and everolimus arms, respectively. Immune-mediated hepatitis requiring systemic immunosuppression occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=5) and Grade 2 (n=1). In 205 and 039, hepatitis occurred in 11% (30/263) of patients receiving OPDIVO. Immune-mediated hepatitis occurred in 3.4% (9/263): Grade 3 (n=7) and Grade 2 (n=2).

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 Dermatitis

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 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

Hypophysitis, adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus can occur with OPDIVO treatment. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency during and after treatment, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer 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. Administer insulin for type 1 diabetes. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In 069 and 067, hypophysitis occurred in 9% (36/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=8), Grade 2 (n=25), and Grade 1 (n=3). In 037, 066, and 067, hypophysitis occurred in 0.9% (7/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=2). In 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In 069 and 067, adrenal insufficiency occurred in 5% (21/407) of patients receiving OPDIVO with YERVOY: Grade 4 (n=1), Grade 3 (n=7), Grade 2 (n=11), and Grade 1 (n=2). In 037, 066, and 067, adrenal insufficiency occurred in 1% (8/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=5), and Grade 1 (n=1). In 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In 025, adrenal insufficiency occurred in 2.0% (8/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=4), and Grade 1 (n=1). In 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In 069 and 067, hypothyroidism or thyroiditis occurred in 22% (89/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=6), Grade 2 (n=47), and Grade 1 (n=36). Hyperthyroidism occurred in 8% (34/407) of patients: Grade 3 (n=4), Grade 2 (n=17), and Grade 1 (n=13). In 037, 066, and 067, hypothyroidism or thyroiditis occurred in 9% (73/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=37), Grade 1 (n=35). Hyperthyroidism occurred in 4.4% (35/787) of patients receiving OPDIVO: Grade 3 (n=1), Grade 2 (n=12), and Grade 1 (n=22). In 057, Grade 1 or 2 hypothyroidism, including thyroiditis, occurred in 7% (20/287) and elevated thyroid stimulating hormone occurred in 17% of patients receiving OPDIVO. Grade 1 or 2 hyperthyroidism occurred in 1.4% (4/287) of patients. In 025, thyroid disease occurred in 11% (43/406) of patients receiving OPDIVO, including one Grade 3 event, and in 3.0% (12/397) of patients receiving everolimus. Hypothyroidism/thyroiditis occurred in 8% (33/406) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=17), and Grade 1 (n=14). Hyperthyroidism occurred in 2.5% (10/406) of patients receiving OPDIVO: Grade 2 (n=5) and Grade 1 (n=5). In 205 and 039, hypothyroidism/thyroiditis occurred in 12% (32/263) of patients receiving OPDIVO: Grade 2 (n=18) and Grade 1: (n=14). Hyperthyroidism occurred in 1.5% (4/263) of patients receiving OPDIVO: Grade 2: (n=3) and Grade 1 (n=1). In 069 and 067, diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/407) of patients: Grade 4 (n=3), Grade 3 (n=1), Grade 2 (n=1), and Grade 1 (n=1). In 037, 066, and 067, diabetes mellitus or diabetic ketoacidosis occurred in 0.8% (6/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=3), and Grade 1 (n=1). In 025, hyperglycemic adverse events occurred in 9% (37/406) patients.

Diabetes mellitus or diabetic ketoacidosis occurred in 1.5% (6/406) of patients receiving OPDIVO: Grade 3 (n=3), Grade 2 (n=2), and Grade 1 (n=1). In 205 and 039, diabetes mellitus occurred in 0.8% (2/263) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1).

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

Immune-Mediated Nephritis and Renal Dysfunction

Immune-mediated nephritis can occur with OPDIVO treatment. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 increased serum creatinine, withhold and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue. In 069 and 067, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients: Grade 4 (n=4), Grade 3 (n=3), and Grade 2 (n=2). In 037, 066, and 067, nephritis and renal dysfunction of any grade occurred in 5% (40/787) of patients receiving OPDIVO. Immune-mediated nephritis and renal dysfunction occurred in 0.8% (6/787) of patients: Grade 3 (n=4) and Grade 2 (n=2). In 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In 025, renal injury occurred in 7% (27/406) of patients receiving OPDIVO and 3.0% (12/397) of patients receiving everolimus. Immune-mediated nephritis and renal dysfunction occurred in 3.2% (13/406) of patients receiving OPDIVO: Grade 5 (n=1), Grade 4 (n=1), Grade 3 (n=5), and Grade 2 (n=6). In 205 and 039, nephritis and renal dysfunction occurred in 4.9% (13/263) of patients treated with OPDIVO. This included one reported case (0.3%) of Grade 3 autoimmune nephritis.

Immune-Mediated Rash

Immune-mediated rash can occur with OPDIVO treatment. Severe rash (including rare cases of fatal toxic epidermal necrolysis) occurred in the clinical program of OPDIVO. Monitor patients for rash. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4. In 069 and 067, immune-mediated rash occurred in 22.6% (92/407) of patients receiving OPDIVO with YERVOY: Grade 3 (n=15), Grade 2 (n=31), and Grade 1 (n=46). In 037, 066, and 067, immune-mediated rash occurred in 9% (72/787) of patients receiving OPDIVO: Grade 3 (n=7), Grade 2 (n=15), and Grade 1 (n=50). In 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In 025, rash occurred in 28% (112/406) of patients receiving OPDIVO and 36% (143/397) of patients receiving everolimus. Immune- mediated rash, defined as a rash treated with systemic or topical corticosteroids, occurred in 7% (30/406) of patients receiving OPDIVO: Grade 3 (n=4), Grade 2 (n=7), and Grade 1 (n=19). In 205 and 039, rash occurred in 22% (58/263) of patients receiving OPDIVO. Immune-mediated rash occurred in 7% (18/263) of patients on OPDIVO: Grade 3 (n=4), Grade 2 (n=3), and Grade 1 (n=11).

Immune-Mediated Encephalitis

Immune-mediated encephalitis can occur with OPDIVO treatment. 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 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In 205 and 039, encephalitis occurred in 0.8% (2/263) of patients after allogeneic HSCT after OPDIVO.

Other Immune-Mediated Adverse Reactions

Based on the severity of adverse reaction, permanently discontinue or withhold treatment, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. In < 1.0% of patients receiving OPDIVO, the following clinically significant, immune-mediated adverse reactions occurred: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, and sarcoidosis. Across clinical trials of OPDIVO as a single agent administered at doses of 3 mg/kg and 10 mg/kg, additional clinically significant, immune- mediated adverse reactions were identified: motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

Severe infusion reactions have been reported in <1.0% of patients in clinical trials of OPDIVO. 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 069 and 067, infusion- related reactions occurred in 2.5% (10/407) of patients receiving OPDIVO with YERVOY: Grade 2 (n=6) and Grade 1 (n=4). In 037, 066, and 067, Grade 2 infusion related reactions occurred in 2.7% (21/787) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=8), and Grade 1 (n=11). In 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In 205 and 039, hypersensitivity/infusion- related reactions occurred in 16% (42/263) of patients receiving OPDIVO: Grade 3 (n=2), Grade 2 (n=24), and Grade 1 (n=16).

Complications of Allogeneic HSCT after OPDIVO

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

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

Embryo-fetal Toxicity

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

Lactation

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

Serious Adverse Reactions

In 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm relative to the OPDIVO arm. The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO. 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 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO. 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 057, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pulmonary embolism, dyspnea, pleural effusion, and respiratory failure. In 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In 205 and 039, among all patients (safety population [n=263]), adverse reactions leading to discontinuation (4.2%) or to dosing delays (23%) occurred. The most frequent serious adverse reactions reported in ≥1% of patients were infusion-related reaction, pneumonia, pleural effusion, pyrexia, rash and pneumonitis. Ten patients died from causes other than disease progression, including 6 who died from complications of allogeneic HSCT. Serious adverse reactions occurred in 21% of patients in the safety population (n=263) and 27% of patients in the subset of patients evaluated for efficacy (efficacy population [n=95]).

Common Adverse Reactions

In 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In 066, the most common adverse reactions (≥20%) reported with OPDIVO vs dacarbazine were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In 057, the most common adverse reactions (≥20%) reported with OPDIVO were fatigue (49%), musculoskeletal pain (36%), cough (30%), decreased appetite (29%), and constipation (23%). In 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO vs everolimus were asthenic conditions (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In 205 and 039, among all patients (safety population [n=263]) and the subset of patients in the efficacy population (n=95), respectively, the most common adverse reactions (reported in at least 20%) were fatigue (32% and 43%), upper respiratory tract infection (28% and 48%), pyrexia (24% and 35%), diarrhea (23% and 30%), and cough (22% and 35%). In the subset of patients in the efficacy population (n=95), the most common adverse reactions also included rash (31%), musculoskeletal pain (27%), pruritus (25%), nausea (23%), arthralgia (21%), and peripheral neuropathy (21%).

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%).

Trials and Patient Populations

CheckMate 069 and 067 – advanced melanoma alone or in combination with YERVOY; CheckMate 037 and 066 – advanced melanoma; CheckMate 057 – non-squamous non-small cell lung cancer (NSCLC); CheckMate 025 – renal cell carcinoma; CheckMate 205/039 – classical Hodgkin lymphoma.

On June 4, 2016 Halozyme Therapeutics, Inc. (NASDAQ: HALO), a biotechnology company developing novel oncology and drug-delivery therapies, repprted results from a final analysis of 135 metastatic pancreatic cancer patients who were treated in Stage One of HALO 109-202, a phase 2 clinical study of its investigational new drug PEGPH20 in combination with ABRAXANE (nab-paclitaxel) and gemcitabine (PAG arm) as compared to ABRAXANE and gemcitabine alone (AG arm) (Press release, Halozyme, JUN 4, 2016, View Source [SID:1234513006]).

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This final analysis of secondary and exploratory endpoints was conducted using the Ventana companion diagnostic to retrospectively identify high levels of hyaluronan (HA). The key results based on a February 2016 data cut-off showed in the HA-high patient population:

Median progression-free survival (PFS) was 9.2 months in the PAG arm versus 6.0 months in the AG arm, hazard ratio (HR) with a 95 percent confidence interval (CI): 0.46 (0.15, 1.40);
Overall response rate (ORR) of 50 percent, including one complete response in the PAG arm versus 33 percent and all partial responses in the AG arm;
Median duration of response (DoR) of 8.1 months in the PAG arm versus 3.7 months in the AG arm;
The exploratory analysis of median overall survival (OS) was similar between the treatment arms — 11.8 months vs. 10.9 months in the PAG vs. AG arms respectively. Factors potentially having an impact on these results include less aggressive disease among patients in the AG arm and a greater than 40 percent discontinuation rate of PEGPH20 treatment at the time of the clinical hold, resulting in all patients receiving AG alone in both arms;
The rate of thromboembolic (TE) events reduced from 43 percent to 9 percent in the PAG arm and from 25 percent to 6 percent in the AG arm with the introduction of prophylaxis with low molecular weight heparin (enoxaparin) from Stage One to Stage Two of the study.
"We are encouraged by the positive trends in this final Stage One dataset, even with PEGPH20 treatment being discontinued for more than 40 percent of patients in the PAG arm due to the prior clinical hold," said Dr. Athena Countouriotis, senior vice president and chief medical officer. "The safety profile continues to show the benefit of prophylactic enoxaparin use and the dataset continues to support our ongoing phase 3 study."

Prior interim analyses were based on patient follow up through December 2014. Results announced today include 14 months of additional follow up through February 2016. Stage One of HALO 202 enrolled a total of 146 patients between May 2013 to July 2014. The study was placed on clinical hold from April to July 2014 during which time PEGPH20 was discontinued while patients in both arms continued to receive treatment with ABRAXANE and gemcitabine alone. Stage Two enrolled a total of 133 patients as of February 2016 and Halozyme remains blinded to the overall efficacy. The company projects to report mature PFS and ORR results from Stage Two late in the fourth quarter.

Dr. Andrea Bullock, attending physician in Gastrointestinal Oncology at Beth Israel Deaconess Medical Center and an Instructor in Medicine at Harvard University said: "As one of the highest enrollers in the HALO 202 study, I am encouraged by the final data from Stage One in the HA-high patients. While the sample size remains small, the median PFS and ORR continue to favor the PEGPH20 combination treatment arm compared to the standard of care AG arm. I look forward to the Stage Two results later this year and to participating in the phase 3 global study very soon."

Halozyme’s ongoing phase 3 study, HALO 301, uses the Ventana companion diagnostic to prospectively identify HA-high patients and mirrors the design of the phase 2 study including the current inclusion/exclusion criteria; 2:1 randomization; and dosing regimens. This double-blinded placebo-controlled study plans to enroll a total of 420 patients at approximately 200 centers within 20 countries. The co-primary endpoints are PFS and OS, with a target hazard ratio of 0.59 for PFS, which is well supported by the final results from Stage One of HALO 202.

Halozyme is the only oncology biotech targeting HA, a glycosaminoglycan – or chain of natural sugars throughout the body – that can accumulate around cancer cells inhibiting other therapies. PEGPH20 is designed to degrade HA to improve the access to tumor cells for chemotherapy, monoclonal antibodies and other immuno-therapy agents.

About HALO 301
HALO 301 is a phase 3 global, randomized, double-blind placebo controlled clinical trial evaluating investigational new drug PEGPH20 as a first-line therapy for potential treatment of patients with metastatic pancreatic cancer. The trial will be conducted at approximately 200 sites with two co-primary endpoints of progression free survival and overall survival in patients receiving investigational new drug PEGPH20 in combination with gemcitabine and ABRAXANE (nab-paclitaxel) compared to gemcitabine and nab-paclitaxel alone. Secondary endpoints also include objective response rate and overall survival. More information may be found at clinicaltrials.gov (search HALO 301 or trial identifier NCT02715804) or www.HALO301.com.

About PEGPH20
PEGPH20 is an investigational PEGylated form of Halozyme’s proprietary recombinant human hyaluronidase under clinical development for the potential systemic treatment of tumors that accumulate hyaluronan.

FDA granted orphan drug designation to PEGPH20 for treatment of pancreatic cancer and fast track for PEGPH20 in combination with gemcitabine and nab-paclitaxel for the treatment of metastatic pancreatic cancer. Additionally, the European Commission, acting on the recommendation from the Committee for Orphan Medicinal Products of the European Medicines Agency, designated investigational drug PEGPH20 an orphan medicinal product for the treatment of pancreatic cancer.

On June 04, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO) reported the presentation of updated data from an ongoing Phase 1b clinical trial of its immunotherapy product candidate CRS-207 in combination with pemetrexed and cisplatin (standard of care chemotherapy) as front-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) (Press release, Aduro BioTech, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175099 [SID:1234512991]). The results from the first of two cohorts were presented today in a poster presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Meeting (ASCO) (Free ASCO Whitepaper) held in Chicago. Of the 36 evaluable patients, disease control was observed in 94% (34/36), including 3% (1/36) with a complete response, 56% (20/36) with partial responses and 36% (13/36) experiencing stable disease following treatment with CRS-207 and chemotherapy. Prior to receiving chemotherapy, 31% (11/36) of patients experienced some tumor shrinkage (range: -1% to -43%) after receiving CRS-207 alone. The estimated median overall survival was 16.4 months (95% CI: 11.0 – 20.6 months). CRS-207 was generally well-tolerated with no treatment-related serious adverse events or cumulative toxicities when administered with chemotherapy.

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"The observed responses with the combination of CRS-207 and standard chemotherapy are unprecedented in mesothelioma," said Dean Fennell, Ph.D., F.R.C.P., professor of Thoracic Medical Oncology at the University of Leicester and president of the International Mesothelioma Interest Group (iMig). "Pleural mesothelioma is a devastating disease, and these data suggest that immunotherapy has the potential to advance treatment options for these patients."

Dirk G. Brockstedt, Ph.D., executive vice president of Research and Development at Aduro added, "These results demonstrate that CRS-207 induces anti-tumor activity in patients with malignant pleural mesothelioma. We are looking forward to the results from the study’s second cohort, which is evaluating the addition of immune modulating doses of cyclophosphamide to the CRS-207 chemotherapy combination. Preclinical data suggest that the simultaneous inhibition of regulatory T-cells through the addition of a checkpoint inhibitor may amplify the tumor response and overall survival seen with CRS-207. As such, the combination of CRS-207 with a checkpoint inhibitor could be the regimen we advance in our mesothelioma program going forward."

The multi-center Phase 1b study enrolled chemotherapy-naïve patients with unresectable MPM and good performance status (ECOG 0 or 1) to receive two doses of CRS-207, followed by up to six cycles of chemotherapy and two additional CRS-207 doses. Clinically stable patients receive CRS-207 maintenance every eight weeks and are followed every eight weeks until disease progression. Objectives of the study are safety, immunogenicity, objective tumor responses and tumor marker kinetics.

A second cohort of 22 patients is receiving an immunomodulatory dose of cyclophosphamide one day prior to each CRS-207 administration in the same treatment regimen utilized in the first cohort. This cohort is fully enrolled and patient follow-up is ongoing.

About Malignant Pleural Mesothelioma
Mesothelioma is a form of cancer that affects the smooth layer of mesothelial cells that surround the chest, lungs, heart and abdomen. Malignant pleural mesothelioma (MPM), which affects the thin balloon-shaped lining of the lungs, is the most common form of this disease and accounts for approximately 3,000 cases a year in the United States. MPM is an aggressive disease with a poor prognosis. Most MPM patients are not candidates for surgical resection. Based on prior studies, expected median time to progression is 5.7 months and median overall survival is 12.1 months with combination pemetrexed and cisplatin chemotherapy.I The tumor-associated antigen mesothelin is overexpressed on the majority of mesothelioma tumors.

About LADD and CRS-207
LADD is Aduro’s proprietary platform of live, attenuated double-deleted Listeria monocytogenes strains that have been engineered to generate a potent innate immune response and to express tumor-associated antigens to induce tumor-specific T cell-mediated immunity.

CRS-207 is one of a family of product candidates based on Aduro’s LADD immunotherapy platform that has been engineered to express the tumor-associated antigen mesothelin, which is over-expressed in many cancers including mesothelioma and pancreatic, non-small cell lung, ovarian, endometrial and gastric cancers.

On June 4, 2016 Novartis reported at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the first results from the Tasigna (nilotinib) Treatment-free Remission (TFR) clinical trial program (Press release, Novartis, JUN 4, 2016, View Source [SID:1234513052]). These studies evaluated the potential to maintain molecular response (MR) after stopping therapy in adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase who achieved a sustained deep level of molecular response with Tasigna – a concept called TFR[3]. Findings from two open label trials, ENESTfreedom and ENESTop, showed that more than 50% of Ph+ CML patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping Tasigna both in the first-line setting and after switching from Glivec (imatinib)*[1],[2]. Discussions with regulatory authorities are underway with potential submissions in 2016.

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Results from the ENESTfreedom study found that more than half (51.6%) of 190 CML patients (confidence interval [CI] 95%: 44.2%-58.9%) who achieved a sustained deep molecular response following at least three years of first-line treatment with Tasigna were able to discontinue therapy and remain in TFR for 48 weeks[1]. ENESTfreedom did not meet its primary objective, the percentage of patients in major molecular response (MMR; BCR-ABL1 International Scale [IS] <= 0.1%) at 48 weeks in the TFR phase, per the original statistical assumption that the lower limit of the 95% CI will be equal to or greater than 50%[1]. The median treatment duration in this trial was 3.6 years which is a short length of tyrosine kinase inhibitor (TKI) exposure prior to attempting TFR. Of the 86 patients who restarted treatment with Tasigna due to loss of MMR, 98.8% were able to regain MMR (n=85) and 88.4% were able to regain MR4.5 (BCR-ABL1 IS <= 0.0032%; n=76) [1]. By weeks 7.9 and 15.0 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MMR and MR4.5, respectively1. One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with Tasigna[1].

"ENESTfreedom is the first trial to show that, after a short treatment duration with nilotinib of 3.6 years, more than 50 percent of patients who stopped therapy were able to remain treatment-free at 48 weeks," said Dr. Andreas Hochhaus, Head of the Department of Hematology and Medical Oncology, Jena University Hospital, Germany, and primary investigator for the ENESTfreedom study. "Findings from the nilotinib TFR trials add to the existing body of research exploring the discontinuation of tyrosine kinase inhibitor treatment in CML and may help to establish safe and appropriate criteria for eligible patients to stop treatment[1],[2],[3]."

ENESTop, the second Novartis TFR trial at ASCO (Free ASCO Whitepaper), evaluated 126 patients who were able to achieve a sustained deep molecular response with Tasigna, but not with prior Glivec therapy[2]. In this trial, nearly 6 out of 10 (57.9%) patients (95% CI: 48.8%-66.7%) who achieved a sustained deep molecular response following at least three years of Tasigna therapy maintained a molecular response 48 weeks after stopping treatment[2]. The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 (BCR-ABL1 IS <= 0.01%) or loss of MMR within 48 weeks of Tasigna discontinuation in the TFR phase[2]. In the study, 51 patients with confirmed loss of MR4.0 or loss of MMR restarted Tasigna[2]. Of these patients, 98.0% (n=50) regained at least MMR, with 94.1% (n=48) and 92.2% (n=47) regaining MR4.0 and MR4.5, respectively[2]. By weeks 12.0 and 13.1 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MR4.0 and MR4.5, respectively[2]. One patient entered the treatment reinitiation phase but did not regain MMR by 20 weeks and discontinued the study. The BCR-ABL1 for this patient was 62.2% at the start of Tasigna retreatment and 9.8% at study exit[2].

"Novartis has been at the forefront of advancements in the treatment and understanding of CML for 20 years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The exploration of TFR in patients treated with Tasigna, which includes Novartis support of eight TFR studies, is the next step in our commitment to advancing care for patients living with this disease."

Results from ENESTfreedom were presented today in an oral session (Abstract #7001, 3:12 p.m. CDT) at ASCO (Free ASCO Whitepaper) in Chicago. Data from ENESTop will be presented in a poster session on June 6 (Abstract #7054, 8:00-11:00 a.m. CDT). Both studies are ongoing, with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna. These are the first presentations of data from the Novartis Tasigna TFR clinical trial program.

An important part of the Tasigna TFR studies is regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5. Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 and MMR and need for treatment initiation[1],[2].

No new major safety findings were observed in these studies in patients treated with Tasigna beyond those in the known safety profile of Tasigna[1],[2]. In ENESTfreedom, 24.7% of patients experienced musculoskeletal pain during the first year of the TFR phase versus 16.3% while still taking Tasigna in the one-year consolidation phase[1]. In ENESTop, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking Tasigna in the consolidation phase[2]. No patients progressed to advance phase/blast crisis in the two studies[1],[2].

Stopping CML treatment is currently not a clinical recommendation and should only be attempted in the context of a clinical study. Discontinuation of treatment in ENESTfreedom and ENESTop was conducted under the conditions of the trials and in patients who met the rigorous predefined criteria of the trials[1],[2].

Novartis commitment to CML
Novartis is supporting eight studies as part of its TFR clinical trial program, which includes ENESTfreedom and ENESTop, as well as two other ongoing company-sponsored TFR studies and four investigator-initiated studies that are now underway in more than 100 global sites across 40 countries. Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition and, today, the company continues its long-standing commitment to the global CML community. Novartis follows the science and builds upon existing evidence to explore what could be the next major contribution in the treatment of Ph+ CML through these TFR trials as well as investigational compounds.

About ENESTfreedom
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults with Ph+ CML after the patients had achieved a response of MR4.5 with Tasigna and a sustained deep molecular response for one year as a first-line treatment.

About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML in the chronic phase after patients had achieved and sustained deep molecular response for one year with Tasigna following Glivec.

About Tasigna (nilotinib)
Tasigna (nilotinib) is approved in more than 122 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec (imatinib), and in more than 120 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. Women taking Tasigna should not breastfeed.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

Please see full Prescribing Information including Boxed WARNING at www.tasigna.com (link is external).

About Glivec (imatinib)
Glivec (imatinib) is approved in more than 110 countries, for the treatment of adult patients in all phases of Ph+ CML, for the treatment of patients with KIT (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST.

Not all indications are available in every country.

Glivec Important Safety Information
Glivec is contraindicated in patients who are hypersensitive to imatinib or any of the excipients.

Glivec can cause fetal harm when administered to a pregnant woman. Women should not become pregnant, and should be advised of the potential risk to the unborn child.

Glivec has been associated with severe edema (swelling) and serious fluid retention. Cytopenias (anemia, neutropenia, thrombocytopenia) are common, generally reversible and usually managed by withholding Glivec or dose reduction. Monitor blood counts regularly. Severe congestive heart failure and left ventricle dysfunction, severe liver problems including cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Caution in patients with cardiac dysfunction and hepatic dysfunction. Monitor carefully. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. Skin reactions, hypothyroidism in patients taking levothyroxine replacement, GI perforation, in some cases fatal, tumor lysis syndrome which can be life threatening have also been reported with Glivec. Correct dehydration and high uric acid levels prior to treatment. Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use. In patients with hypereosinophilic syndrome and heart involvement, cases of heart disease have been associated with the initiation of Glivec therapy. Growth retardation has been reported in children taking Glivec. The long-term effects of extended treatment with Glivec on growth in children are unknown.

The most common side effects include fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash. Glivec should be taken with food and a large glass of water.

Please see full Prescribing Information available at www.glivec.com (link is external).

On June 4, 2016 Array BioPharma (Nasdaq: ARRY), Pierre Fabre and Merck KGaA, Darmstadt, Germany, reported that they have jointly initiated the BEACON CRC (Binimetinib, Encorafenib And Cetuximab Combined to treat BRAF-mutant Colorectal Cancer) trial, a randomized, global Phase 3 clinical trial designed to assess the safety and efficacy of binimetinib (MEK inhibitor), encorafenib (BRAF inhibitor) and Erbitux (monoclonal antibody) in comparison to Erbitux and irinotecan-based therapy in patients with BRAF-mutant colorectal cancer (BRAFm CRC) (Press release, Array BioPharma, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175101 [SID:1234512992]). The primary endpoint is overall survival (OS) and key secondary endpoints include progression-free survival (PFS) and objective response rate (ORR).

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Array BioPharma. (PRNewsFoto/Array BioPharma Inc.)
"We are pleased to announce the initiation of this innovative Phase 3 trial studying the effects of binimetinib, encorafenib and Erbitux for patients with BRAF-mutant colorectal cancer," said Victor Sandor, M.D., Chief Medical Officer of Array. "We believe the encouraging results shown in our Phase 2 study suggest that concurrent inhibition of EGFR and MAPK signaling pathways has the potential to improve outcomes for this high unmet need patient population."

Trial Design
BEACON CRC is a randomized, open-label, global study evaluating the efficacy and safety of binimetinib, encorafenib and Erbitux in patients with BRAFm metastatic CRC who have previously received first-line systemic therapy. Approximately 615 patients are expected to be randomized 1:1:1 to receive triplet therapy (binimetinib, encorafenib and Erbitux), doublet therapy (encorafenib and Erbitux) or the control arm (irinotecan-based therapy and Erbitux).

The primary endpoint of the trial is overall survival (OS) of the triplet therapy compared to the control arm. The secondary endpoints address efficacy of the doublet therapy compared to the control arm, and the triplet therapy compared to the doublet therapy. Other key secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response, safety and tolerability. Health related quality of life data will also be assessed.

"Historical studies suggest that BRAF-mutant colorectal cancer patients who have progressed after first-line systemic treatment have an estimated median overall survival of less than 6 months," said Josep Tabernero, MD, PhD, Head of Medical Oncology and the Institute of Oncology at Vall d’Hebron University Hospital. "The BEACON CRC trial will explore innovative combinations which have the potential to offer new treatment options to these patients who currently have few good choices remaining."

The trial will be conducted at over 250 investigational sites in North America, South America, Europe and the Asia Pacific region. Patient enrollment is expected to be completed in 2018.

About the Collaboration
Array BioPharma is the owner of binimetinib and encorafenib and will act as the global sponsor of the study. Pierre Fabre licensed commercial rights to binimetinib and encorafenib for Europe and other global markets from Array in December 2015. As part of their collaboration, Pierre Fabre has elected to co-fund 40% of the cost of the BEACON CRC trial. Merck KGaA, Darmstadt, Germany, is the owner of Erbitux outside the United States and Canada, and will supply Erbitux to all trial sites outside the United States and Canada as part of the collaboration. If successful, results would support regulatory submissions for all three parties.

About BRAF-mutant Colorectal Cancer
Colorectal cancer is the third most common cancer among men and women in the United States, with more than 134,000 new cases and nearly 50,000 deaths from the disease projected in 2016. In the United States, BRAF mutations occur in 8 to 15 percent of patients with colorectal cancer and represent a poor prognosis for these patients. Historical published PFS and OS results after first-line treatment range from 1.8 to 2.5 months and 4 to 6 months, respectively, and published response rates from various studies for EGFR-based therapy in this population range from 6 percent to 8 percent.

About Binimetinib & Encorafenib
MEK and BRAF are key protein kinases in the MAPK signaling pathway (RAS-RAF-MEK-ERK). Research has shown this pathway regulates several key cellular activities including proliferation, differentiation, survival and angiogenesis. Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, such as melanoma, non-small cell lung, colorectal and thyroid cancers. Binimetinib is a late-stage small molecule MEK inhibitor and encorafenib is a late-stage small molecule BRAF inhibitor, both of which target key enzymes in this pathway.

Binimetinib and encorafenib are being studied in Phase 3 trials in advanced cancer patients, including the COLUMBUS trial studying encorafenib in combination with binimetinib in patients with BRAF-mutant melanoma and the recently initiated BEACON trial that will study encorafenib in combination with binimetinib and cetuximab in patients with BRAF V600E-mutant colorectal cancer.

About Erbitux
Erbitux, marketed by Merck KGaA, Darmstadt, Germany, globally except North America, is a highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.

The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately 5% of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization in over 90 countries world-wide for the treatment of colorectal cancer and for the treatment of squamous cell carcinoma of the head and neck (SCCHN). Merck KGaA, Darmstadt, Germany, licensed the right to market Erbitux outside the US and Canada from ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, in 1998. Merck KGaA, Darmstadt, Germany, has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas.