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KEYTRUDA® (pembrolizumab) Showed Continued Overall Survival Benefit Compared to Chemotherapy with Longer Follow-Up in Patients with Previously Treated Metastatic Non-Small Cell Lung Cancer in Data to Be Presented at ESMO 2016 Congress

On October 9, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, demonstrated superiority in overall survival (OS) at 18 months compared to standard of care chemotherapy (docetaxel) in patients with metastatic non-small cell lung cancer (NSCLC) previously treated with platinum-containing chemotherapy whose tumors expressed PD-L1 (tumor proportion score [TPS] of one percent or more), as well as patients with high levels of PD-L1 expression (TPS of 50 percent or more) (Press release, Merck & Co, OCT 9, 2016, http://www.mercknewsroom.com/news-release/oncology-newsroom/keytruda-pembrolizumab-showed-continued-overall-survival-benefit-comp [SID:SID1234515682]). These data, from the phase 2/3 KEYNOTE-010 trial, will be presented at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology, in Copenhagen (Abstract #LBA48).

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"These findings – which show superior survival with longer follow-up across patients with PD-L1 expression (tumor proportion score of one percent or more), as well as improved quality of life – point to KEYTRUDA as a durable treatment option for many previously treated patients with advanced non-small cell lung cancer," said Roy S. Herbst, M.D., Ph.D., professor of medicine and chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital at Yale New Haven. "These data also reinforce the value of using PD-L1 as a biomarker to identify patients who are likely to benefit from KEYTRUDA."

In additional data at the ESMO (Free ESMO Whitepaper) 2016 Congress from KEYNOTE-010, an analysis of patient-reported health-related quality of life outcomes showed more patients treated with KEYTRUDA (pembrolizumab) reported positive outcomes compared to patients treated with chemotherapy (Abstract #1219P).

Separately at the ESMO (Free ESMO Whitepaper) 2016 Congress, researchers presented an analysis of PD-L1 prevalence across three separate studies, including KEYNOTE-010. Overall, 66 percent of patients with metastatic NSCLC expressed any level of PD-L1, and 28 percent expressed high levels of PD-L1 (Abstract #1060P).

"Our research in immuno-oncology continues to show tremendous promise, with our goal being to extend the lives of significant numbers of patients with non-small cell lung cancer," said Roger Dansey, M.D., senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "In this longer-term analysis of KEYNOTE-010, among patients who responded to treatment, four times as many patients receiving KEYTRUDA were still alive without disease progression compared to docetaxel. It is gratifying to see these results continue with additional follow-up."

Merck has a robust clinical development program for KEYTRUDA in lung cancer, with multiple registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 350 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

Efficacy and Safety Findings from KEYNOTE-010 (Abstract #LBA48)

KEYNOTE-010 is a global, open-label, randomized, pivotal phase 2/3 study evaluating KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) compared to standard of care chemotherapy (docetaxel, 75 mg/m2 every three weeks) in patients with previously treated metastatic NSCLC. The primary endpoints were OS and progression-free survival (PFS) and were assessed based on patients whose tumors expressed PD-L1 (TPS of one percent or more) and high levels of PD-L1 (TPS of 50 percent or more). Secondary endpoints included overall response rate (ORR) and duration of response. KEYNOTE-010 is the first study of its kind to evaluate the potential of an immunotherapy compared to chemotherapy based on prospective measurement of PD-L1 expression in patients with metastatic NSCLC. As previously announced, the study met its primary objective, showing that KEYTRUDA significantly improved OS compared to chemotherapy in patients with PD-L1 expression (TPS of one percent or more). Findings were similar in patients who received the FDA-approved dose of KEYTRUDA (2 mg/kg every three weeks) and an investigational dose of KEYTRUDA (10 mg/kg every three weeks). These data also served as the basis for the KEYTRUDA (pembrolizumab) application approval by the European Medicines Agency (EMA) in July of this year and are currently under review by the U.S. Food and Drug Administration (FDA) for the second-line or greater NSCLC treatment setting.

At the ESMO (Free ESMO Whitepaper) 2016 Congress, data from this study of 1,034 patients included six months of additional follow-up, with a median follow-up of 19.2 months (range, 11.7-29.7), and showed superior outcomes of OS, PFS, and ORR with KEYTRUDA compared to docetaxel in patients with PD-L1 expression (TPS of one percent or more) as well as high levels of PD-L1 expression (TPS of 50 percent or more) – with consistency of outcomes across KEYTRUDA doses.

In patients with PD-L1 expression (TPS of one percent or more), OS at 18 months was 37 percent (HR, 0.72 [95% CI, 0.60-0.87]; p=0.0003) with KEYTRUDA 2 mg/kg, 43 percent (HR, 0.60 [95% CI, 0.50-0.73]; p<0.00001) with KEYTRUDA 10 mg/kg, and 24 percent with docetaxel. Among all patients, median OS was 10.5 months with KEYTRUDA 2 mg/kg, 13.6 months with KEYTRUDA 10 mg/kg, and 8.6 months with docetaxel. ORR was 19 percent (95% CI, 15-23, p=0.00025) with KEYTRUDA 2 mg/kg, 20 percent (95% CI, 16-25, p=0.00004) with KEYTRUDA 10 mg/kg and 10 percent (95% CI, 7-13) with docetaxel. Responses to KEYTRUDA continued to be durable; among patients with any level of PD-L1 expression who responded to treatment, 60 percent on each of the KEYTRUDA treatment arms were alive, progression-free, and had not received additional therapy for their disease, compared to 15 percent in the docetaxel treatment arm.

In patients with high levels of PD-L1 expression (TPS of 50 percent or more), OS at 18 months was 46 percent (HR, 0.54 [95% CI, 0.39-0.73]; p=0.00004) with KEYTRUDA 2 mg/kg, 52 percent with KEYTRUDA 10 mg/kg (HR, 0.48 [95% CI, 0.35-0.66]; p<0.00001), and 24 percent with docetaxel. In this group, median OS was 15.8 months with KEYTRUDA 2 mg/kg, 18.8 months with KEYTRUDA 10 mg/kg, and 8.2 months with docetaxel. ORR was 29 percent (95% CI, 22-38, p<0.00001) with KEYTRUDA 2 mg/kg, 32 percent (95% CI, 24-40, p<0.00001) with KEYTRUDA 10 mg/kg, and nine percent (95% CI, 5-14) with docetaxel. Responses to KEYTRUDA continued to be durable; among patients with high levels of PD-L1 expression who responded to treatment, 68 and 63 percent on the KEYTRUDA 2 mg/kg and 10 mg/kg treatment arms, respectively, were alive, progression-free, and had not received additional therapy for their disease, compared to 15 percent in the docetaxel treatment arm.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies of KEYTRUDA. Treatment-related adverse events remained lower with KEYTRUDA compared to docetaxel. Among the total study population, 13, 17, and 36 percent of patients experienced Grades 3-5 treatment-related adverse events with KEYTRUDA (pembrolizumab) 2 mg/kg, KEYTRUDA 10 mg/kg, and docetaxel, respectively. Compared with the previous analysis, two additional patients in the KEYTRUDA 2 mg/kg arm and five patients in the KEYTRUDA 10 mg/kg arm experienced immune-mediated adverse events, none of which led to death. Grade 3-5 immune-mediated adverse events that occurred in two or more patients included pneumonitis (n=14), severe skin toxicities (n=8), and colitis (n=4). Additional immune-mediated adverse events observed in at least two patients in the KEYTRUDA arms of the study included hypothyroidism, hyperthyroidism, pancreatitis, adrenal insufficiency, myositis, thyroiditis, hepatitis, hypophysitis, and type 1 diabetes mellitus. In this study to date, there have been 10 treatment-related adverse events that led to death, two with KEYTRUDA 2 mg/kg, three with KEYTRUDA 10 mg/kg, and five with docetaxel.

These data will be presented in a poster discussion session on Oct. 9 from 2:45 – 4:15 p.m. CEST (Abstract #LBA48) (Location: Oslo).

Patient-Reported Outcomes Findings from KEYNOTE-010 (Abstract #1219P)

Also reported at the ESMO (Free ESMO Whitepaper) 2016 Congress were health-related quality of life (HRQoL) outcomes from the KEYNOTE-010 trial. Findings were based on patient-reported assessments using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC QLQ Lung Cancer 13, and EuroQol-5D-3L instruments to measure for outcomes such as physical, role, emotional, cognitive, and social functioning, as well as lung cancer and treatment-related symptoms, among other measures.

Overall, from baseline to the 12-week assessment, patients treated with KEYTRUDA (2 mg/kg or 10 mg/kg every three weeks) reported numeric improvements, some of which were significant, in HRQoL and prolonged time to deterioration of lung cancer symptoms (defined using a composite endpoint of cough, dyspnea, and chest pain) compared with docetaxel (75 mg/m2 every three weeks).

These findings, along with results from additional patient-reported outcomes analyses, suggest that HRQoL and symptoms were maintained or improved more with KEYTRUDA than with docetaxel.

These data were presented in a poster session on Oct. 8 from 1 – 2 p.m. CEST (Location: Hall E).

PD-L1 Prevalence Findings from KEYNOTE-001, -010, and -024 (Abstract #1060P)

Results from a third NSCLC abstract at the ESMO (Free ESMO Whitepaper) 2016 Congress explored, for the first time, the prevalence of PD-L1 in patients screened across multiple studies. The analysis assessed 4,784 patients with NSCLC who had tumors evaluable for PD-L1 expression and were screened for eligibility in three registrational studies of KEYTRUDA (pembrolizumab) – KEYNOTE-001, KEYNOTE-010, and KEYNOTE-024. Based on this pooled analysis, 66 percent of patients across all three trials were determined to express PD-L1 (TPS of one percent or more) and 28 percent were determined to have high levels of PD-L1 expression (TPS of 50 percent or more). These findings were similar across demographic and disease characteristics examined, including prior lines of therapy, age, tumor source (primary and metastases), and histology (squamous and non-squamous).

These data will be presented in a poster session on Oct. 9 from 1 – 2 p.m. CEST (Location: Hall E).

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 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 (pembrolizumab) 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)

Immune-mediated pneumonitis occurred in 19 (3.5%) of 550 patients, including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis and occurred more frequently in patients with a history of asthma/chronic obstructive pulmonary disease (5.4%) or prior thoracic radiation (6.0%). 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 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. 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 1 (0.2%) of 550 patients, which was Grade 3 in severity. 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 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) 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 (pembrolizumab) 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 patients receiving KEYTRUDA. 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 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% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

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 (pembrolizumab).

KEYTRUDA was discontinued due to adverse reactions in 14% of 550 patients. Serious adverse reactions occurred in 38% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. The most common adverse reactions (reported in at least 20% of patients) were fatigue (44%), cough (29%), decreased appetite (25%), and dyspnea (23%).

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.

Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study

On October 9, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported updated results from the Phase 1 CheckMate -016 trial, which evaluated the safety and tolerability (primary endpoint) of Opdivo at different doses as part of a regimen with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC) (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515662]). These updated results include findings for the Opdivo and Yervoy combinations [Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm] with approximately two years of follow-up, which showed the overall response rate (ORR; secondary endpoint) was 40.4% (n=47) in both arms. Of the 38 responders in both treatment arms, 39.5% (n=15) had an ongoing response, with a median duration of response of 20.4 months (95% CI: 8.54 – NE) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and 19.7 months (95% CI: 8.08 – NE) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm. The overall survival rate at 12 months was 81% and 85% for Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm, respectively, and at 24 months was 67% and 70%, respectively. There were fewer Grade 3/4 treatment-related adverse events reported in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm (38.3%) than with Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm (61.7%).

These results will be presented at the 2016 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress during a poster session on Sunday, October 9 from 1:00 – 2:00 p.m. CEST (Abstract #1062P).

"There remains a significant unmet need for treatment options that offer ongoing responses and increase survival for patients with renal cell carcinoma, the most common type of kidney cancer," said Asim Amin, M.D., Ph.D., Levine Cancer Institute, Carolinas HealthCare System. "The results from CheckMate -016 are encouraging and warrant further study, as they show with nearly two years of follow-up, patients in each Opdivo and Yervoy combination arm had a response that is ongoing in almost 40% of the patients."

Nearly a third of renal cell carcinoma (RCC) diagnoses occur once the disease has metastasized, or spread, to other parts of the body. At Stage IV, survival rates are low, with approximately 12% of advanced kidney cancer patients alive at five years.

"The findings reported at ESMO (Free ESMO Whitepaper) for CheckMate -016 validate our approach to studying the combination of our two Immuno-Oncology agents, Opdivo and Yervoy, to improve patient outcomes in metastatic renal cell carcinoma," said Vicki Goodman, M.D., development lead, Melanoma and Genitourinary Cancers, Bristol-Myers Squibb. "Our Phase 3 program for the Opdivo and Yervoy combination in the first line metastatic renal cell carcinoma is ongoing, and we hope to confirm these early findings through our continued research."

About CheckMate -016

CheckMate -016 is a multicenter, open-label, Phase 1 trial of Opdivo in combination with Yervoy, sunitinib or pazopanib in previously treated and treatment-naïve patients with metastatic renal cell carcinoma (mRCC). In the arms evaluating the combination regimen of Opdivo and Yervoy, which included 47 patients each, patients were randomized to receive Opdivo 3 mg/kg and Yervoy 1 mg/kg or Opdivo 1 mg/kg and Yervoy 3 mg/kg by intravenous infusion every three weeks for four doses, followed by Opdivo 3 mg/kg by intravenous infusion every two weeks until progression or toxicity. Prior systemic therapy was administered in 46.8% and 55.3% in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg and Opdivo 1 mg/kg plus Yervoy 3 mg/kg arms, respectively. The primary endpoints were to assess the safety and tolerability, and secondary endpoints were to assess objective response rate (ORR), duration of response (DOR), overall survival (OS) and progression-free survival (PFS).

In the study, fewer patients in the Opdivo 3 mg/kg and Yervoy 1 mg/kg arm experienced Grade 3/4 treatment-related adverse events (AEs) than those in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm (38.3% and 61.7%). Increased lipase was the most common Grade 3/4 treatment-related AE in both arms (14.9% with Opdivo 3 mg/kg and Yervoy 1 mg/kg; and 27.7% with Opdivo 1 mg/kg and Yervoy 3 mg/kg). Grade 3/4 treatment-related select AEs in the Opdivo 3 mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms were, respectively, gastrointestinal (4.3% and 23.4%), hepatic (6.4% and 21.3%), renal (4.3% and 4.3%), endocrinopathy (4.3% and 0.0%) and skin (0.0% and 2.1%). Discontinuations due to treatment-related AEs included five and 13 patients in the Opdivo 3 mg/kg and Yervoy 1 mg/kg and Opdivo 1 mg/kg and Yervoy 3 mg/kg arms, respectively. Treatment-related AEs leading to discontinuation in >5% of patients were increased alanine aminotransferase (ALT; 10.6%) and colitis (6.4%) in the Opdivo 1 mg/kg and Yervoy 3 mg/kg arm. No treatment-related deaths occurred in either arm. Based on these results, further development of the Opdivo 1 mg/kg and Yervoy 3 mg/kg regimen was not pursued.

Key efficacy results in previously treated and treatment-naïve mRCC patients are summarized below.

Opdivo 3 mg/kg plus
Yervoy 1 mg/kg
(n=47) Opdivo 1 mg/kg plus
Yervoy 3 mg/kg
(n=47)
Confirmed ORR, n (%); 95% CI 19 (40.4)
26.4 – 55.7
19 (40.4)
26.4 – 55.7
Best overall response,a n (%)
Complete response
Partial response
Stable disease
Disease progression
5 (10.6)
14 (29.8)
19 (40.4)
8 (17.0)
0 (0.0)
19 (40.4)
17 (36.2)
8 (17.0)
Median DOR, mos. (range) 20.4
(95% CI: 8.54 – NE)
19.7
(95% CI: 8.08 – NE)
12-month OS rate (%) 81 85
24-month OS rate 67 70
Median OS, mos. (range); 95% CI Not reached 32.6 (25.99–NE)
Median PFS, mos. (range) 6.6 (3.55 – 14.9) 9.1 (5.62 – 15.67)
a Best overall response was indeterminate in one patient (2.1%) in the Opdivo 3 mg/kg plus Yervoy 1 mg/kg arm and in two patients (4.3%) in the Opdivo 1 mg/kg plus Yervoy 3 mg/kg arm.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 100,000 deaths worldwide each year. Clear-cell RCC is the most prevalent type of RCC and constitutes 80% to 90% of all cases. Renal cell carcinoma is approximately twice as common in men as it is in women, with the highest rates of the disease found in North America and Europe. Globally, the five-year survival rate for those diagnosed with advanced kidney cancer is 12%.

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

Two Major Studies to Be Presented at ESMO 2016 Congress Presidential Symposium Demonstrate Potential of Merck’s KEYTRUDA® (pembrolizumab) for the First-Line Treatment of Metastatic Non-Small Cell Lung Cancer in a Broad Range of Patients

On October 9, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported results from two major studies of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) at the ESMO (Free ESMO Whitepaper) 2016 Congress, the annual meeting of the European Society for Medical Oncology:

In KEYNOTE-024, which evaluated squamous and non-squamous NSCLC patients whose tumors expressed high levels of PD-L1 (tumor proportion score, or TPS, of 50 percent or more), KEYTRUDA provided a 50 percent reduction in the risk of disease progression or death and a 40 percent reduction in the risk of death compared to platinum doublet, the current standard of care (Press release, Merck & Co, OCT 9, 2016, View Source [SID:SID1234515683]). These data were also published today in The New England Journal of Medicine. Based upon the results observed from KEYNOTE-024, to date KEYTRUDA is the only anti-PD-1 to demonstrate superior progression-free survival (PFS) and overall survival (OS) compared to chemotherapy for the first-line treatment of both squamous and non-squamous NSCLC in patients whose tumors express high levels of PD-L1 and do not express EGFR or ALK genetic aberrations.

In KEYNOTE-021, Cohort G, which included patients with metastatic non-squamous NSCLC regardless of PD-L1 expression level, KEYTRUDA (pembrolizumab) plus chemotherapy (carboplatin plus pemetrexed) achieved a 55 percent objective response rate (ORR) compared to 29 percent for chemotherapy alone, the standard of care, and reduced the risk of disease progression or death by 47 percent. To date, KEYTRUDA is the only anti-PD-1 therapy to demonstrate superior efficacy in combination with chemotherapy compared to chemotherapy alone in patients receiving first-line treatment. These data were published today in The Lancet Oncology.

"Chemotherapy has been the standard treatment for most patients with advanced non-small cell lung cancer for decades, but survival rates remain low," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "Our new data suggest that KEYTRUDA treatment can offer meaningful improvement over chemotherapy in a broad array of patients. In this sense, these studies may represent a turning point in worldwide efforts to control lung cancer. We sincerely thank the patients and the clinical investigators for their participation in our studies. Together we are working to improve the health of more and more patients with cancer."

Merck has submitted KEYNOTE-024 data to regulatory agencies in the United States, Europe, and Japan. The U.S. Food and Drug Administration has granted Breakthrough Therapy Designation and Priority Review, with a PDUFA, or target action, date of Dec. 24, 2016.

Merck is currently advancing multiple registration-enabling studies in NSCLC with KEYTRUDA as monotherapy and in combination, including the combination of KEYTRUDA plus a platinum/pemetrexed-based chemotherapy regimen in patients with previously untreated, non-squamous NSCLC in the ongoing phase 3 KEYNOTE-189 trial. The KEYTRUDA clinical development program includes more than 350 clinical trials across more than 30 tumor types, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

KEYNOTE-024: Data Showed KEYTRUDA was Superior to Chemotherapy for PFS and OS in First-Line Treatment of Metastatic NSCLC

KEYNOTE-024 included 305 patients who were previously untreated and whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more). Patients were randomized to receive a 200 mg fixed dose of KEYTRUDA every three weeks (n=154) or four to six cycles of investigator’s choice of one of five platinum-based chemotherapy regimens (n=151): carboplatin or cisplatin plus pemetrexed, carboplatin or cisplatin plus gemcitabine, or carboplatin plus paclitaxel. Pemetrexed maintenance therapy was permitted for patients with non-squamous histologies. Patients randomized to the control arm had the option of crossing over to KEYTRUDA (pembrolizumab) upon disease progression. The median follow-up was 11.2 months (range, 6.3-19.7). The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.

The findings published in The New England Journal of Medicine demonstrated that KEYTRUDA reduced the risk of progression or death by 50 percent compared to chemotherapy (HR, 0.50 [95% CI, 0.37-0.68]; p<0.001). The median PFS for KEYTRUDA was 10.3 months (95% CI, 6.7-not reached) compared to 6.0 months for chemotherapy (95% CI, 4.2-6.2). At six months, 62.1 percent of patients treated with KEYTRUDA were alive and had no disease progression (95% CI, 53.8-69.4) compared to 50.3 percent of those receiving chemotherapy (95% CI, 41.9-58.2). This benefit was observed in all study subgroups.

Additionally, KEYTRUDA resulted in a 40 percent reduction in the risk of death compared with chemotherapy (HR, 0.60 [95% CI, 0.41-0.89]; p=0.005); this finding includes the 66 patients (43.7%) on the chemotherapy arm who crossed over in-study to receive KEYTRUDA once their cancer had progressed; median OS was not reached in either group. Further, ORR was 44.8 percent for patients receiving KEYTRUDA (95% CI, 36.8-53.0), including six complete responses, compared to 27.8 percent with chemotherapy (95% CI, 20.8-35.7), including one complete response.

"These data from KEYNOTE-024 demonstrate the potential of KEYTRUDA to change the way non-small cell lung cancer is currently treated," said Dr. Martin Reck, head of the thoracic oncology dept., LungenClinic Grosshansdorf, Germany, and lead author of The New England Journal of Medicine paper. "This provides additional evidence that testing for PD-L1 levels should become standard in lung cancer at first diagnosis to guide treatment decisions."

Additional Findings and Safety Information from KEYNOTE-024

The safety of KEYTRUDA was consistent with what has been seen in previous trials among patients with metastatic NSCLC. The most common treatment-related adverse events for KEYTRUDA were diarrhea (n=22), fatigue (n=16), and pyrexia (n=16). Grade 3-5 treatment-related adverse events for KEYTRUDA included diarrhea (n=6) and pneumonitis (n=4). There was one treatment-related death in a patient receiving KEYTRUDA (cause unknown).

Additionally, based on an analysis of duration of response, a pre-specified exploratory endpoint, the median duration of response was not reached with KEYTRUDA (range, 1.9+ to 14.5+ months). The median duration of response with the chemotherapy group was 6.3 months (range, 2.1+ to 12.6+). Median time to response was 2.2 months for both groups.

About KEYNOTE-024

KEYNOTE-024 is a randomized, phase 3 study (ClinicalTrials.gov, NCT02142738) evaluating KEYTRUDA (pembrolizumab) as monotherapy compared to standard of care platinum-based chemotherapy in the treatment of patients with metastatic NSCLC. Patients enrolled were those who had received no prior systemic chemotherapy treatment for their advanced disease, whose tumors did not harbor an EGFR sensitizing mutation or ALK translocation, and whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more) as determined by a central laboratory using an FDA approved companion diagnostic, the Dako PD-L1 IHC 22C3 PharmDx test, from Agilent Technologies.

KEYNOTE-021, Cohort G: KEYTRUDA Combined with Chemotherapy Showed Higher Response Rates Compared to Chemotherapy Alone as First-Line Treatment of Metastatic NSCLC

KEYNOTE-021, Cohort G, included 123 previously untreated patients with metastatic non-squamous NSCLC regardless of PD-L1 expression and whose tumors did not have EGFR mutations or ALK translocations. Patients were randomized to receive KEYTRUDA plus platinum doublet chemotherapy with pemetrexed and carboplatin (n=60) or platinum doublet chemotherapy alone (n=63). Patients randomized to the chemotherapy-only arm had the option of crossing over to KEYTRUDA monotherapy upon disease progression. The median follow-up was 10.6 months (range, 0.8-19.3).

The findings published in The Lancet Oncology demonstrated that ORR nearly doubled by adding KEYTRUDA to chemotherapy, with an ORR of 55 percent (n=33/60) compared to 29 percent (n=18/63) for chemotherapy alone (treatment difference 26%, 95% CI, 9-42%, p=0.0016); all responses were partial. Median duration of response was not reached in either group (range, 1.4+-13.0+ for KEYTRUDA plus chemotherapy; 1.4+-15.2+ for chemotherapy alone). Responses in both groups were durable, with 88 percent (n=29/33) of responders in the KEYTRUDA plus chemotherapy group and 78 percent (n=14/18) of responders in the chemotherapy alone group experiencing ongoing response at the time of data cut-off.

Additionally, the KEYTRUDA combination significantly reduced the risk of disease progression or death compared to chemotherapy alone (hazard ratio 0.53, 95% CI, 0.31-0.91, p=0.0102). Median PFS was 13.0 months with KEYTRUDA plus chemotherapy compared to 8.9 months with chemotherapy alone. OS was similar between the two arms, with 92 percent survival at six months in both, and 75 percent and 72 percent survival at 12 months in the KEYTRUDA combination and chemotherapy alone, respectively.

Of treated patients on the KEYTRUDA (pembrolizumab) plus chemotherapy arm, 47 percent remained on treatment as of the cut-off date, compared to 31 percent on chemotherapy alone. Of the treated patients who discontinued treatment on the chemotherapy-only arm, 52 percent (n=32/62) subsequently received anti-PD-L1 therapy, with 32 percent crossing over to KEYTRUDA monotherapy as allowed by the study protocol and 19 percent receiving it outside of study crossover.

"The results from KEYNOTE-021 show that pembrolizumab plus chemotherapy nearly doubled the number of patients responding to treatment than chemotherapy alone," said Dr. Corey Langer, director of thoracic oncology and professor of medicine at the Hospital of the University of Pennsylvania and lead author of The Lancet Oncology paper. "We are now gaining a better understanding that pembrolizumab combined with chemotherapy may play an important role in the first-line treatment of patients with non-small cell lung cancer."

Additional Safety Information from KEYNOTE-021, Cohort G

The most common treatment-related adverse events (occurring in at least 15% of patients) for KEYTRUDA plus chemotherapy were fatigue, nausea, anemia, rash, vomiting, diarrhea, increased AST, constipation, decreased appetite, increased ALT, dysgeusia, and decreased neutrophils. Grade 3-4 treatment-related adverse events in this arm included fatigue, nausea, anemia, rash, vomiting, increased AST, increased ALT, and decreased neutrophils. The most common immune-mediated adverse events in patients receiving KEYTRUDA plus chemotherapy were hypothyroidism and hyperthyroidism. Additionally, pneumonitis, infusion reactions, and severe skin toxicity were noted. These immune-mediated adverse events occurred at similar rates to patients receiving KEYTRUDA as a single agent. There was one treatment-related death from sepsis in a patient receiving KEYTRUDA plus chemotherapy, and two (one from sepsis and one from pancytopenia) in patients receiving chemotherapy alone.

About KEYNOTE-021, Cohort G

Cohort G of the multicenter, open-label, phase 1/2 multi-cohort KEYNOTE-021 study evaluated the efficacy and safety of KEYTRUDA in combination with pemetrexed and carboplatin compared with pemetrexed and carboplatin in patients with metastatic, non-squamous, EGFR- and ALK-negative NSCLC in the first-line treatment setting. Patients were randomized 1:1 to four cycles of KEYTRUDA (200 mg plus carboplatin AUC 5 (5 mg/mL/min) plus pemetrexed 500 mg/m2 every three weeks), or carboplatin plus pemetrexed alone, followed by maintenance pemetrexed with or without KEYTRUDA. Randomization was stratified by PD-L1 expression (positive expression defined as TPS of one percent or more; negative expression defined as TPS of less than one percent). Patients randomized to the chemotherapy arm were allowed to cross over to KEYTRUDA (pembrolizumab) monotherapy if they experienced disease progression. Response was assessed by blinded, independent central review using RECIST 1.1 every six weeks for the first 18 weeks, every nine weeks through the first year, and every 12 weeks in the second year. The primary endpoint was ORR; secondary endpoints included PFS, duration of response, and OS.

About KEYTRUDA (pembrolizumab)

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 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

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)

Immune-mediated nephritis occurred in patients receiving KEYTRUDA. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA (pembrolizumab) for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

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

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck Oncology, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 350 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

Opdivo (nivolumab) Stabilized Patient-reported Outcomes in Patients With Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck in Pivotal Phase 3 CheckMate -141 Study

On October 9, 2016 Bristol-Myers Squibb Company (NYSE: BMY) reported new patient-reported quality-of-life data from an exploratory endpoint in the pivotal Phase 3 CheckMate -141 trial evaluating Opdivo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck after platinum therapy compared to investigator’s choice of therapy (methotrexate, docetaxel or cetuximab) (Press release, Bristol-Myers Squibb, OCT 9, 2016, View Source [SID:SID1234515663]). Outcome assessments showed Opdivo stabilized patients’ symptoms and functioning, including physical, role and social functioning across three separate instruments. Both PD-L1 expressors and non-expressors treated with investigator’s choice of therapy experienced statistically significant worsening of patient-reported outcomes from baseline to week 15 versus Opdivo. In addition, Opdivo more than doubled the time to deterioration for most functional domains measured and significantly delayed the time to worsening symptoms of fatigue, dyspnea and insomnia, compared to investigator’s choice of therapy.

These findings will be presented today, October 9, during a Presidential Symposium at the 2016 European Society for Medical Oncology Congress from 4:25-4:40 p.m. CEST (Abstract #LBA4) and will be simultaneously published in The New England Journal of Medicine.

"Patients living with this form of advanced head and neck cancer often experience debilitating physiological effects as well as emotional and social challenges brought on by the condition despite current treatment options," said Kevin Harrington, M.D., Ph.D., Professor in Biological Cancer Therapies at The Institute of Cancer Research, London, and a Consultant Clinical Oncologist at The Royal Marsden NHS Foundation Trust in London. "These patient-reported outcomes are encouraging, as they help us understand the potential for Opdivo to impact important quality-of-life measures for this patient population."

Squamous cell carcinoma of the head and neck accounts for approximately 90% of all head and neck cancers and may impact a patient’s physiological function (e.g., breathing, swallowing, eating, drinking), personal characteristics (e.g., appearance, speaking, voice), sensory function (e.g., taste, smell, hearing) as well as psychological and social functioning.

John O’Donnell, Ph.D., M.A., vice president, head, Health Economics and Outcomes Research, Bristol-Myers Squibb, commented, "At Bristol-Myers Squibb, we are committed to improving outcomes in advanced cancers and are proud to apply our Immuno-Oncology science to study the way people live with squamous cell carcinoma of the head and neck. The quality-of-life data from CheckMate -141 are important because they provide additional insights into how Opdivo may help patients with this difficult-to-treat disease."

About CheckMate -141

CheckMate -141 is a Phase 3, open-label, randomized trial that evaluated Opdivo versus investigator’s choice of therapy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with tumor progression within six months of platinum therapy in the adjuvant, primary, recurrent or metastatic setting.

Patient-reported outcomes (PRO) data were collected using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), EORTC Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35) and the 3-level EQ-5D questionnaire (EQ-5D). The questionnaires were administered at baseline (cycle 1, day 1), week 9 and at six-week intervals thereafter while patients were on treatment. Clinical relevance was assessed using an established minimally important difference (MID) of ≥10 points for EORTC subscales.

Both the EORTC QLQ-C30 and EORTC QLQ-H&N35 questionnaires showed there were significant differences in PROs between patients treated with Opdivo and those treated with investigator’s choice of therapy at 15 weeks. In the EORTC QLQ-C30, while patients treated with Opdivo had stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant and clinically meaningful worsening of physical, role and social functioning (p<0.001 versus Opdivo), fatigue (p<0.001 versus Opdivo), dyspnea (p<0.001 versus Opdivo) and appetite loss (p=0.004 versus Opdivo). Opdivo more than doubled the median time to deterioration for global health status (7.7 versus 3.0 months), physical functioning (7.8 versus 3.6 months), role functioning (8.6 versus 3.8 months), cognitive functioning (7.8 versus 3.3 months) and social functioning (7.7 versus 3.0 months), compared with investigator’s choice of therapy. In emotional functioning, Opdivo demonstrated a median time to deterioration of 6.7 months versus 4.7 months for investigator’s choice of therapy. Opdivo also reduced the rate of clinically meaningful deterioration in fatigue, insomnia and dypsnea by 50% (p=0.008).

Responses to the QLQ-H&N35 questionnaire showed while patients treated with Opdivo reported stable PROs relative to baseline, those treated with investigator’s choice of therapy had significant worsening in pain (p=0.022 versus Opdivo) as well as significant and clinically meaningful worsening in sensory problems (p<0.001 versus Opdivo) and social contact problems (p=0.001 versus Opdivo). Compared with investigator’s choice of therapy, Opdivo reduced the rate of clinically meaningful deterioration in pain by 74% (p<0.001 versus investigator’s choice of therapy), sensory problems by 62% (p=0.002 versus investigator’s choice of therapy) and opening mouth problems by 51% (p=0.029 versus investigator’s choice of therapy).

Patients treated with Opdivo experienced stable health status, as measured by the EQ-5D VAS, whereas those in the investigator’s choice arm experienced worsening of health status, with a statistically significant difference at 15 weeks (p=0.037). Median time to deterioration of health status was nearly triple with 9.1 months for patients receiving Opdivo versus 3.3 months for those in the investigator’s choice arm.

About Head & Neck Cancer

Cancers that are known as head and neck cancers usually begin in the squamous cells that line the moist mucosal surfaces inside the head and neck, such as inside the mouth, nose and throat. Head and neck cancer is the seventh most common cancer globally, with an estimated 600,000 new cases per year and 223,000-300,000 deaths per year. The global incidence of squamous cell carcinoma of the head and neck (SCCHN) is expected to increase by 17% between 2012 and 2022. The five-year survival rate is reported as less than 4% for metastatic Stage IV disease. Risk factors for SCCHN include tobacco and alcohol consumption. The Human Papilloma Virus (HPV) infection also is a risk factor leading to rapid increase in oropharyngeal SCCHN in Europe and North America.

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

About Opdivo

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

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.

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 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).

Immune-Mediated 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

Immune-Mediated Nephritis and Renal Dysfunction

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

Other Immune-Mediated Adverse Reactions

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

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

Serious Adverse Reactions

Common Adverse Reactions

CheckMate Trials and Patient Populations

TRACON Pharmaceuticals Presents Final Updated Phase 1b Results for TRC105 in Combination with Inlyta® in Renal Cell Carcinoma at the ESMO 2016 Congress

On October 9, 2016 TRACON Pharmaceuticals (NASDAQ:TCON), a clinical stage biopharmaceutical company focused on the development and commercialization of novel targeted therapeutics for cancer, wet age-related macular degeneration and fibrotic diseases, reported final updated results from a Phase 1b clinical trial combining TRC105 with Inlyta (axitinib) in patients with advanced or metastatic renal cell carcinoma (RCC) (Press release, Tracon Pharmaceuticals, OCT 9, 2016, View Source;p=irol-newsArticle&ID=2210295 [SID:SID1234515718]). Data were presented today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2016 Congress in Copenhagen, Denmark. Preliminary data from this trial were previously presented at the Kidney Cancer Association meeting in November 2015 and the ASCO (Free ASCO Whitepaper) Genitourinary Cancers Symposium in February 2015.

The open-label dose escalation and expansion Phase 1b study enrolled a total of 18 patients (17 of whom were evaluable for response) who had received at least one prior line of therapy with a VEGF receptor tyrosine kinase inhibitor (VEGFR TKI). The median number of prior therapies in the group was three with a range of one to six. All patients in the trial received a combination of TRC105 and Inlyta. Data are summarized in the table below.

Summary of Phase 1b Results for TRC105-Inlyta Combination
Patients ORR Stable
Disease Overall Disease
Control Median PFS Median PFS in Clear Cell
RCC Subset (n=12)
N = 17 29%
(5/17) 59%
(10/17) 88%
(15/17) 11.3 months 11.3 months
For comparison, the objective response rate (ORR) seen in the large subgroup of VEGFR TKI-refractory patients treated with Inlyta (n=194) in the Inlyta AXIS Phase 3 study in second line clear cell RCC patients (a separate trial) was 11.3%, and median progression-free survival (PFS) was 4.8 months.

All patients in TRACON’s Phase 1b study have now completed treatment and the randomized Phase 2b TRAXAR clinical trial of TRC105 in combination with Inlyta is currently enrolling patients with advanced or metastatic RCC. TRACON expects top-line data from the TRAXAR study to be available in the first half of 2017. A Trials-in-Progress poster for the TRAXAR study was also presented at the meeting. The poster presentations are available on the Publications page under the News section of the TRACON website at www.traconpharma.com.

The following key additional data from the Phase 1b study were also presented at the meeting:

The recommended Phase 2 dose of TRC105 of 10 mg/kg dosed weekly was well-tolerated in combination with Inlyta and no dose limiting toxicities were observed.
The most common adverse events were low grade epistaxis, headache, fatigue, diarrhea, and gingival bleeding.
The Inlyta dose was escalated from 5 mg BID to 7 mg BID in 22% of patients and to 10 mg BID in 11% of patients.
Serum concentrations of TRC105 above target concentrations were maintained continuously at the 8 mg/kg and 10 mg/kg TRC105 dose levels.
Plasma levels of TGF-b receptor 3 (betaglycan) at baseline were significantly higher in patients with a partial response, while levels of osteopontin were significantly lower at baseline for patients that achieved a partial response. Both markers correlated with time on study and their potential prognostic/predictive value are being investigated in the Phase 2b TRAXAR study.
About the TRAXAR Phase 2b Clinical Trial in RCC

The Phase 2b TRAXAR clinical trial is a multicenter, open-label, randomized clinical trial of TRC105 in combination with Inlyta versus Inlyta in patients with advanced or metastatic RCC. The primary endpoint of the Phase 2b study is progression-free survival. The company expects to enroll approximately 150 patients who have failed one prior VEGF inhibitor in the study. Patients may have also failed one prior mTOR inhibitor and one prior immunotherapy. For additional information on this clinical trial, please visit www.clinicaltrials.gov, identifier NCT01806064.

About TRC105 (carotuximab)

TRC105 (carotuximab) is a novel, clinical stage antibody to endoglin, a protein overexpressed on proliferating endothelial cells that is essential for angiogenesis, the process of new blood vessel formation, and also expressed on fibroblasts, a cell that causes fibrosis. TRC105 is currently being studied in multiple Phase 2 clinical trials sponsored by TRACON or the National Cancer Institute for the treatment of solid tumor types in combination with VEGF inhibitors. The ophthalmic formulation of TRC105, DE-122, is currently in a Phase 1/2 trial for patients with wet AMD. TRC205, a second generation antibody to endoglin, is undergoing preclinical testing in models of fibrosis. For more information about the clinical trials, please visit TRACON’s website at View Source

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Category: Uncategorized

KEYTRUDA® (pembrolizumab) Showed Continued Overall Survival Benefit Compared to Chemotherapy with Longer Follow-Up in Patients with Previously Treated Metastatic Non-Small Cell Lung Cancer in Data to Be Presented at ESMO 2016 Congress

Updated Results Presented for the Opdivo (nivolumab) and Yervoy (ipilimumab) Combination in Metastatic Renal Cell Carcinoma From Phase 1 Study

Two Major Studies to Be Presented at ESMO 2016 Congress Presidential Symposium Demonstrate Potential of Merck’s KEYTRUDA® (pembrolizumab) for the First-Line Treatment of Metastatic Non-Small Cell Lung Cancer in a Broad Range of Patients

Opdivo (nivolumab) Stabilized Patient-reported Outcomes in Patients With Previously Treated Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck in Pivotal Phase 3 CheckMate -141 Study

TRACON Pharmaceuticals Presents Final Updated Phase 1b Results for TRC105 in Combination with Inlyta® in Renal Cell Carcinoma at the ESMO 2016 Congress