On December 6, 2016 CTI BioPharma Corp. (CTI BioPharma) (NASDAQ and MTA: CTIC) reported data from PERSIST-2, a randomized Phase 3 clinical trial comparing pacritinib with physician-specified best available therapy (BAT), for the treatment of high risk, thrombocytopenic myelofibrosis patients (platelet counts less than 100,000 per microliter) in a late-breaking oral session at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, December 3-6 in San Diego, CA (Press release, CTI BioPharma, DEC 6, 2016, View Source [SID1234516956]). Pacritinib is an investigational oral multikinase inhibitor. Data presented at ASH (Free ASH Whitepaper) (Abstract #LBA-5) show that in myelofibrosis patients a statistically significant response rate in spleen volume reduction (SVR) with pacritinib therapy was observed compared to BAT that included use of the approved JAK1/JAK2 inhibitor ruxolitinib (p=0.001). The co-primary endpoint of reduction of Total Symptom Score (TSS) was not achieved (p=0.079) but trended toward improvement in TSS. Irrespective of prior ruxolitinib treatment, pacritinib therapy resulted in a statistically significant higher proportion of patients with SVR than patients on BAT.

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"Patients with myelofibrosis who have low platelet counts are often intolerant of ruxolitinib therapy and have no effective treatment options," said John Mascarenhas, M.D., Associate Professor, The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai and the presenter of the results in an oral presentation at ASH (Free ASH Whitepaper). "Data from PERSIST-2 suggest that pacritinib dosed on a twice-daily schedule may prove to be effective therapy for thrombocytopenic myelofibrosis patients with an adequate safety profile to fill an important unmet clinical need."

PERSIST-2 Results Presented at ASH (Free ASH Whitepaper)

PERSIST-2 was a randomized (1:1:1), controlled, open-label, multinational Phase 3 clinical trial evaluating pacritinib compared to best available therapy (BAT), including the approved JAK1/JAK2 inhibitor ruxolitinib, for patients with myelofibrosis whose platelet counts were less than or equal to 100,000 per microliter (≤100,000/μL). Three hundred eleven (311) patients were randomized to receive 200 mg pacritinib twice daily (BID), 400 mg pacritinib once daily (QD) or BAT. Clinical studies for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration (FDA) in February 2016. At the time, the FDA noted interim overall survival results from the PERSIST-2 showing a detrimental effect on survival were consistent with the results from PERSIST-1. Two hundred twenty-one (221) patients (74 pacritinib BID; 75 pacritinib QD; 72 BAT) were enrolled at least 24 weeks prior to the full clinical hold and were potentially evaluable for the Week 24 efficacy endpoint (ITT efficacy population). In the ITT efficacy population at study entry, 46 percent (101/221) of patients had platelet counts less than 50,000 per microliter (<50,000/μL), and 59 percent (130/221) were anemic (hemoglobin <10 g/dL). Normal platelet counts range from 150,000 to 450,000 per microliter. The percentage of patients in the ITT efficacy population who received prior ruxolitinib was as follows: 41 percent (31/75) pacritinib QD; 42 percent (31/74) pacritinib BID; and 46 percent (33/72) BAT.

Safety analyses were based on all patients exposed to study treatment of any duration.

The co-primary endpoints of the trial were the proportion of patients achieving a 35 percent or greater reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) and the proportion of patients achieving a Total Symptom Score (TSS) reduction of 50 percent or greater using the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to Week 24. The primary objective of the study was to compare pooled pacritinib arms versus BAT and the secondary objectives were to compare pacritinib BID and QD arms individually to BAT. Study was designed to evaluate the study objectives with sample size of 300. At the time of clinical hold, study enrollment was completed with 311 patients randomized, but only 221 patients had the potential to be evaluated for efficacy endpoints at Week 24.

As previously reported, the PERSIST-2 trial met one of the co-primary endpoints showing a statistically significant response rate in SVR in patients with myelofibrosis treated with pacritinib combining the once- and twice-daily arms compared to BAT. Although the PERSIST-2 trial did not meet the other co-primary endpoint of greater than 50 percent reduction in TSS, the results approached marginal significance compared to BAT. Although secondary objectives could not be evaluated formally due to the study not achieving one of the primary objectives, when the two pacritinib dosing arms were evaluated separately versus BAT, pacritinib given twice daily showed a higher percent of SVR and TSS responses compared to BAT; whereas, pacritinib given once daily showed only a higher percent SVR responses compared to BAT.

Spleen Volume Reduction of ≥35%; Total Symptom Score Reduction of ≥50% at Week 24


Pacritinib
BAT
p-value*
Pooled BID and QD – Primary objectives
SVR
18%
3%
0.001
TSS
25%
14%
0.079

BID – 200 mg twice daily – Secondary objectives
SVR
22%
3%
0.001
TSS
32%
14%
0.011

QD – 400 mg once daily – Secondary objectives
SVR
15%
3%
0.017
TSS
17%
14%
0.652

* p-value for the secondary objectives were nominal p-values and used for reference.


A total of 45 percent of the BAT patients randomized received ruxolitinib at some point on the study.

There was no significant difference in overall survival (OS) across treatment arms, censored at the time of clinical hold. Hazard ratios (95% confidence intervals (CI)) were 0.68 (0.30-1.53) for pacritinib BID versus BAT and 1.18 (0.57-2.44) for pacritinib QD versus BAT. Overall mortality rates at that time were comparable between arms: 9 percent BID versus 14 percent QD and 14 percent BAT.

The most common treatment-emergent adverse events (AEs), occurring in 20 percent or more of patients treated with pacritinib within 24 weeks, of any grade, were gastrointestinal (generally manageable diarrhea, nausea and vomiting) and hematologic (anemia and thrombocytopenia) and were generally less frequent for BID versus QD administration. The most common serious treatment-emergent AEs (incidence of ≥5 percent reported in any treatment arm irrespective of grade) were anemia, thrombocytopenia, pneumonia and acute renal failure none of which exceeded 8 percent individually in any arm.

"In this randomized Phase 3 clinical trial in thrombocytopenic patients with advanced myelofibrosis that allowed for prior therapy with a JAK inhibitor and allowed use of ruxolitinib in the best available therapy arm," said Srdan (Serge) Verstovsek, M.D., Ph.D., Director, Clinical Research Center for MPNs at the University of Texas MD Anderson Cancer Center and principal investigator for the PERSIST-2 Phase 3 clinical trial of pacritinib, "the data demonstrates pacritinib’s activity in this challenging patient population and shows the potential for pacritinib to effectively retreat patients following failure of anti-JAK2 treatment."

"CTI BioPharma would like to thank all the patients and physicians that participated in the PERSIST-2 trial," said Richard Love, Interim President and CEO of CTI BioPharma. "We are committed to bringing pacritinib to the many myelofibrosis patients in need of new therapies and will continue to work with the regulatory agencies to move the process forward."

Data will be presented today by John Mascarenhas, M.D., in a late-breaking oral session at 8:30 a.m. PT and was selected as part of the official ASH (Free ASH Whitepaper) press program. The presentation will be available at www.ctibiopharma.com following the conclusion of the meeting.

About the Phase 3 Development Program of Pacritinib

Pacritinib was evaluated in two Phase 3 clinical trials, known as the PERSIST program, for patients with myelofibrosis, with one trial in a broad set of patients without limitations on platelet counts, the PERSIST-1 trial; and the other in patients with low platelet counts, the PERSIST-2 trial. In August 2014, pacritinib was granted Fast Track designation by the FDA for the treatment of intermediate and high risk myelofibrosis including, but not limited to, patients with disease-related thrombocytopenia (low platelet counts); patients experiencing treatment-emergent thrombocytopenia on other JAK2 inhibitor therapy; or patients who are intolerant of, or whose symptoms are not well controlled (sub-optimally managed) on other JAK2 therapy.

Clinical studies under the CTI BioPharma investigational new drug (IND) for pacritinib are currently subject to a full clinical hold issued by the U.S. Food and Drug Administration in February 2016. At the time, the FDA noted interim overall survival results from the PERSIST-2 showing a detrimental effect on survival were consistent with the results from PERSIST-1 and that deaths in PERSIST-2 in pacritinib-treated patients include intracranial hemorrhage, cardiac failure and cardiac arrest.

PERSIST-1 was a randomized (2:1), controlled, open-label, multinational Phase 3 trial evaluating the efficacy and safety of pacritinib compared to BAT, excluding JAK2 inhibitors, which included a broad range of currently utilized treatments – in 327 patients with myelofibrosis (primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis), regardless of the patients’ platelet counts. The study included patients with severe or life-threatening thrombocytopenia. Patients were randomized to receive 400 mg pacritinib once daily or BAT, excluding JAK2 inhibitors. As previously reported, the trial met its primary endpoint of spleen volume reduction (35 percent or greater from baseline to Week 24 by MRI/CT scan) in the intent-to-treat population (ITT).

About Pacritinib

Pacritinib is an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R. The JAK family of enzymes is a central component in signal transduction pathways, which are critical to normal blood cell growth and development, as well as inflammatory cytokine expression and immune responses. Mutations in these kinases have been shown to be directly related to the development of a variety of blood-related cancers, including myeloproliferative neoplasms, leukemia and lymphoma. In addition to myelofibrosis, the kinase profile of pacritinib suggests its potential therapeutic utility in conditions such as acute myeloid leukemia, or AML, myelodysplastic syndrome, or MDS, chronic myelomonocytic leukemia, or CMML, and chronic lymphocytic leukemia, or CLL, due to its inhibition of c-fms, IRAK1, JAK2 and FLT3.

About Myelofibrosis and Myeloproliferative Neoplasms

Myelofibrosis is one of three main types of myeloproliferative neoplasms (MPN), which are a closely related group of progressive blood cancers. The three main types of MPNs are primary myelofibrosis (PMF), polycethemia vera (PV) and essential thrombocythemia (ET).1

Myelofibrosis is a serious and life-threatening bone marrow disorder caused by the accumulation of malignant bone marrow cells that triggers an inflammatory response and scars the bone marrow. The replacement of bone marrow with scar tissue limits its ability to produce red blood cells, prompting the spleen and liver to take over this function. Symptoms that arise from this disease include enlargement of the spleen, anemia, extreme fatigue and pain.

The estimated prevalence of MPNs suggest there are approximately 300,000 people living with the disease in the U.S., of which myelofibrosis accounts for approximately 18,000 patients.2 In Europe, there is a wide variation of prevalence observed across data sources. Myelofibrosis has a median age of 64 at the time of diagnosis3 and is a progressive disease with approximately 20 percent of patients eventually developing acute myeloid leukemia (AML).4 The median survival for high-risk myelofibrosis patients is less than 1.5 years, while the median survival for patients with myelofibrosis overall is approximately 6 years.4

On December 6, 2016 Bristol-Myers Squibb Company (NYSE:BMY) reported updated results for Opdivo monotherapy (3 mg/kg every two weeks [n=98]) and in combination with Yervoy (Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks [n=61]) in previously treated small cell lung cancer (SCLC) patients, a cohort of the Phase 1/2 open-label CheckMate -032 trial (Press release, Bristol-Myers Squibb, DEC 6, 2016, View Source [SID1234516949]). The confirmed objective response rate (primary objective) was 25% (95% CI: 15, 37) in patients who received Opdivo plus Yervoy and was 11% (95% CI: 6, 19) with Opdivo alone with additional follow-up. Response was observed regardless of platinum sensitivity or prior lines of therapy. With the combination, three patients experienced a complete response. The estimated two-year overall survival rate (secondary objective) was 30% with Opdivo plus Yervoy and was 17% with Opdivo alone. In this updated analysis, no new safety signals were observed. Grade 3/4 treatment-related discontinuation rates were 10% in the Opdivo plus Yervoy group and 4% in the Opdivo group.

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"Small cell lung cancer is a highly aggressive, rapidly progressive disease with most patients relapsing within a year of diagnosis. There have been no significant changes in systemic treatment options in the last 30 years," said Matthew D. Hellmann, M.D., study investigator, Memorial Sloan Kettering Cancer Center. "In the CheckMate -032 trial, we observed that responses occurred in a quarter of patients with small cell lung cancer treated with the combination of nivolumab and ipilimumab. Responses were associated with promising survival, including 30% of these patients alive at two years after beginning treatment with the combination. These data offer important new information in the study of nivolumab plus ipilimumab as a potential treatment option for some patients with small cell lung cancer."

These results will be presented today at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer in Vienna, Austria, during a Mini Oral Session at 2:45-2:51 p.m. CET.

Nick Botwood, M.D., development lead, Lung, Bristol-Myers Squibb commented, "In the small cell lung cancer cohort of CheckMate -032, we observed promising response and survival rates when Yervoy is added to Opdivo. We find these results encouraging, and through our broad lung development program, are committed to further investigating Opdivo as monotherapy and in combination with Yervoy for small cell lung cancer patients in two ongoing Phase 3 trials."

About CheckMate -032

CheckMate -032 is an ongoing Phase 1/2 open-label trial, evaluating the safety and efficacy of Opdivo monotherapy, or Opdivo combined with Yervoy, in advanced or metastatic solid tumors at different doses and schedules. The trial included both PD-L1 expressors and non-expressors. The primary objective was investigator-assessed confirmed objective response rate (ORR) per RECIST version 1.1. Secondary objectives included safety, overall survival (OS), progression-free survival (PFS) and duration of response (DOR). Biomarker analysis was an exploratory objective.

The CheckMate -032 small cell lung cancer (SCLC) cohort included 217 patients with progressive disease after one or more prior lines of therapy, including a first-line platinum-based chemotherapy regimen. In this analysis, patients received Opdivo monotherapy 3 mg/kg administered intravenously every two weeks or Opdivo 1 mg/kg plus Yervoy 3 mg/kg every three weeks for four cycles, followed by Opdivo 3 mg/kg every two weeks. All patients were treated until disease progression or unacceptable toxicity. Patients were followed for a median of 21 months in the combination cohort and 15.7 months in the Opdivo monotherapy cohort. Across cohorts, 73% were evaluable for PD-L1 expression at baseline; 17% (of PD-L1 evaluable samples) had ≥1% tumor PD-L1 expression.

In addition to the survival and response data reported, additional efficacy findings included confirmed partial response in 21 patients in the Opdivo and Yervoy combination arm and 11 patients in the Opdivo-only arm. Confirmed stable disease was consistent across both treatment arms (25 patients in combination arm; 24 patients in monotherapy arm). Median DOR was 11.7 months in the combination group (95% CI: 4.0, NR); DOR was not reached in the monotherapy group. In the combination and monotherapy arms, respectively, 33% (5/15) and 27% (3/11) of responders had ongoing responses lasting approximately >18 months after treatment initiation.

The most commonly reported Grade 3/4 treatment-related adverse events (AE) in ≥10% of patients on the monotherapy and combination arms, respectively, were fatigue (1%, 0%), pruitius (0%, 2%), diarrhea (0%, 5%), nausea (0%, 2%), rash (0%, 5%), hypothyroidism (0%, 2%), maculopapular rash (0%, 3%) and increased lipase (0%, 8%). In the Opdivo-only group 4% of patients discontinued treatment due to Grade 3/4 treatment-related AEs, and 10% in the combination group. No additional treatment-related deaths were reported. At prior disclosure, two treatment related deaths occurred with the combination (myasthenia gravis and worsening of renal failure). Grade 3/4 treatment-related limbic encephalitis occurred in 1 patient in the monotherapy group. Treatment-related pneumonitis occurred in 4 patients in the monotherapy group (two Grade 3/4 events) and 1 patient in the combination group (one Grade 3/4 event).

About Small-Cell Lung Cancer

Small cell lung cancer (SCLC) is one of two main types of lung cancer, which has been the most common cancer in the world for several decades and accounts for about 10-15% of all lung cancers. Survival rates vary depending on the stage of the cancer when it is diagnosed and five-year survival rates tend to be lower than non-small cell lung cancer, as SCLC is faster growing and symptoms are often not detected until the cancer is at an advanced stage. Globally, the five-year survival rate for Stage I SCLC is between 20% and 40%; for Stage IV SCLC, the five-year survival rate drops to 1%.

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

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 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 the confirmatory trials

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

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.

OPDIVO (nivolumab) is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

IMPORTANT SAFETY INFORMATION

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS

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

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

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

Immune-Mediated Pneumonitis

OPDIVO can cause immune-mediated pneumonitis. Fatal cases have been reported. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids for Grade 2 or more severe pneumonitis. Permanently discontinue for Grade 3 or 4 and withhold until resolution for Grade 2. In patients receiving OPDIVO monotherapy, fatal cases of immune-mediated pneumonitis have occurred. Immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated pneumonitis occurred in 6% (25/407) of patients.

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

OPDIVO can cause immune-mediated colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO monotherapy for Grade 2 or 3 and permanently discontinue for Grade 4 or recurrent colitis upon re-initiation of OPDIVO. When administered with YERVOY, withhold OPDIVO and YERVOY for Grade 2 and permanently discontinue for Grade 3 or 4 or recurrent colitis. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated colitis occurred in 26% (107/407) of patients including three fatal cases.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) patients. Across all YERVOY-treated patients in that study (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis.

Immune-Mediated Hepatitis

OPDIVO can cause immune-mediated hepatitis. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated hepatitis occurred in 13% (51/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3-5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%.

Immune-Mediated Neuropathies

In a separate Phase 3 study of YERVOY 3 mg/kg, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported.

Immune-Mediated Endocrinopathies

OPDIVO can cause immune-mediated hypophysitis, immune-mediated adrenal insufficiency, autoimmune thyroid disorders, and Type 1 diabetes mellitus. Monitor patients for signs and symptoms of hypophysitis, signs and symptoms of adrenal insufficiency, thyroid function prior to and periodically during treatment, and hyperglycemia. Administer hormone replacement as clinically indicated and corticosteroids for Grade 2 or greater hypophysitis. Withhold for Grade 2 or 3 and permanently discontinue for Grade 4 hypophysitis. Administer corticosteroids for Grade 3 or 4 adrenal insufficiency. Withhold for Grade 2 and permanently discontinue for Grade 3 or 4 adrenal insufficiency. Administer hormone-replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. Withhold OPDIVO for Grade 3 and permanently discontinue for Grade 4 hyperglycemia.

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients. In patients receiving OPDIVO with YERVOY, hypophysitis occurred in 9% (36/407) of patients. In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994) of patients. In patients receiving OPDIVO with YERVOY, adrenal insufficiency occurred in 5% (21/407) of patients. In patients receiving OPDIVO monotherapy, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients.

Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO monotherapy. In patients receiving OPDIVO with YERVOY, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with YERVOY. In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients. In patients receiving OPDIVO with YERVOY, diabetes occurred in 1.5% (6/407) of patients.

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

Immune-Mediated Nephritis and Renal Dysfunction

OPDIVO can cause immune-mediated nephritis. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids for Grades 2-4 increased serum creatinine. Withhold OPDIVO for Grade 2 or 3 and permanently discontinue for Grade 4 increased serum creatinine. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients.

Immune-Mediated Skin Adverse Reactions and Dermatitis

OPDIVO can cause immune-mediated rash, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some cases with fatal outcome. Administer corticosteroids for Grade 3 or 4 rash. Withhold for Grade 3 and permanently discontinue for Grade 4 rash. For symptoms or signs of SJS or TEN, withhold OPDIVO and refer the patient for specialized care for assessment and treatment; if confirmed, permanently discontinue. In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients. In patients receiving OPDIVO with YERVOY, immune-mediated rash occurred in 22.6% (92/407) of patients.

In a separate Phase 3 study of YERVOY 3 mg/kg, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3-5) occurred in 13 (2.5%) patients. 1 (0.2%) patient died as a result of toxic epidermal necrolysis. 1 additional patient required hospitalization for severe dermatitis.

Immune-Mediated Encephalitis

OPDIVO can cause immune-mediated encephalitis. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold OPDIVO in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out other causes. If other etiologies are ruled out, administer corticosteroids and permanently discontinue OPDIVO for immune-mediated encephalitis. In patients receiving OPDIVO monotherapy, encephalitis occurred in 0.2% (3/1994) of patients. Fatal limbic encephalitis occurred in one patient after 7.2 months of exposure despite discontinuation of OPDIVO and administration of corticosteroids. Encephalitis occurred in one patient receiving OPDIVO with YERVOY (0.2%) after 1.7 months of exposure.

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. Across clinical trials of OPDIVO the following clinically significant immune-mediated adverse reactions occurred in <1.0% of patients receiving OPDIVO: uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), myositis, myocarditis, rhabdomyolysis, motor dysfunction, vasculitis, and myasthenic syndrome.

Infusion Reactions

OPDIVO can cause severe infusion reactions, which have been reported in <1.0% of patients in clinical trials. Discontinue OPDIVO in patients with Grade 3 or 4 infusion reactions. Interrupt or slow the rate of infusion in patients with Grade 1 or 2. In patients receiving OPDIVO monotherapy, infusion-related reactions occurred in 6.4% (127/1994) of patients. In patients receiving OPDIVO with YERVOY, infusion-related reactions occurred in 2.5% (10/407) of patients.

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 HSCT 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 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO . The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (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 (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.6%), colitis (10% and 1.6%), and pyrexia (10% and 0.6%). In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 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]). In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infections, and sepsis.

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (59%), rash (53%), diarrhea (52%), nausea (40%), pyrexia (37%), vomiting (28%), and dyspnea (20%). The most common (≥20%) adverse reactions in the OPDIVO (n=313) arm were fatigue (53%), rash (40%), diarrhea (31%), and nausea (28%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) 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 (≥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 Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO were cough and dyspnea at a higher incidence than investigator’s choice.

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 067 – advanced melanoma alone or in combination with YERVOY; Checkmate 037 and 066 – advanced melanoma; Checkmate 017 – squamous non-small cell lung cancer (NSCLC); Checkmate 057 – non-squamous NSCLC; Checkmate 025 – renal cell carcinoma; Checkmate 205/039 – classical Hodgkin lymphoma; Checkmate 141 – squamous cell carcinoma of the head and neck.

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

On December 6, 2016 AstraZeneca reported data from the AURA3 trial that data is supportive of Tagrisso (osimertinib) potentially becoming the new standard of care for 2nd-line treatment of patients with epidermal growth factor receptor (EGFR) T790M mutation-positive locally-advanced or metastatic non-small cell lung cancer (NSCLC)(Press release, AstraZeneca, DEC 6, 2016, View Source [SID1234516948]). The first randomised Phase III data showed that Tagrisso 2nd-line therapy improved progression-free survival (PFS) by 5.7 months compared with standard platinum-based doublet chemotherapy (Hazard Ratio [HR]=0.3). The results were presented at the 17th World Conference on Lung Cancer (WCLC) in Vienna, Austria, hosted by the International Association for the Study of Lung Cancer, and published simultaneously online in The New England Journal of Medicine.

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AURA3


Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The confirmatory Phase III data suggest the potential for Tagrisso to replace chemotherapy as the standard of care for patients who have progressed following EGFR tyrosine kinase inhibitor treatment. As lung cancer is the most common type of cancer to spread to the brain, it is also encouraging to see the activity of Tagrisso in patients with central nervous system metastases whose prognosis is often particularly poor."

AURA3 data showed Tagrisso offered a statistically-significant improvement in PFS versus standard platinum-based doublet chemotherapy (10.1 months vs 4.4 months, hazard ratio [HR] 0.30; 95% confidence interval (CI):0.23, 0.41; p<0.001). In the 34% of patients with central nervous system (CNS) metastases at baseline, PFS was also significantly greater with Tagrisso than with platinum-based doublet chemotherapy (8.5 months vs 4.2 months, HR 0.32; 95% CI: 0.21, 0.49).

Dr. Vassiliki A Papadimitrakopoulou, from the University of Texas MD Anderson Cancer Center, Houston, Texas, USA, said: "The results of AURA3 are not only statistically significant, but clinically meaningful because it is the first time a targeted medicine like Tagrisso has shown improvement in progression-free survival over standard platinum-pemetrexed chemotherapy. It’s very rewarding to be able to give this type of news to patients, as it highlights the major advances we are making in targeted lung cancer treatments."

Professor Tony Mok, from the Chinese University of Hong Kong, Hong Kong said: "The superiority of Tagrisso in progression free survival and response rate over platinum-pemetrexed chemotherapy suggests we may be moving towards a new standard of care for patients with resistance to EGFR TKI. With the publication of the AURA3 data, clinicians should perform T790M mutation testing to ensure Tagrisso be given to patients who are most likely to benefit."

The AURA3 safety data for Tagrisso were in line with previous experience. Grade ≥3 drug-related adverse events (AEs) were reported in 6% of patients (n=16) treated with Tagrisso and 34% (n=46) treated with platinum-based doublet chemotherapy. The most common drug-related AEs in the Tagrisso group, were diarrhoea (29% overall; 1% Grade ≥3) and rash (28% overall; <1% Grade ≥3) and, in the chemotherapy group, they were nausea (47% overall; 3% Grade ≥3) and decreased appetite (32% overall; 3% Grade ≥3).

The data for AURA3 are consistent with those previously presented in the Phase II trials, AURA2 and AURA extension. This consistency extends to testing of tissue and plasma samples for the detection of the EGFR T790M resistance mutation. In AURA3, approximately half of patients with T790M in tumour tissue also had the T790M mutation detected in plasma. Clinical benefits were reported with Tagrisso compared to platinum-based doublet chemotherapy, irrespective of whether the T790M mutation was identified by plasma ctDNA or tissue testing. When feasible, tissue testing is recommended for patients with a negative plasma T790M test.

Tagrisso was granted accelerated approval by the US Food and Drug Administration (FDA) in November 2015 for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, who have progressed on or after EGFR TKI therapy. In the EU, Tagrisso was granted conditional marketing authorisation for adult patients with locally advanced or metastatic EGFR T790M NSCLC, irrespective of previous EGFR-TKI treatment by the European Medicines Agency (EMA) in February 2016.

In addition, Tagrisso received approval in Japan in March 2016 for the treatment of patients with EGFR T790M mutation-positive inoperable or recurrent NSCLC that is resistant to EGFR TKI therapy, and it is currently under fast track review in China, where nearly half of lung cancer patients are thought to have the EGFR mutation.

NOTES TO EDITORS

To view and download additional supporting materials including backgrounders, infographics and images, please visit: View Source where they are available throughout WCLC 2016.

About AURA3

AURA3 compared the efficacy and safety of Tagrisso<> 80mg once daily and platinum-based doublet chemotherapy (platinum-pemetrexed) in 419 patients with EGFR T790M mutation-positive, locally-advanced or metastatic NSCLC whose disease had progressed on or after treatment with a previous EGFR tyrosine kinase inhibitor (TKI). The trial was carried out in more than 130 locations worldwide, including the USA, Canada, Europe, China, Japan, Korea, Taiwan and Australia.

The primary endpoint of the trial was PFS, and secondary endpoints included overall survival (OS), overall response rate (ORR), duration of response (DoR), disease control rate (DCR), safety and measures of health-related quality of life (HRQoL).

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths and more than breast, prostate and colorectal cancers combined. Among patients with lung cancer, 25% to 40% have brain metastases at some time in the course of their disease. Patients who have the EGFRm form of NSCLC, which occurs in 10-15% of NSCLC patients in the US and Europe and 30-40% of NSCLC patients in Asia, are particularly sensitive to treatment with currently-available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to treatment, leading to disease progression. Approximately two-thirds of patients develop resistance to approved EGFR-TKIs such as gefitinib and erlotinib due to the secondary mutation, T790M.

About Tagrisso

Tagrisso (osimertinib, AZD9291) 80mg once daily tablet is approved in the US, EU, Japan, Canada, Switzerland, Israel, Mexico, Australia and a number of other countries as the first treatment for patients with locally-advanced or metastatic EGFR T790M mutation-positive NSCLC. Tagrisso is also approved in South Korea in the same indication. Eligibility for treatment with Tagrisso is dependent on confirmation that the EGFR T790M mutation is present in the tumour.

Tagrisso has one of the fastest development programmes, from start of clinical trials to approval in just over two and a half years. Tagrisso is as an irreversible EGFR inhibitor, born out of scientific exploration and engineered to combat the mechanism of resistance by targeting the T790M resistance mutation. Tagrisso is also investigated in the adjuvant and metastatic first-line settings, including in patients with and without brain metastases, in leptomeningeal disease, and in combination with other treatments.