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New KEYTRUDA® (pembrolizumab) Data in Advanced Urothelial Cancer Demonstrate Overall Response Rate of 24 Percent in Cisplatin-Ineligible Patients

On October 8, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported positive findings from the phase 2 KEYNOTE-052 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in previously untreated patients with unresectable (inoperable) or metastatic urothelial cancer who are ineligible for cisplatin-based therapy. Data presented at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology, showed an overall response rate (ORR) of 24 percent (n=24/100) (95% CI, 16-34) in the total study population, which included patients with and without PD-L1 expression.

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"We have a growing body of evidence of KEYTRUDA’s activity in a range of cancers and treatment settings including the first-line treatment of patients with advanced urothelial cancer who will not tolerate cisplatin-based therapy," said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 350 clinical studies, including more than 100 trials that combine KEYTRUDA with other cancer treatments. Merck has the largest immuno-oncology clinical development program in bladder cancer with 27 trials involving KEYTRUDA, including four registration-enabling studies currently underway.

"There have been very few advancements in the treatment of bladder cancer in the past several decades, and patients with urothelial cancer who are ineligible for cisplatin-based therapy are in significant need of new approaches to care," said Dr. Dean F. Bajorin, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. "These data are exciting and demonstrate the potential for an anti-PD-1 therapy, such as pembrolizumab, to address the unmet treatment need that exists today for cisplatin-ineligible patients with this type of urothelial cancer."

Findings from KEYNOTE-052 are being presented at the ESMO (Free ESMO Whitepaper) 2016 Congress by Dr. Arjun V. Balar, medical oncologist and assistant professor of medicine at the Perlmutter Cancer Center at NYU Langone Medical Center, on Oct. 8 from 9:30 – 9:45 a.m. CEST (Abstract: # LBA32_PR) and are featured in the official ESMO (Free ESMO Whitepaper) press program.

Additional Findings from KEYNOTE-052

KEYNOTE-052 is an open-label, phase 2 study evaluating KEYTRUDA (pembrolizumab) (200 mg every three weeks) monotherapy as a first-line treatment in an estimated 350 patients with unresectable (inoperable) or metastatic urothelial cancer (a type of bladder cancer) who are ineligible for cisplatin-based therapy. The primary endpoints include ORR in all patients enrolled in the study (total study population) and in patients with PD-L1 positive tumors (expression of one percent or more). Secondary endpoints include duration of response, progression-free survival (PFS), and overall survival (OS). Tumor response was measured according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 as assessed by blinded independent central review.

Findings presented at the ESMO (Free ESMO Whitepaper) 2016 Congress are from the planned interim analysis of the first 100 patients, which was intended to evaluate ORR and determine the PD-L1-high expression cut-point as examined by expression in tumor and immune cells. Forty-five percent of patients (n=45/100) had an ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) score of two, 30 percent (n=30/100) had a PS score of one, and 24 percent (n=24/100) had a PS score of zero.

In the total study population, ORR was 24 percent (n=24/100) (95% CI, 16-34) with a complete response rate of six percent (n=6/100) (95% CI, 2-13). Review of the outcomes based on PD-L1 expression showed that in patients with PD-L1 expression of less than one percent, ORR was 18 percent (n=6/33) (95% CI, 7-36) with a complete response rate of three percent (n=1/33) (95% CI, 0.1-16); in patients with PD-L1 expression greater than or equal to one percent and less than 10 percent, ORR was 15 percent (n=5/33) (95% CI, 5-32) with no complete responses; and, in patients expressing PD-L1 at levels equal to or greater than 10 percent, ORR was 37 percent (n=11/30) (95% CI, 20-56) with a complete response rate of 13 percent (n=4/30) (95% CI, 4-31). Among the 24 percent of patients in the total study population who were responding to treatment, the median duration of response had not been reached (range 1.4+ to 9.8+ months), with 83 percent of patients (n=20/24) having responses of six months or longer.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported KEYTRUDA studies. The treatment-related adverse events observed in this trial (any grade occurring in five percent or more of patients) were fatigue (n=14), pruritus (n=12), pyrexia (n=8), decreased appetite (n=7), diarrhea (n=7), rash (n=7), chills (n=6), hypothyroidism (n=6), and nausea (n=6). Grade 3-4 treatment-related adverse events observed (occurring in 2 or more patients) were fatigue (n=4), muscle spasms (n=2), decreased appetite (n=1), and diarrhea (n=1). Immune-mediated adverse events of Grade 3-4 were nephritis (n=1) and pneumonitis (n=2). Five patients discontinued due to a treatment-related adverse event; there were no treatment-related deaths.

TESARO AND ENGOT ANNOUNCE PRESENTATION OF SUCCESSFUL NIRAPARIB PHASE 3 ENGOT-OV16/NOVA TRIAL RESULTS DURING ESMO 2016

On October 8, 2016 TESARO, Inc. (NASDAQ:TSRO), an oncology-focused biopharmaceutical company, and ENGOT, the European Network for Gynaecological Oncological Trial groups, reported the presentation of the niraparib Phase 3 ENGOT-OV16/NOVA clinical trial results at the ESMO (Free ESMO Whitepaper) 2016 Congress, the congress of the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper), by Dr. Mansoor Raza Mirza, M.D., Medical Director of the Nordic Society of Gynecologic Oncology (NSGO) and principal investigator on the ENGOT-OV16/NOVA trial (Press release, TESARO, OCT 8, 2016, View Source [SID:SID1234515655]). These data were discussed during the ESMO (Free ESMO Whitepaper) press briefing in Copenhagen as part of the congress, and were simultaneously published online in the New England Journal of Medicine.1 The results will also be presented by Dr. Mirza later today during Presidential Symposium 1 (Abstract #LBA3_PR) at ESMO (Free ESMO Whitepaper).

An infographic accompanying this announcement is available at
View Source

ENGOT-OV16/NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who were in response to their most recent platinum-based chemotherapy. This trial was designed to assess progression free survival (PFS) in a broad population of patients who were assigned to one of two cohorts based upon germline BRCA mutation status. The ENGOT-OV16/NOVA trial successfully achieved its primary endpoint in both cohorts, demonstrating that niraparib treatment significantly prolonged PFS compared to control in patients who were germline BRCA mutation (gBRCAmut) carriers and in patients who were not germline BRCA mutation (non-gBRCAmut) carriers. In addition, within the non-gBRCA cohort, niraparib treatment significantly prolonged PFS compared to control for the prospectively defined patient population with tumors deficient in homologous recombination (HRDpos) as determined by the Myriad myChoice HRD test. A high proportion of patients in both treatment groups in both cohorts had received three or more prior lines of chemotherapy.

"These landmark results are extremely encouraging for the ovarian cancer community," said Dr. Mirza. "The effectiveness of platinum-based chemotherapy diminishes over time, and PFS and platinum-free intervals generally become shorter after each round of platinum treatment. In addition, the incidence of infection and risk of neuropathy and hypersensitivity with certain chemotherapy agents rises with subsequent cycles. An oral maintenance treatment that could lengthen the PFS interval between rounds of platinum-based chemotherapy would be very meaningful for patients with ovarian cancer, who often live with a fear of recurrence after ending active treatment."

"We would like to thank the patients, their families and the caregivers that participated in the ENGOT-OV16/NOVA study, as well as our partners at ENGOT for their diligence in executing this trial," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "We believe the results of this Phase 3 study demonstrated a meaningful benefit for women with platinum sensitive, recurrent ovarian cancer."

Primary Endpoint Results:

Statistically Significant PFS Results in the gBRCAmut Cohort
Among patients who were germline BRCA mutation carriers, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.27 (95% CI, 0.173-0.410). The median PFS for patients treated with niraparib was 21.0 months, compared to 5.5 months for control (p<0.0001).

Statistically Significant PFS Results in the non-gBRCAmut Cohort
Niraparib showed statistical significance for patients in the non-germline BRCA mutant cohort. The niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.45 (95% CI, 0.338-0.607). The median PFS for patients treated with niraparib was 9.3 months, compared to 3.9 months for control (p<0.0001).

Statistically Significant PFS Results in non-gBRCAmut Cohort for Patients with HRD-Positive Tumors
For patients who were not germline BRCA mutation carriers but whose tumors were determined to be HRD positive using the Myriad myChoice HRD test, the niraparib arm successfully achieved statistical significance over the control arm for the primary endpoint of PFS, with a hazard ratio of 0.38 (95% CI, 0.243-0.586). The median PFS for patients with HRD-positive tumors who were treated with niraparib was 12.9 months, compared to 3.8 months for control (p<0.0001).

Secondary Endpoint Results:

Secondary endpoint analyses, including chemotherapy-free interval, time to first subsequent treatment, and PFS 2 were all statistically significant and favored niraparib over control for patients in both the gBRCAmut and non-gBRCAmut cohorts. Patient-reported outcome results from validated survey tools indicated that niraparib-treated patients reported no difference from control in measures associated with quality of life. Data for overall survival are immature (HR 0.73; 95% CI, 0.480 to 1.125; p=0.1545), as fewer than 20% of events had occurred at the time of analysis.

Safety Results:

The most common (≥10%) treatment-emergent grade 3/4 adverse events in the niraparib arm were thrombocytopenia (33.8%), anemia (25.3%), and neutropenia (19.6%) with treatment discontinuation for these events of 3.3%, 1.4% and 1.9%, respectively. Thrombocytopenia was not associated with grade 3/4 bleeding events. The majority of these hematological laboratory abnormalities occurred within the first three cycles; following dose modifications the incidence of these lab abnormalities decreased and thrombocytopenia and neutropenia were infrequent beyond cycle 3. The rates of MDS/AML in the niraparib (1.4%) and control (1.1%) arms were similar. There were no deaths among patients during study treatment.

"Despite diagnostic and treatment advances, ovarian cancer remains the deadliest gynecologic cancer, and the need for new therapeutic options that prolong response remains critical," said David Barley, CEO of the National Ovarian Cancer Coalition. "The results of the NOVA trial are encouraging, and could offer patients and their families a treatment option during the stressful period that follows platinum-based chemotherapy where the majority of patients receive no treatment."

Investor Briefing and Webcast
TESARO will webcast an investor and analyst briefing in Copenhagen on Saturday, October 8 at 7:00 PM local time in Copenhagen in conjunction with the ESMO (Free ESMO Whitepaper) annual meeting. At this briefing, TESARO management will review the niraparib development program and data presented at ESMO (Free ESMO Whitepaper) and answer questions from investors and analysts. This event will be webcast live and archived for 30 days, and may be accessed from the TESARO Investor Events and Presentations webpage at www.tesarobio.com. A reception will begin at 6:30 PM local time for those institutional investors and analysts attending this event in Copenhagen; please RSVP to [email protected] in order to attend.

About the Phase 3 ENGOT-OV16/NOVA Clinical Trial of Niraparib
NOVA is a double-blind, placebo-controlled, international Phase 3 trial of niraparib that enrolled 553 patients with recurrent ovarian cancer who were in a response to their most recent platinum-based chemotherapy. Patients were enrolled into one of two independent cohorts based on germline BRCA mutation status. One cohort enrolled patients who were germline BRCA mutation carriers (gBRCAmut), and the second cohort enrolled patients who were not germline BRCA mutation carriers (non-gBRCAmut) and included patients with HRD-positive and HRD-negative tumors. Within each cohort, patients were randomized 2:1 to receive niraparib or placebo and were treated continuously with placebo or 300 milligrams of niraparib, dosed as three 100 milligram tablets once per day, until progression. The primary endpoint of this study was progression-free survival (PFS). Secondary endpoints include patient-reported outcomes, chemotherapy-free interval length, PFS 2, overall survival, and other measures of safety and tolerability. More information about this trial is available at View Source

About Niraparib
Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in four ongoing pivotal trials. TESARO is building a robust niraparib franchise by assessing activity across multiple tumor types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development program for niraparib includes a Phase 3 trial in patients with platinum-sensitive, recurrent ovarian cancer (the NOVA trial); a Phase 3 trial in patients with first-line ovarian cancer (the PRIMA trial); a registrational Phase 2 treatment trial in patients with ovarian cancer (the QUADRA trial); and a Phase 3 trial for the treatment of patients with BRCA-mutant breast cancer (the BRAVO trial). Several combination studies are also underway, including trials of niraparib plus pembrolizumab and bevacizumab. Janssen Biotech has licensed rights to develop and commercialize niraparib specifically for patients with prostate cancer worldwide, except in Japan.

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to niraparib for the treatment of patients with recurrent platinum-sensitive ovarian, fallopian tube, or primary peritoneal cancer. TESARO has initiated a rolling submission of a New Drug Application (NDA) for niraparib to the FDA, and intends to complete this submission during the fourth quarter. The Marketing Authorization Application (MAA) for niraparib is planned for submission to the European Medicines Agency (EMA) in the fourth quarter.

Niraparib is an investigational agent and, as such, has not been approved by the U.S. FDA, the European Medicines Agency (EMA), or any other regulatory agencies.

About Ovarian Cancer
Approximately 22,000 women are diagnosed each year with ovarian cancer in the United States, and more than 65,000 women are diagnosed annually in Europe. Ovarian cancer is the fifth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. If approved, niraparib may address the difficult "watchful waiting" periods experienced by patients with recurrent ovarian cancer in between cycles of platinum-based chemotherapy.

Results From CheckMate-275 Validate Further Study of Opdivo (nivolumab) in Patients With Advanced Form of Bladder Cancer

On October 8, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported results from the CheckMate -275 trial, in which Opdivo had a confirmed objective response rate (ORR), the primary endpoint, of 19.6% (95% CI: 15.0 – 24.9) in platinum-refractory patients with metastatic urothelial carcinoma (Press release, Bristol-Myers Squibb, OCT 8, 2016, View Source [SID:SID1234515653]). Responses were observed in both PD-L1 expressors and non-expressors. The confirmed ORR in patients expressing PD-L1 ≥1% was 23.8% (95% CI: 16·5 – 32·3) and 16.1% (95% CI: 10.5 – 23.1) in patients expressing PD-L1 <1%. In patients expressing PD-L1 ≥5%, the confirmed ORR was 28.4% (95% CI: 18.9 – 39.5) and 15.8% (95% CI: 10.8 – 21.8) in patients expressing PD-L1 <5%. The median duration of response was not reached in the overall population with a minimum follow-up of six months, and responses were ongoing in 77% of patients. The safety profile of Opdivo in this study was consistent with the safety profile of Opdivo in other tumor types.

These data will be presented today, October 8, at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress during an oral proffered paper session from 9:15 – 9:30 a.m. CEST (Abstract #LBA31_PR).

"The prognosis for patients with metastatic urothelial carcinoma progressing despite platinum-based chemotherapy is poor, and treatment options have historically been quite limited," said Matthew Galsky, M.D., professor of medicine and director of Genitourinary Medical Oncology, The Tisch Cancer Institute at Icahn School of Medicine at Mount Sinai. "In the CheckMate -275 study, we observe that with Opdivo, patients who responded experienced rapid and durable responses, including patients with PD-L1 expressing and non-expressing tumors. These results are encouraging and provide new information to the scientific community on the potential of Opdivo as a treatment option for this type of advanced bladder cancer."

Urothelial carcinoma, a common type of bladder cancer, accounts for approximately 90% of cases. The majority of bladder cancers are diagnosed at an early stage, but approximately 78% of patients will experience a recurrence within five years.

Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb, commented, "There is a significant unmet need for new treatment approaches for progressive metastatic urothelial carcinoma. The results from CheckMate -275 show treatment with Opdivo resulted in durable and clinically meaningful objective response of 19.6% in all-treated patients. Based on these findings, we believe Opdivo has the potential to become an important new treatment option for patients with platinum-refractory advanced bladder cancer."

About CheckMate -275

CheckMate -275 is a Phase 2, single-arm clinical trial evaluating the safety and efficacy of Opdivo in 270 patients with metastatic or unresectable urothelial carcinoma who have progressed or recurred following treatment with a platinum-based agent in the metastatic setting or within one year after neoadjuvant/adjuvant platinum therapy. The trial enrolled patients regardless of PD-L1 expression. The primary endpoint was confirmed objective response rate (ORR) based on assessments by the blinded independent review committee in all treated patients and in patients with tumor PD-L1 expression ≥1% and ≥5%. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and quality of life. Patients received Opdivo 3 mg/kg administered intravenously every two weeks and were assessed for response beginning eight weeks from randomization and continuing every eight weeks for 48 weeks, then every 12 weeks until progression or discontinuation.

The confirmed ORR was 19.6% (95% CI: 15.0 – 24.9) for all treated patients. About half of the overall patient population (46%) had a PD-L1 expression of ≥1%, and approximately 30% had a PD-L1 expression of ≥5%. Higher responses observed among patients with PD-L1 expression ≥1% (23.8%; 95% CI: 16.5 – 32.3) and ≥5% (28.4%; 95% CI: 18.9 – 39.5). Responses to Opdivo were also observed in patients with PD-L1 <1% (16.1%; 95% CI: 10.5 – 23.1) and <5% (15.8%; 95% CI: 10.8 – 21.8).

Among the 52 patients who responded to treatment, the median time to a response was 1.9 months (1.6 – 5.9 months). Median duration of response was not reached, with an ongoing response among 77% of the responders at the time of the analysis.

The median PFS was 2.0 months in all treated patients (95% CI: 1.87 – 2.63), 1.87 months for patients with PD-L1 <1% (95% CI: 1.77 – 2.04), and 3.55 months in patients with PD-L1 ≥1% (95% CI: 1.94 – 3.71). The median OS was 8.74 months in all treated patients (95% CI: 6.05 – N.A.), 5.95 months in patients with PD-L1 <1% (95% CI: 4.30 – 8.08), and 11.3 months in patients with PD-L1 expression ≥1% (95% CI: 8.74 – N.A.). In addition, quality of life is maintained for patients remaining on study over 41 weeks on two quality of life measures – the EORTC (European Organisation for Research and Treatment of Cancer) QLQ-C30 and the EQ-5D Visual Analog Scale.

The safety profile of Opdivo in CheckMate -275 was consistent with the safety profile of Opdivo in other tumor types. Among the 270 patients who received Opdivo, 64.4% experienced a treatment-related adverse event (AE) of any grade, with grade 3 or 4 in 17.8%. The most frequently reported treatment-related AEs of any grade included fatigue (16.7%), pruritis (9.3%), diarrhea (8.9%), decreased appetite (8.1%), hypothyroidism (7.8%), nausea (7.0%), asthenia (5.9%), rash (5.9%) and pyrexia (5.6%). The most frequent treatment-related grade 3-4 AEs were fatigue (1.9%), diarrhea (1.9%), asthenia (1.5%) and rash (1.1%). Overall, 4.8% of patients discontinued therapy due to treatment-related AEs of any grade, and 3.0% discontinued therapy due to grade 3-4 treatment-related AEs.

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 Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol-Myers Squibb’s scientific expertise in the field of Immuno-Oncology and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has enrolled more than 25,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 57 countries, including the United States, the European Union and Japan. In October 2015, the company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 47 countries, including the United States and the European Union.

U.S. FDA-APPROVED INDICATIONS FOR OPDIVO

OPDIVO (nivolumab) as a single agent is indicated for the treatment of patients with 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 057, one patient (0.3%) developed immune-mediated hepatitis. In CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 025, hypophysitis occurred in 0.5% (2/406) of patients receiving OPDIVO: Grade 3 (n=1) and Grade 1 (n=1). In CheckMate 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 CheckMate 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 CheckMate 057, 0.3% (1/287) of OPDIVO-treated patients developed adrenal insufficiency. In CheckMate 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 CheckMate 205 and 039, adrenal insufficiency (Grade 2) occurred in 0.4% (1/263) of patients receiving OPDIVO. In CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 057, Grade 2 immune-mediated renal dysfunction occurred in 0.3% (1/287) of patients receiving OPDIVO. In CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 057, immune-mediated rash occurred in 6% (17/287) of patients receiving OPDIVO including four Grade 3 cases. In CheckMate 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 CheckMate 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 CheckMate 067, encephalitis was identified in one patient (0.2%) receiving OPDIVO with YERVOY. In CheckMate 057, fatal limbic encephalitis occurred in one patient (0.3%) receiving OPDIVO. In CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 057, Grade 2 infusion reactions requiring corticosteroids occurred in 1.0% (3/287) of patients receiving OPDIVO. In CheckMate 025, hypersensitivity/infusion-related reactions occurred in 6% (25/406) of patients receiving OPDIVO and 1.0% (4/397) of patients receiving everolimus. In CheckMate 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 CheckMate 205 and 039, who underwent allogeneic HSCT after discontinuing OPDIVO (15 with reduced-intensity conditioning, 2 with myeloablative conditioning). Thirty-five percent (6/17) of patients died from complications of allogeneic HSCT after OPDIVO. Five deaths occurred in the setting of severe or refractory GVHD. Grade 3 or higher acute GVHD was reported in 29% (5/17) of patients. Hyperacute GVHD was reported in 20% (n=2) of patients. A steroid-requiring febrile syndrome, without an identified infectious cause, was reported in 35% (n=6) of patients. Two cases of encephalitis were reported: Grade 3 (n=1) lymphocytic encephalitis without an identified infectious cause, and Grade 3 (n=1) suspected viral encephalitis. Hepatic veno-occlusive disease (VOD) occurred in one patient, who received reduced-intensity conditioned allogeneic 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 CheckMate 067, serious adverse reactions (73% and 37%), adverse reactions leading to permanent discontinuation (43% and 14%) or to dosing delays (55% and 28%), and Grade 3 or 4 adverse reactions (72% and 44%) all occurred more frequently in the OPDIVO plus YERVOY arm 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 037, the most common adverse reaction (≥20%) reported with OPDIVO was rash (21%). In CheckMate 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 CheckMate 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 CheckMate 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 CheckMate 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%).

CheckMate 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

Merck Announces Longer-Term Follow-Up of Overall Survival Data for KEYTRUDA® (pembrolizumab) in Patients with Advanced Melanoma from KEYNOTE-002 Presented at ESMO 2016 Congress

On October 8, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported findings from the final overall survival (OS) analysis from the KEYNOTE-002 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, compared to investigator-choice chemotherapy with a crossover to KEYTRUDA design, in patients with ipilimumab-refractory advanced melanoma (Press release, Merck & Co, OCT 8, 2016, View Source [SID:SID1234515684]). Results presented at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology, in Copenhagen include follow-up of up to 35 months for the study’s co-primary endpoints of OS and progression-free survival (PFS). Data showed prolonged OS with KEYTRUDA (2 mg/kg and 10 mg/kg), with a median OS of 13.4 months and 14.7 months and a two-year OS rate of 35.9 percent and 38.2 percent, respectively, compared to a median OS of 11.0 months and a two-year OS rate of 29.7 percent with chemotherapy.

"Now, with longer follow-up, we continue to show clinically meaningful outcomes with KEYTRUDA as monotherapy in these ipilimumab-refractory patients," said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories. "These results provide further evidence supporting the use of KEYTRUDA as a standard of care for patients with advanced melanoma."

Today, KEYTRUDA is approved for the treatment of advanced melanoma in more than 50 countries, including the United States and throughout Europe. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 350 clinical studies, including more than 100 trials that combine KEYTRUDA (pembrolizumab) with other cancer treatments.

The final analysis from KEYNOTE-002 is being presented at the ESMO (Free ESMO Whitepaper) 2016 Congress by Dr. Omid Hamid, director of the Melanoma Center at The Angeles Clinic and Research Institute, on Oct. 8 from 2:45 – 4:15 p.m. CEST (Abstract: #1107O).

Additional Findings from KEYNOTE-002

KEYNOTE-002 is a multicenter, randomized, controlled phase 2 study of KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to investigator’s choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide) in patients with ipilimumab-refractory advanced melanoma (n=540). The co-primary endpoints were PFS and OS; secondary endpoints included overall response rate (ORR), duration of response, and safety. Tumor response was assessed at week 12, then every six weeks through week 48, followed by every 12 weeks thereafter as assessed by independent central review using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Per the study protocol, after three months, patients who experienced disease progression on the chemotherapy arm were eligible to cross over to receive KEYTRUDA. In total, 55 percent (n=98/179) of patients in the chemotherapy arm crossed over to receive KEYTRUDA monotherapy.

In the final analysis, which included the 98 patients who crossed over from the chemotherapy arm to receive KEYTRUDA, the median OS was 13.4 months with KEYTRUDA 2 mg/kg (95% CI, 11.0-16.4 months) and 14.7 months with KEYTRUDA 10 mg/kg (95% CI 11.3-19.5 months), compared to 11.0 months with chemotherapy (95% CI, 8.9-13.8 months) (hazard ratio: 0.86 [95% CI, 0.67-1.10; p=0.1173] and hazard ratio: 0.74 [95% CI, 0.57-0.96; p=0.0106], respectively); the two-year (24-month) OS rate was 35.9 percent and 38.2 percent with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), compared to 29.7 percent with chemotherapy.

While improvements in OS between KEYTRUDA (2 mg/kg or 10 mg/kg) and chemotherapy did not meet the protocol-specified significance threshold, longer follow-up continued to show a clinically meaningful improvement in PFS, the study’s co-primary endpoint, with PFS of up to 31 months in patients treated with KEYTRUDA. Median PFS was approximately three months for each of the patient groups (95% CI of 2.8-3.8 months with KEYTRUDA 2 mg/kg; 95% CI of 2.8-5.2 months with KEYTRUDA 10 mg/kg; and 95% CI of 2.6-2.8 months with chemotherapy) (hazard ratio: 0.58 [95% CI, 0.46-0.73; p<0.0001] and hazard ratio: 0.47 [95% CI, 0.37-0.60; p<0.0001], respectively). The two-year PFS rate was 16.0 percent and 21.9 percent with KEYTRUDA (pembrolizumab) (2 mg/kg and 10 mg/kg, respectively), compared to less than one percent (0.6 percent) of patients treated with chemotherapy.

ORR was 22.2 percent and 27.6 percent with KEYTRUDA (2 mg/kg and 10 mg/kg, respectively), compared to 4.5 percent with chemotherapy. At the time of analysis, 50 percent and 58 percent of patients who responded to KEYTRUDA (2 mg/kg and 10 mg/kg, respectively) were alive with no subsequent progression or anti-tumor therapy, compared to 12 percent of patients who responded to chemotherapy.

With longer follow-up, adverse events have remained consistent with previously reported safety data. Treatment-related immune-mediated adverse events of Grade 3-4 were pneumonitis, colitis (10 mg/kg only), adrenal insufficiency, severe skin toxicity, hypophysitis, hepatitis, nephritis (2 mg/kg only), pancreatitis (10 mg/kg only), and myasthenia (10 mg/kg only).

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2016, an estimated 76,380 people are expected to be diagnosed and an estimated 10,130 people are expected to die of the disease in the U.S. alone. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 percent.

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks.

Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test with disease progression on or after platinum-containing chemotherapy, at a dose of 2 mg/kg every three weeks. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy at a fixed dose of 200 mg every three weeks. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA (pembrolizumab) in Melanoma

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2.0%) of 1567 patients, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 31 (2%) of 1567 patients, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA (pembrolizumab) for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in 16 (1%) of 1567 patients, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 13 (0.8%) of 1567 patients, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1567 patients, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1567 patients, including Grade 3 (0.1%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in 7 (0.4%) of 1567 patients, including Grade 2 (0.2%), 3 (0.2%), and 4 (0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Other clinically important immune-mediated adverse reactions can occur. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA (pembrolizumab) when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 1567 patients: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2117 patients. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

In KEYNOTE-002, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculopapular rash (1%). The most common adverse reactions with KEYTRUDA vs chemotherapy were fatigue (43% with KEYTRUDA), pruritus (28% vs 8%), rash (24% vs 8%), constipation (22% vs 20%), nausea (22% with KEYTRUDA), diarrhea (20% vs 20%), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA

It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

Novartis breakthrough therapy LEE011 plus letrozole demonstrates superior progression-free survival as first-line treatment for HR+/HER2- advanced breast cancer compared to a standard of care

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.

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].