On October 8, 2016 Results from the pivotal Phase III MONALEESA-2 study show LEE011 (ribociclib) plus letrozole significantly extended progression-free survival (PFS) compared to a standard of care, letrozole, as a first-line treatment in postmenopausal women with hormone receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer (median PFS, 95% CI (19.3 months – not reached) vs. 14.7 months (13.0 – 16.5 months); HR=0.556; p=0.00000329)[1] (Press release, Novartis, OCT 8, 2016, View Source [SID:SID1234515679]). Novartis reported that the data will be featured in the official press briefing at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress and presented as a late-breaker during the Presidential Symposium at 16:30 CEST (Abstract LBA1_PR). The results will also be published simultaneously online in The New England Journal of Medicine.

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The results demonstrate that LEE011 plus letrozole reduced the risk of death or progression by 44% over letrozole alone. The combination significantly improved PFS across all patient subgroups, regardless of disease characteristics or demographics[1]. More than half of women with measurable disease taking LEE011 plus letrozole saw their tumor size shrink by at least 30% (overall response rate (ORR) in patients with measurable disease = 53% vs 37%, p=0.00028)[1].

"The MONALEESA-2 results show the combination of LEE011 plus letrozole represents a significant step forward in the management of HR+ metastatic breast cancer and, if approved, would be a major addition to the treatment options these patients have," said Gabriel N. Hortobagyi, MD, Professor of Medicine, Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center and MONALEESA-2 Principal Investigator. "Women living with metastatic breast cancer will be on treatment for the rest of their lives, so it is critical to find treatment options that effectively delay progression."

Most adverse events in the MONALEESA-2 trial were mild to moderate in severity, identified early through routine monitoring, and generally managed through dose interruption and reduction[1]. The discontinuation rate due to adverse events in the MONALEESA-2 trial was 7.5% for LEE011 plus letrozole and 2.1% for letrozole alone[1].

The most common grade 3/4 (most severe) adverse events were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (60% vs 1%), leukopenia (21% vs 1%), elevated alanine aminotransferase (9% vs 1%), lymphopenia (7% vs 1%) and elevated aspartate aminotransferase (6% vs 1%)[1]. The most common all-grade adverse events (>=35% of patients in either arm, regardless of relationship to study treatment) were as follows for LEE011 plus letrozole compared to letrozole alone: neutropenia (74% vs 5%), nausea (52% vs 29%), infections (50% vs 42%), fatigue (37% vs 30%), and diarrhea (35% vs 22%)[1]. Nausea, infections, fatigue, and diarrhea were mostly grade 1 or 2[1].

"We are excited about these strong results that show LEE011 has the potential to be an effective first-line treatment option that could improve outcomes for women with HR+/HER2- advanced breast cancer," said Bruno Strigini, CEO, Novartis Oncology. "Following the Breakthrough Therapy designation granted by the FDA in August of this year, we look forward to working closely with health authorities to bring a much needed new treatment option to these patients as quickly as possible."

The MONALEESA-2 findings validate the use of a selective CDK4/6 inhibitor in combination with hormonal therapy as initial treatment for HR+/HER2- advanced breast cancer. Due to the significant extension of PFS and clinical benefit seen with LEE011, analysis of the primary endpoint (PFS) in MONALEESA-2 was stopped early in May 2016 as recommended by the Independent Data Monitoring Committee. Follow up to measure overall survival is ongoing.

About LEE011 (ribociclib)
LEE011 (ribociclib) is a selective cyclin dependent kinase inhibitor, a new class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated in a cell, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring cancer cells do not grow uncontrollably.

LEE011 has been studied in non-clinical models and is currently being evaluated in combination with additional endocrine agents as part of the MONALEESA (Mammary ONcology Assessment of LEE011’s Efficacy and SAfety) clinical trial program. LEE011 is not approved for any indication in any market at this time.

LEE011 was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the MONALEESA Clinical Trial Program
Novartis is continuing to assess LEE011 through the robust MONALEESA clinical trial program, which includes MONALEESA-2, MONALEESA-3, and MONALEESA-7. These trials are evaluating LEE011 in multiple endocrine therapy combinations across a broad range of patients, including men and premenopausal women.

MONALEESA-2 is a Phase III randomized, double blind, placebo controlled, multicenter global registration trial to evaluate the safety and efficacy of LEE011 in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer[2].

The trial randomized 668 patients in a 1:1 ratio stratified by the presence of liver and/or lung metastases at 223 clinical trial sites globally[1]. Patients received LEE011 600 mg/daily (three weeks on and one week off), or placebo, in combination with letrozole 2.5 mg/daily.

The primary endpoint of the trial was PFS[2]. Secondary endpoints included: overall survival, overall response rate, clinical benefit rate, health-related quality of life, safety and tolerability[2].

MONALEESA-2 is the only Phase III trial of a CDK4/6 inhibitor in the first-line setting to be stopped early due to superior PFS results, as LEE011 plus letrozole met the primary endpoint at the first efficacy analysis.

The MONALEESA-3 trial is evaluating LEE011 in combination with fulvestrant compared to fulvestrant alone in men and post-menopausal women with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy.

The MONALEESA-7 trial is investigating LEE011 in combination with endocrine therapy and goserelin compared to endocrine therapy and goserelin alone in pre-menopausal women with HR+/HER2- advanced breast cancer who have not previously received endocrine therapy. Both Phase III trials, MONALEESA-3 and MONALEESA-7 are fully enrolled.

About Advanced Breast Cancer
Up to one-third of patients with early-stage breast cancer will subsequently develop metastatic disease[3]. Metastatic breast cancer is the most serious form of the disease and occurs when the cancer has spread to other parts of the body, such as the brain, bones or liver[4]. Advanced breast cancer comprises metastatic breast cancer (stage 4) and locally advanced breast cancer (stage 3) [4]. Survival rates for women living with advanced breast cancer are lower than those for women with earlier stage disease. The 5-year relative survival rate for stage 3 breast cancer is approximately 72%, while metastatic (stage 4) breast cancer has a 5-year relative survival rate of approximately 22%[5].

On October 8, 2016 Leap Therapeutics, Inc. reported the presentation of top-line data from its clinical trial of DKN-01 combination therapy in patients with cholangiocarcinoma at the European Society for Medical Oncology 2016 Congress (ESMO 2016) in Copenhagen, Denmark (Press release, Leap Therapeutics, OCT 8, 2016, View Source [SID:SID1234515668]). Lipika Goyal, MD, of Massachusetts General Hospital, an investigator on the study, presented a poster entitled "Phase I study of DKN-01, an anti-DKK1 monoclonal antibody, in combination with gemcitabine and cisplatin in patients with advanced biliary cancer." DKN-01 is a humanized monoclonal antibody targeting Dickkopf-1 (DKK1), a secreted protein that modulates cell signaling of the Wnt pathways and that promotes an immunosuppressive tumor microenvironment. Published studies have indicated that DKK1 expression levels are elevated in patients with cholangiocarcinoma and associated with worse overall survival.

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The two-part open-label, dose-escalating study enrolled 27 patients with cholangiocarcinoma who were treated with DKN-01 in combination with gemcitabine and cisplatin. In Part A, patients received DKN-01 at either 150 (n=4) or 300 mg (n=3) with 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin on days 1 and 8 of each 21-day cycle. The Part B expansion portion of the study evaluated the 300 mg dose of DKN-01 in combination with gemcitabine and cisplatin in 20 additional patients. The primary objective of this study was to evaluate the safety, pharmacokinetics, and efficacy of DKN-01 in combination with gemcitabine and cisplatin in treatment-naïve and previously-treated patients.

Data from the study showed that DKN-01 in combination with gemcitabine and cisplatin was well tolerated and safe at each dose level. There were no DKN-01 reported related serious adverse events or dose limiting toxicities. At the selected 300 mg DKN-01 dose level, 7 of 21 evaluable patients (33%) experienced a partial response and 20 patients experienced a partial response or stable disease, representing a disease control rate of 95%. The median progression-free survival and overall survival have not yet been reached, as many patients remain on study receiving therapy.

"Patients with advanced cholangiocarcinoma have no approved therapies beyond standard gemcitabine/cisplatin chemotherapy and desire better clinical outcomes. These early but promising results from the ongoing single arm study of DKN-01 in combination with gemcitabine and cisplatin demonstrate the potential of DKN-01 in aggressive cancers, such as cholangiocarcinoma, and provide a strong rationale for further clinical development," commented Andrew Zhu, MD, of Massachusetts General Hospital, an investigator in the study and co-author on the poster.

About Cholangiocarcinoma

Cholangiocarcinoma is a cancer that starts in the bile duct, a thin tube about 4 to 5 inches long that reaches from the liver to the small intestine. The major function of the bile duct is to move a fluid called bile from the liver and gallbladder to the small intestine, where it helps digest the fats in food. The Cholangiocarcinoma Foundation estimates that approximately 6,000 patients will be diagnosed with cholangiocarcinoma in the United States each year, with publications estimating that nearly 200,000 patients are diagnosed worldwide each year. The majority of cholangiocarcinoma cases are diagnosed with advanced stage disease with a 5-year survival rate of less than 10%. The standard treatment option for advanced patients is systemic chemotherapy and supportive care.

About DKN-01

DKN-01 is a humanized IgG4 monoclonal antibody with neutralizing activity against the Dickkopf-1 (DKK1) protein. High levels of DKK1 expression has been associated with poor prognosis in multiple cancers, and DKK1 has a critical role in mediating Wnt signaling pathways and maintaining an immunosuppressive tumor microenvironment. DKN-01 is currently being studied in clinical trials in esophageal cancer and cholangiocarcinoma. DKN-01 additionally demonstrated single agent activity in NSCLC in a Phase 1 dose escalation study.

On October 8, 2016 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported data from the positive, pivotal Phase III OAK study of TECENTRIQ (atezolizumab) at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Annual Meeting in Copenhagen, Denmark (Press release, Genentech, OCT 8, 2016, View Source [SID:SID1234515659]). The study showed TECENTRIQ helped people live a median of 13.8 months, 4.2 months longer than those treated with docetaxel chemotherapy (median overall survival [OS]: 13.8 vs. 9.6 months; HR = 0.73, 95% CI: 0.62 – 0.87). The OAK study evaluated people with non-small cell lung cancer (NSCLC) whose disease had progressed on or after treatment with one or more platinum-based chemotherapy (second-line and third-line). The study enrolled people regardless of their programmed death-ligand 1 (PD-L1) status and included both squamous and non-squamous disease types. Adverse events (AEs) were consistent with those observed in previous TECENTRIQ studies.

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"TECENTRIQ is the first and only anti-PD-L1 cancer immunotherapy to help people with metastatic NSCLC live significantly longer than chemotherapy regardless of their PD-L1 expression level or their disease histology," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Even people whose disease had low or no observed PD-L1 expression still showed a significant benefit from the medicine."

The FDA granted Breakthrough Therapy Designation (BTD) for TECENTRIQ for the treatment of people with PD-L1-positive NSCLC whose disease has progressed during or after platinum-based chemotherapy (and appropriate targeted therapy for those with an EGFR mutation-positive or ALK-positive tumor). Genentech’s Biologics License Application (BLA) for NSCLC was granted Priority Review with an action date of Oct. 19, 2016.

Genentech has eight Phase III lung studies underway evaluating TECENTRIQ alone or in combination with other treatments in people with early and advanced stages of lung cancer.

Full results from the OAK study will be presented in the Presidential Symposium in a presentation by Fabrice Barlesi, Assistance Publique Hôpitaux de Marseille, Marseille, France (abstract #LBA44) on Sunday, Oct. 9, 4:25 p.m. Central European Time (CET). Primary analysis from OAK, a randomized Phase III study comparing atezolizumab with docetaxel in advanced NSCLC


About the OAK study

OAK is a global, multicenter, open-label, randomized, controlled Phase III study that evaluated the efficacy and safety of TECENTRIQ compared with docetaxel in 1,225 people with locally advanced or metastatic NSCLC whose disease had progressed following previous treatment with platinum-containing chemotherapy, with the primary analysis consisting of the first 850 randomized patients. Approximately one-quarter of patients had squamous disease (26 percent). Patients were randomized (1:1) to receive either TECENTRIQ administered intravenously at 1200 mg every 3 weeks or docetaxel administered intravenously at 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. The co-primary endpoints were OS in all randomized patients (intention-to-treat [ITT] population) and in a PD-L1-selected subgroup in the primary analysis population. A summary of the OAK results is included below.

Overall survival results

Study group

ITT

(first 850 randomized patients)

TC1/2/3 or IC1/2/3

( PD-L1 expression on >1% TC or IC)

TC0 or IC0

( PD-L1 expression on <1% TC and IC)

Treatment arm

T = TECENTRIQ

D = Docetaxel

T

D

T

D

T

D

N=

425

425

241

222

180

199

Median OS (months)

13.8

9.6

15.7

10.3

12.6

8.9

HR*

(95% CI)



P** value

HR 0.73,

95% CI: 0.62 – 0.87



P = .0003

HR 0.74,

95% CI: 0.58 – 0.93



P = .0102

HR 0.75,

95% CI: 0.59 – 0.96

P = . 0205

Overall survival by histology

Histology

Non-squamous

Squamous

Treatment arm

T = TECENTRIQ

D = Docetaxel

T

D

T

D

N=

313

315

112

110

Median OS
(months)

15.6

11.2

8.9

7.7

Unstratified HR

(95% CI)

HR 0.73,

95% CI: 0.60 – 0.89

HR 0.73,

95% CI: 0.54 – 0.98

Safety-evaluable population (N=1187)

· Adverse events were consistent with those observed in previous studies of TECENTRIQ.

· Fewer people receiving TECENTRIQ experienced treatment-related Grade 3-4 AEs compared to docetaxel (15% vs. 43%).

· AEs occurring more frequently (5% or more) for TECENTRIQ were musculoskeletal pain (11% for TECENTRIQ vs. 4% for docetaxel) and pruritus (8% for TECENTRIQ vs. 3% for docetaxel).

· There were no deaths related to TECENTRIQ and 1 related to docetaxel.

The demographics and baseline characteristics were balanced between two arms. Patients had a median age of 64 years and 61% were male. 25% had 2 prior lines of therapies, and 18% never smoked. Baseline ECOG performance status was 0 (37%) or 1 (63%). About 17% of people in the docetaxel arm received immunotherapy as the subsequent therapy.

*Unstratified for the TC0 and IC0 subgroup, stratified for others.

**Stratified log-rank p value.

CI: confidence interval; ITT: intention-to-treat; HR: hazard ratio; TC: tumor cells; IC: tumor-infiltrating immune cells; PD-L1: programmed death-ligand 1; OS: overall survival

About Lung Cancer

According to the American Cancer Society, it is estimated that more than 224, 000 Americans will be diagnosed with lung cancer in 2016, and NSCLC accounts for up to 85 percent of all lung cancers. It is estimated that approximately 60 percent of lung cancer diagnoses in the United States are made when the disease is in the most advanced stages.

About TECENTRIQ (atezolizumab)

TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1. TECENTRIQ is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the activation of T cells. TECENTRIQ may also affect normal cells.

TECENTRIQ is the first and only anti-PDL1 cancer immunotherapy approved by the FDA, and is indicated for the treatment of people with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-based chemotherapy, or whose disease has worsened within 12 months of receiving platinum-based chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant). This indication for TECENTRIQ 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.

TECENTRIQ U.S. Indication (pronounced ‘tē-SEN-trik’)

TECENTRIQ is a prescription medicine used to treat:

A type of bladder cancer called urothelial carcinoma. TECENTRIQ may be used when bladder cancer has spread or cannot be removed by surgery (advanced urothelial carcinoma) and,
The patient has tried chemotherapy that contains platinum, and it did not work or is no longer working.
It is not known if TECENTRIQ is safe and effective in children.

Important Safety Information

Important Information About TECENTRIQ

TECENTRIQ can cause the immune system to attack normal organs and tissues in many areas of the body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.

Getting medical treatment right away may help keep these problems from becoming more serious. The healthcare provider may treat the patient with corticosteroid or hormone replacement medicines. The healthcare provider may delay or completely stop treatment with TECENTRIQ if severe side effects occur.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.



TECENTRIQ can cause serious side effects, including:

Lung Problems (pneumonitis) – Signs and symptoms of pneumonitis may include: new or worsening cough, shortness of breath, or chest pain
Liver Problems (hepatitis) – Signs and symptoms of hepatitis may include: yellowing of the skin or the whites of the eyes, severe nausea or vomiting, pain on the right side of the stomach area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, feeling less hungry than usual
Intestinal Problems (colitis) – Signs and symptoms of colitis may include: diarrhea (loose stools) or more bowel movements than usual, blood in the stools or dark, tarry, sticky stools, severe stomach area (abdomen) pain or tenderness
Hormone Gland Problems (especially the pituitary, thyroid, adrenal glands and pancreas) – Signs and symptoms that the hormone glands are not working properly may include: headaches that will not go away or unusual headaches, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness, feeling cold, constipation, voice gets deeper, urinating more often than usual, nausea or vomiting, stomach area (abdomen) pain
Nervous System Problems (neuropathy, meningoencephalitis) – Signs of nervous system problems may include: severe muscle weakness, numbness or tingling in hands and feet, fever, confusion, changes in mood or behavior, extreme sensitivity to light, neck stiffness
Inflammation of the Eyes – Symptoms may include blurry vision, double vision, other vision problems, eye pain or redness
Severe Infections – Symptoms of infection may include: fever, cough, frequent urination, flu-like symptoms, pain when urinating
Severe Infusion Reactions – Signs and symptoms of infusion reactions may include: chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, fever, feeling like passing out, back or neck pain, facial swelling
Before receiving TECENTRIQ, patients should tell their healthcare provider about all of their medical conditions, including if they:

have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus; have had an organ transplant; have lung or breathing problems; have liver problems; have a condition that affects the nervous system, such as myasthenia gravis or Guillain-Barre syndrome; or are being treated for an infection.
are pregnant or plan to become pregnant.
o TECENTRIQ can harm an unborn baby.

o If patients are able to become pregnant, they should use an effective method of birth control during treatment and for at least 5 months after the last dose of TECENTRIQ.

are breastfeeding or plan to breastfeed.
o It is not known if TECENTRIQ passes into the breast milk.

o Do not breastfeed during treatment and for at least 5 months after the last dose of TECENTRIQ.

The most common side effects of TECENTRIQ include:

feeling tired
decreased appetite
nausea
urinary tract infection
fever
constipation
These are not all the possible side effects of TECENTRIQ. Patients should ask their healthcare provider or pharmacist for more information.

Patients should tell their healthcare provider about all of the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements.

Report side effects to the FDA at (800) FDA-1088, or View Source . Report side effects to Genentech at (888) 835-2555.

Please visit View Source for the TECENTRIQ full Prescribing Information for additional Important Safety Information.

On October 8, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported superior efficacy with Yervoy 10 mg/kg versus placebo on all survival endpoints in the Phase 3 trial CA184-029 (EORTC 18071) evaluating stage III melanoma patients who are at high risk of recurrence following complete surgical resection (Press release, Bristol-Myers Squibb, OCT 8, 2016, View Source [SID:SID1234515652]).

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In the study, Yervoy compared with placebo significantly improved overall survival (OS) (HR=0.72 [95.1% CI: 0.58-0.88; p=0.001]), a secondary endpoint, with five-year OS rates at 65.4% in the Yervoy group and 54.4% in the placebo group. Distant metastasis-free survival (DMFS), a secondary endpoint, was also significantly improved versus placebo (HR=0.76 [95.8% CI: 0.64-0.92; p=0.002]) and had five-year DMFS rates of 48.3% and 38.9% in the Yervoy and placebo groups, respectively. In this updated five-year analysis, the recurrence-free survival (primary endpoint) benefit observed previously with Yervoy was maintained (HR=0.76 [95% CI: 0.64-0.89; p<0.001). The safety profile remained consistent with the initial analysis, with no new deaths or safety signals. The most common grade 3/4 immune-related adverse events in the Yervoy group were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%).

These data were featured today, October 8, during the 2016 European Society for Medical Oncology Congress Press Program and simultaneously published in The New England Journal of Medicine. The data will also be presented today during a Presidential Symposium from 5:00-5:15 p.m. CEST (Abstract #LBA2_PR).

"Despite surgical intervention, most patients with stage III melanoma experience disease recurrence and progress to metastatic disease, reinforcing the unmet need for effective systemic therapies in the adjuvant setting," said Alexander M.M. Eggermont, M.D., Ph.D., director general, Cancer Institute Gustave Roussy in Villejuif, France. "The impact of Yervoy on overall survival, distant-metastasis free survival, and recurrence-free survival observed in study -029 offers physicians new insights in the treatment of adjuvant melanoma."

In stage III melanoma, the disease has not yet spread to distant lymph nodes or to other parts of the body and requires surgical resection of the primary tumor as well as the involved lymph nodes. The stage III patient population is heterogeneous with disease-specific survival rates of 78%, 59%, and 40% for stage IIIA, IIIB, and IIIC melanoma, respectively.

"The results from study -029 are important data for the scientific community and underscore our ongoing dedication to improving survival across stages of melanoma," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "Yervoy is the first immune checkpoint inhibitor to demonstrate a statistically significant survival benefit for high-risk patients with fully resected stage III melanoma. With further evaluation of our Immuno-Oncology agents and different dosing options, we remain committed to further research across the full continuum of melanoma treatment."

About CA184-029 (EORTC 18071)

CA184-029 (EORTC 18071), a study initiated in 2008 by the European Organization for Research and Treatment of Cancer (EORTC), is a Phase 3, double-blind, placebo-controlled randomized trial evaluating the efficacy and safety of Yervoy 10 mg/kg in the adjuvant setting for high-risk stage III melanoma. The independently-run trial involved 99 centers across 19 countries from the EORTC’s pan-European network and specialized infrastructure. The trial enrolled eligible patients, which included those ≥18 years of age who underwent complete resection of stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis). In the trial, patients were randomized to receive Yervoy 10 mg/kg (n=475) or placebo (n=476) as an intravenous infusion every 3 weeks for 4 doses, followed by Yervoy 10 mg/kg or placebo every 12 weeks from Week 24 to Week 156 (three years), or until documented disease recurrence or unacceptable toxicity. Yervoy was studied across a broad range of patient characteristics, including patients with stage IIIa with lymph node >1 mm (20%), IIIb (44%) or IIIc with no in-transit metastases (36%); 42% had ulcerated primary lesions, and 58% had macroscopic lymph node involvement.

The primary endpoint was recurrence-free survival (RFS), defined as the time between the date of randomization and the date of first recurrence or death, as assessed by the Independent Review Committee. This analysis was the basis of the Yervoy approval in the United States for adjuvant treatment of melanoma at a dose of 10 mg/kg in October 2015. Secondary endpoints include overall survival (OS), distant metastases-free survival (DMFS), safety and health-related quality of life.

In the study, Yervoy significantly improved RFS, the primary endpoint, versus placebo across all patient groups. Updated five-year results demonstrated RFS remained significantly longer for Yervoy versus placebo, with a median RFS of 27.6 months (95% CI: 19.3-37.2) versus 17.1 months (95% CI: 13.6-21.6), respectively (HR=0.76; 95% CI: 0.64-0.89; p<0.001).

Yervoy also demonstrated a significant improvement in OS, a secondary endpoint of the study, with a 28% reduction in the risk of death versus placebo (HR=0.72 [95% CI: 0.58-0.88; p=0.001]) and an estimated five-year OS rate of 65.4% (95% CI: 60.8-69.6) for Yervoy versus 54.4% (95% CI: 49.7-58.9) for placebo. In addition, Yervoy showed a 24% reduction in the risk of developing distant metastases versus placebo (HR=0.76 [95.8% CI: 0.64-0.92; p=0.002]), with an estimated five-year DMFS rate of 48.3% with Yervoy versus 38.9% with placebo. The median DMFS was 48.3 months with Yervoy versus 27.5 months with placebo.

The safety profile of Yervoy based on this updated analysis was consistent with previously reported findings from CA184-029 (EORTC 18071). In those initial findings, five patient deaths occurred due to drug-related adverse events (AE); no new deaths have since been reported. Among the 471 patients who received Yervoy, 465 (98.7%) experienced an AE of any grade, and 255 patients (54.1%) experienced a grade 3 or 4 AE, whereas among 474 placebo-treated patients, 432 (91.1%) experienced an AE of any grade, and 124 patients (26.2%) experienced a grade 3 or 4 AE. Immune-related AEs were more frequent with Yervoy than with placebo. The most common grade 3/4 immune-related AEs in the Yervoy group were gastrointestinal (16.1%), hepatic (10.8%), and endocrine (7.9%). The median time to onset of on-study grade 2-5 immune-related AEs ranged from 4.0 weeks (skin immune-related adverse events) to 13.1 weeks (neurological immune-related adverse events). Endocrine grade 2-4 immune-related AEs resolved in 51.5% of patients, and median time to resolution was 54.3 weeks. The majority (82-97%) of all other grade 2-4 immune-related AEs resolved, and median time to resolution ranged from 4.0 to 8.0 weeks.

About Advanced 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 the other organs, such as the lymph nodes, lungs, brain or other areas of the body. Melanoma is separated into five staging categories (Stages 0-IV) based on the in-situ feature, thickness, and ulceration of the tumor, whether the cancer has spread to the lymph nodes, and how far the cancer has spread beyond lymph nodes. Stage III melanoma has reached the regional lymph nodes but has not yet spread to distant lymph nodes or to other parts of the body (metastasized) and requires surgical resection of the primary tumor as well as the local lymph nodes.

Bristol-Myers Squibb: At the Forefront of Immuno-Oncology Science & Innovation

At Bristol-Myers Squibb, patients are at the center of everything we do. Our vision for the future of cancer care is focused on researching and developing transformational Immuno-Oncology (I-O) medicines that will raise survival expectations in hard-to-treat cancers and will change the way patients live with cancer.

We are leading the scientific understanding of I-O through our extensive portfolio of investigational and approved agents, including the first combination of two I-O agents in metastatic melanoma, and our differentiated clinical development program, which is studying broad patient populations across more than 20 types of cancers with 11 clinical-stage molecules designed to target different immune system pathways. Our deep expertise and innovative clinical trial designs uniquely position us to advance the science of combinations across multiple tumors and potentially deliver the next wave of I-O combination regimens with a sense of urgency. We also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and inform which patients will benefit most from I-O therapies.

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

About Yervoy

Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

U.S. Indications and Important Safety Information for YERVOY (ipilimumab)

Indications

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

YERVOY (ipilimumab) is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.

Important Safety Information

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

YERVOY (ipilimumab) 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.

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

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.

Recommended Dose Modifications

Endocrine: Withhold YERVOY for systemic endocrinopathy. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for symptomatic reactions lasting 6 weeks or longer or an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day.

Ophthalmologic: Permanently discontinue YERVOY for Grade 2-4 reactions not improving to Grade 1 within 2 weeks while receiving topical therapy or requiring systemic treatment. All Other Organ Systems: Withhold YERVOY for Grade 2 adverse reactions. Resume YERVOY in patients with complete or partial resolution of adverse reactions (Grade 0-1) and who are receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for Grade 2 reactions lasting 6 weeks or longer, an inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day, and Grade 3 or 4 adverse reactions.

Immune-mediated Enterocolitis:

Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent). Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3-5 days or recurring after symptom improvement. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.

Immune-mediated Hepatitis:

Immune-mediated hepatitis, including fatal cases, can occur with YERVOY. Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution. Withhold YERVOY in patients with Grade 2 hepatotoxicity. Permanently discontinue YERVOY in patients with Grade 3-4 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5× the ULN or total bilirubin elevations >3× the ULN; Grade 3-5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4%. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5× but ≤5× the ULN or total bilirubin elevation >1.5× but ≤3× the ULN; Grade 2). In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID). In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3-4 hepatitis showed evidence of toxic or autoimmune hepatitis.

Immune-mediated Dermatitis:

Immune-mediated dermatitis, including fatal cases, can occur with YERVOY. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically; administer topical or systemic corticosteroids if there is no improvement within 1 week. Withhold YERVOY in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., 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 YERVOY-treated patients (2.5%); 1 patient (0.2%) died as a result of toxic epidermal necrolysis and 1 additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate Grade 2 dermatitis.

Immune-mediated Neuropathies:

Immune-mediated neuropathies, including fatal cases, can occur with YERVOY. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities). Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities), such as Guillain-Barre-like syndromes. Institute medical intervention as appropriate for management for severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).

Immune-mediated Endocrinopathies:

Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY. Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated. Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. In patients receiving YERVOY 3 mg/kg in Trial 1, 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 YERVOY-treated patients (1.8%). 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. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY. In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3-4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies occurred in 93 patients (20%). Of the 39 patients with Grade 3-4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with 1 or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3-4 immune-mediated endocrinopathy was 2.2 months (range: 2 days-8 months). Twenty-seven (69.2%) of the 39 patients were hospitalized for immune-mediated endocrinopathies. Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with 1 or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo- or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days-19.3 months).

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions. Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy. In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. In Trial 2, the following clinically significant immune-mediated adverse reactions were seen in <1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis and fatal myocarditis. Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with <1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.

Embyro-fetal Toxicity

Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with a YERVOY-containing regimen and for 3 months after the last dose of YERVOY.

Lactation

It is not known whether YERVOY is secreted in human milk. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.

Common Adverse Reactions:

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritis (31%), rash (29%), and colitis (8%). The most common adverse reactions (≥5%) in patients who received YERVOY at 10 mg/kg were rash (50%), diarrhea (49%), fatigue (46%), pruritus (45%), headache (33%), weight loss (32%), nausea (25%), pyrexia (18%), colitis (16%), decreased appetite (14%), vomiting (13%), and insomnia (10%).

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