On December 6, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that updated findings from the phase 1b KEYNOTE-028 study investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in previously treated patients with advanced small cell lung cancer (SCLC) and malignant pleural mesothelioma, showed clinical activity and durable responses in some patients (Press release, Merck & Co, DEC 6, 2016, View Source [SID1234516954]). These data were featured in oral presentations at the 17th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer.

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"As data from our initial trials exploring KEYTRUDA mature, we are encouraged to see durable clinical activity in difficult-to-treat cancers such as small cell lung cancer and malignant pleural mesothelioma, where new treatments are clearly needed," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "With our extensive immuno-oncology research program, we are developing KEYTRUDA across a range of thoracic malignancies, and we have additional studies underway in these two cancer types."

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients with PD-L1 positive tumors across 20 different types of cancer. PD-L1 positivity was defined as expression in one percent or more of tumor and associated inflammatory cells or positive staining in stroma. The primary outcome measure is overall response rate (ORR), with secondary outcome measures of progression-free survival (PFS), overall survival (OS), and duration of response.

The KEYTRUDA (pembrolizumab) clinical development program includes more than 30 tumor types in nearly 400 clinical trials, including more than 200 trials that combine KEYTRUDA with other cancer treatments. Merck has initiated a phase 2 trial, KEYNOTE-158, to further evaluate KEYTRUDA in advanced solid tumors including SCLC and malignant pleural mesothelioma.

Results from KEYNOTE-028 SCLC Cohort (Abstract #OA05.01)

Data from the SCLC cohort of the KEYNOTE-028 trial were presented in an oral presentation on Dec. 5 by Dr. Patrick Ott, Dana-Farber Cancer Institute.

Updated findings from 24 heavily pre-treated patients with advanced SCLC demonstrated a confirmed ORR of 33.3 percent (n=8/24) (95% CI, 15.6%-55.3%), including one complete response and seven partial responses. One patient had stable disease and 13 patients had progressive disease. Responses were durable, with a median duration of response of 19.4 months (95% CI, range: 3.6+ to 20.0+).

Additionally, the median PFS was 1.9 months (95% CI, 1.7-5.9), with a six-month PFS rate of 28.6 percent and 12-month PFS rate of 23.8 percent. The median OS was 9.7 months (95% CI, 4.1-NR), with a six-month OS rate of 66.0 percent and a 12-month OS rate of 37.7 percent.

The safety profile of KEYTRUDA was consistent with that observed in previously reported studies. Grade 3-5 treatment-related adverse events were asthenia, blood bilirubin increased, colitis and intestinal ischemia (n=1 for all). Some patients experienced adverse events of special interest, including autoimmune thyroiditis, infusion site reaction, cytokine release syndrome and colitis (n=1 for all).

"These long-term data, which show meaningful response rates and durable responses in certain patients with small cell lung cancer, are encouraging," said Dr. Ott. "With these findings, we are advancing understanding of the potential for immunotherapy to make a difference for these patients."

Results from KEYNOTE-028 Malignant Pleural Mesothelioma Cohort (Abstract #OA13.03)

Data from the malignant pleural mesothelioma cohort of the KEYNOTE-028 trial were presented in an oral presentation on Dec. 6 by Dr. Evan Alley, Abramson Cancer Center, University of Pennsylvania.

Results showed a confirmed ORR of 20.0 percent (n=5/25) (95% CI, 6.8-40.7). All responses were partial responses and 13 patients had stable disease. The median duration of response was 12.0 months (range, 3.7-20.5+). In total, 60.9 percent of evaluable patients experienced a decrease in tumor size.

Additionally, the median PFS was 5.4 months (95% CI, 3.4-7.5), with a six-month PFS rate of 45.8 percent and a 12-month PFS rate of 20.8 percent. Median OS was 18.0 months (95% CI, 9.4-NR), with a six-month OS rate of 83.5 percent and a 12-month OS rate of 62.6 percent.

The safety profile of KEYTRUDA (pembrolizumab) was consistent with that observed in previously reported studies. Grade 3 treatment-related adverse events were ALT increase, appetite decrease, dyspnea, iridocyclitis, neutrophil count decreased, pyrexia and thrombocytopenia (n=1 for all). Some patients experienced adverse events of special interest, including erythema/erythema multiforme, hypothyroidism, infusion-related reaction, iridocyclitis and rhabdomyolysis (n=1 for all). There were no Grade 4 or 5 treatment-related adverse events and no treatment-related deaths.

About KEYTRUDA (pembrolizumab)

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

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

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

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

Lung Cancer

KEYTRUDA is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA (pembrolizumab) is also indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

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. 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. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). 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.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA (pembrolizumab) can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in patients with HNSCC occurring in 28 (15%) of 192 patients with HNSCC, including Grade 3 (0.5%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. 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 (pembrolizumab) 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% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

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

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions with KEYTRUDA vs ipilimumab were fatigue (28% vs 28%), diarrhea (26% with KEYTRUDA), rash (24% vs 23%), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

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

KEYTRUDA was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (reported in at least 20% of patients) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC, with the exception of increased incidences of facial edema (10% all Grades; 2.1% Grades 3 or 4) and new or worsening hypothyroidism.

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.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, 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 nearly 400 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.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 6, 2016 Mateon Therapeutics, Inc. (Nasdaq:MATN), a biopharmaceutical company developing vascular disrupting agents (VDAs) for the treatment of orphan oncology indications, reported the poster presentation of data from its on-going phase 1b OX1222 study of OXi4503 in combination with cytarabine in patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) (Press release, Mateon Therapeutics, DEC 6, 2016, View Source [SID1234516953]).

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OXi4503 is one of Mateon’s two VDAs currently in clinical development. OX1222 is a dose-ranging study of OXi4503 combined with cytarabine in relapsed/refractory AML and MDS. The poster presented at the 58th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) describes results from the initial two cohorts of OX1222, which represent the lowest doses of OXi4503 in the study.

The first cohort enrolled 6 patients at a dose of 3.75 mg/m2 of OXi4503 in combination with an intermediate dose (1g/m2/day x 5 days) of cytarabine. The second cohort enrolled 4 patients at a dose of 4.68 mg/m2 of OXi4503 in combination with the same intermediate dose of cytarabine. Patients enrolled into OX1222 were treatment-resistant, end-stage AML/MDS patients who had on average four prior therapy failures before entering the study.

In total 2 of 10 (20%) patients achieved a complete remission (CR) on treatment and currently remain in CR without further treatment – one at 6 months and the other at 3 months. One patient of six (17%) responded in the 3.75 mg/m2 dose cohort, and one patient of four (25%) responded in the 4.68 mg/m2 dose cohort. The study is currently enrolling patients in the third cohort at 6.25 mg/m2 of OXi4503.

OXi4503 was generally well tolerated in the first two cohorts of the study. The adverse event profile remains similar to that seen in the monotherapy Phase 1b portion of the trial, with coagulopathies and hematological adverse events the most significant events. The most common drug-related SAEs were anemia (30%), neutropenia (30%), D-dimer increase (20%), thrombocytopenia (20%), and AST increase (20%). One patient in the 3.75 mg/m2 cohort experienced a dose-limiting toxicity of hypofibrinogenemia with no clinical evidence of bleeding, which resolved with treatment.

"I am very excited to see two complete remissions out of the ten patients treated to date, as these were heavily pre-treated patients," stated Tara L. Lin, MD, Associate Professor, Division of Hematologic Malignancies & Cellular Therapeutics, University of Kansas Cancer Center. "Our poster presentation at ASH (Free ASH Whitepaper) concluded that OXi4503 in combination with cytarabine demonstrated preliminary evidence of activity in heavily pretreated relapsed/refractory AML patients and that this combination was generally well tolerated through cohorts 1 and 2. I greatly look forward to seeing the results from additional cohorts as the optimal dose of OXi4503 in combination with cytarabine has yet to be determined."

The poster presentation was entitled "A Phase 1b (OX1222) Dose-Finding Study of OXi4503 Combined with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome" and was presented by Justin M. Watts, MD, Assistant Professor of Clinical Medicine at the University of Miami.

On December 6, 2016 Heat Biologics, Inc. (Nasdaq:HTBX), a leader in the development of gp96-based immunotherapies designed to activate a patient’s immune system to fight cancer, reported topline response and survival results in the ongoing Phase 1b study evaluating HS-110, in combination with Bristol-Myers Squibb’s anti-PD-1 checkpoint inhibitor, nivolumab (Opdivo), for the treatment of non-small cell lung cancer (NSCLC), at the International Association for the Study of Lung Cancer Annual Meeting in Vienna, Austria (Press release, Heat Biologics, DEC 6, 2016, View Source [SID1234516950]).

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In an oral presentation, principal investigator, Daniel Morgensztern, MD, Associate Professor of Medicine and Director of Thoracic Oncology, Washington University School of Medicine, reported that one-year results from the first eight trial patients showed that the HS-110/nivolumab combination was well-tolerated, with a safety profile consistent with single agent nivolumab. There were no additional toxicities seen in HS-110/nivolumab combination compared to existing data on single agent nivolumab alone. HS-110 generated a robust antigen-specific immune response in several patients, consistent with the mechanism of action seen in other HS-110 trials. Additionally, the patients who responded best to the combination therapy (immune responders) had longer overall survival and better objective response rate (ORR) than the non-immune responders, even though they had the same baseline immune function.

Immune responders in the study saw a 50% ORR, while non-immune responders saw a 0% ORR. This is important, as checkpoint inhibitors have been shown, independently, to be much more effective in tumors with pre-existing, high tumor-infiltrating lymphocytes (TIL). As such, there now exists an acute need to address the large proportion of non-responders with low-TIL tumors.

Moreover, the immune responders had a better median overall survival (OS) than non-immune responders. The one-year OS is currently 50% for the responders, and 25% for the non-responders. Finally, immune responders also saw a better median OS at 12.7 months, than non-immune responders, who saw a median OS of 7.1 months. Researchers concluded that immune response may correlate with clinical efficacy and that HS-110 may have synergistic activity with immune checkpoint inhibitors.

"We are encouraged by the data generated in the trial," said Dr. Morgensztern. "We were impressed by the ability of HS-110 to activate a CD8+ T cell immune response. The HS-110/nivolumab combination is worth continued exploration in the treatment of lung cancer, as the HS-110 mechanism of action is potentially synergistic with anti-PD-1 checkpoint inhibitors."

"We’ve continued to see ELISPOT analysis correlate with clinical efficacy with HS-110 in NSCLC, an encouraging trend also observed in other trials with HS-110," said Taylor Schreiber, MD, PhD, Heat’s Chief Scientific Officer. "We are seeing trends between TIL status and TIL increases after treatment among these patients, which may speak to the ability of HS-110 to convert "cold" tumors to "hot" tumors to increase the effectiveness of PD-1 checkpoint therapy in lung cancer."

"These new data are further confirmation of the ability of our ImPACT platform, which has been administered to over 200 patients in 4 clinical studies, to generate a robust antigen-specific immune response, an important component of immunotherapy," said Jeff Wolf, Heat’s CEO. "The future of immuno-oncology lies in combining synergistic modalities to create more effective treatments. At Heat, we are actively pursuing opportunities to combine our ImPACT and ComPACT platforms with checkpoint inhibitors, and other promising immunotherapies to improve patient outcomes."

Heat plans to hold an investor call on December 8th at 8:30 a.m. ET to discuss its overall clinical strategy moving forward. The call will be available on the company’s website at www.heatbio.com, or by calling 866-320-0174 for U.S. callers, or +1 785-424-1631 for international callers. A webcast will also be archived on the company’s website and a telephone replay of the call will be available approximately one hour following the call, through midnight December 15, 2016, and can be accessed by calling: 877-481-4010 (U.S. callers) or +1 919-882-2331 (international callers) and entering conference ID: 10169.

The oral presentation will be uploaded to Heat’s website at View Source in line with the conference’s embargo policy.

On December 6, 2016 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported the results of clinical and translational studies on Iclusig (ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (Press release, Ariad, DEC 6, 2016, View Source;p=RssLanding&cat=news&id=2227822 [SID1234516947]). These data were featured in an oral and two poster presentations at the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) taking place in San Diego.

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"The data presented at ASH (Free ASH Whitepaper) include the final report from the Phase 1 trial of ponatinib, with maximum follow-up of more than 7.5 years and median follow-up approaching five years that demonstrated ongoing cytogenetic and molecular responses. A separate study of CP-CML patients with the T315I mutation demonstrated a 72 percent probability of overall survival at 4.5 years among these patients who, prior to ponatinib, had no approved targeted treatment options and had a median survival of less than two years," stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. "In addition, an oral presentation on studies in Ph+ ALL patients provides important new data on the molecular basis for Iclusig’s activity in these patients."

Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial (Poster, Abstract #92516)

The Phase 1 dose-escalation study of ponatinib (starting dose range: 2 to 60 mg once daily) enrolled 81 patients with resistant or refractory hematologic cancers, including 43 patients with chronic-phase CML (CP-CML). Sixty percent of CP-CML patients in this study had failed at least three prior tyrosine kinase inhibitors (TKIs), and 98 percent received at least two prior TKIs. Data presented at ASH (Free ASH Whitepaper) focus on CP-CML patients and represent the longest follow-up of ponatinib patients to-date, through the termination of the study. Data are as of October 18, 2016 and include:

Median follow-up for CP-CML patients was approaching five years (55.4 months) with the maximum follow-up more than 7.5 years (91.3 months).
The median dose intensity was 26.4 mg/day.
Anti-leukemic activity was observed with ponatinib treatment:
Results showed that 72 percent of CP-CML patients had a major cytogenetic response (MCyR), 65 percent had a complete cytogenetic response (CCyR) and 56 percent had a major molecular response (MMR), a key secondary endpoint deeper than cytogenetic response.
Of note, 44 percent of CP-CML patients achieved MR4, 33 percent achieved MR4.5, and 26 percent achieved MR5; MR4, MR4.5 and MR5 are deeper levels of molecular response than MMR.
The median time to MCyR, CCyR and MMR was 2.8, 5.5 and 7.4 months, respectively.
By Kaplan-Meier analysis, among those who achieved response, median duration of MMR was 27.1 months. Median durations of MCyR, CCyR were not reached.
In 12 patients with the T315I mutation, MCyR was reported in 11 (92%) patients, CCyR in 10 (83%) patients and MMR in nine (75%) patients. In 15 patients with other mutations, MCyR was reported in 10 (67%) patients, CCyR in 10 (67%) patients and MMR in eight (53%) patients.
By Kaplan-Meier analysis, the probability of CP-CML patients maintaining MCyR at four years was estimated as 72 percent.
Ten of the 15 CP-CML patients (67%) who started ponatinib at a dose of 30 mg or less achieved MCyR, comparable to the overall response rate of 72 percent. The MCyR, CCyR and MMR rates in patients who received a starting dose of 30 mg/day or less were consistent with the corresponding response rates in the overall population.
The most common treatment-emergent adverse events (AEs) occurring in CP-CML patients were rash (65%), fatigue (63%), abdominal pain (58%), headache (58%), and arthralgia (53%). When analyzed by year, most adverse events occurred in the first year of treatment.
Forty-four percent (19/43) of CP-CML patients experienced any treatment-emergent arterial occlusive events (AOEs), of which 16 (37%) were serious adverse events (SAEs). Three venous thrombotic events (VTEs) and one serious venous thrombotic event were reported.
Long-Term Follow-up of the Efficacy and Safety of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Mutation (Poster, Abstract #93206)

The analysis describes the pooled efficacy and safety of ponatinib in patients with a T315I mutation detected at baseline from final report of the Phase 1 dose-escalation study and the four-year median follow-up of the Phase 2 PACE trial. The analysis includes 76 CP-CML patients with T315I from the Phase 1 trial (n=12) and the PACE trial (n=64). In this analysis, 26 (34%) patients remained on the study, as the Phase 1 study is no longer ongoing. Data presented on these patients are as of October 18, 2016 for the Phase 1 trial and August 3, 2015 for the PACE trial. Key data include:

Median follow-up for patients in this analysis was 40.3 months, with maximum follow-up of 91.4 months (7.6 years).
Among these CP-CML patients with T315I mutations, 50 percent had received treatment with two prior TKIs, and 26 percent had three or more prior TKIs. Overall, CP-CML patients with T315I at baseline in PACE were younger, less heavily treated, and had a shorter time since diagnosis, as compared with the non-T315I CP-CML population in PACE.
Responses continue to be observed in CP-CML patients with T315I patients treated with ponatinib at four years. In the combined analysis of these patients from both trials:
75 percent (57/76) of T315I+ CP-CML patients achieved MCyR, 72 percent achieved CCyR, and 61 percent achieved MMR.
By Kaplan-Meier estimate, 83 percent of patients with response were estimated to maintain MCyR at four years, and 81 percent were estimated to maintain CCyR at four years. The median duration of response has not yet been reached.
The probability for overall survival in CP-CML patients with T315I in PACE at 4.5 years was 72 percent.
The most common treatment-emergent AEs in T315I+ CP-CML patients were rash (55%), dry skin (49%), headache (46%), abdominal pain (43%), fatigue (41%), and nausea (41%). The most common serious treatment-emergent AEs were pancreatitis (9%), myocardial infarction (8%) and coronary artery disease (7%). The safety profile of ponatinib in CP-CML patients with the T315I mutation was comparable to that observed among all CP-CML patients in the Phase 1 and PACE trials.
Thirty-three percent (25/76) of CP-CML patients with T315I experienced treatment-emergent AOEs, and seven percent experienced a VTE. Incidences of AOEs and VTEs in patients with the T315I mutation were similar to those observed in the overall patient population.
Analysis of the Sub-Clonal Origins of Compound Mutations in Patients with Refractory Ph+ Malignancies Treated with Ponatinib (Oral Presentation, Abstract #93238)

In order to analyze the sub-clonal origins of compound mutations, this study profiled potential compound mutational mechanisms using samples from CP-CML and Ph+ ALL patients in the PACE trial. Utilizing a multi-level sequencing strategy that combined Sanger Sequencing (SS), Next Generation Sequencing (NGS), and single molecule Duplex Sequencing (DS), which is more sensitive than NGS, this study utilized mutation burdens and patient specific clinical data to predict the extent of pre-existing mutations. Key data include:

In the PACE study, ponatinib induced high rates of major hematological response (MaHR) and MCyR in Ph+ ALL patients (41% and 47%), even though 91 percent of these patients had received at least two prior TKIs. For these patients, median progression-free survival (PFS) was three months for Ph+ ALL patients.
In TKI refractory patients treated with ponatinib, Ph+ ALL patients gained BCR-ABL compound mutants at end of treatment (EOT) more often than CP-CML patients.
At least 12/20 (60%) Ph+ ALL patients had compound mutations at EOT. In CP-CML patients 4/130 (3%) patients had these compound mutations at EOT.
Direct DS measurements and patient-specific clinical data predict that all resistance mutations in the kinase domain of BCR-ABL are likely to exist before the initiation of ponatinib treatment.
Refractory Ph+ ALL has a higher mutation burden, and a higher leukemia re-initiating fraction, which likely explains the clinical propensity in Ph+ ALL to relapse with on-target mutations as compared to CP-CML. This mutation burden is added to resistance mutations that were already acquired on prior TKI therapy.
Previous TKI failure selects for BCR-ABL mutations in Ph+ ALL and appears to limit the duration of response to ponatinib in Ph+ ALL through the development of compound mutations.
Coupled with estimates of leukemia initiating cell fractions, these data estimate the clinical propensity of Ph+ ALL to acquire on-target mutations. These findings provide a molecular hypothesis for the observation that Ph+ ALL patients treated with ponatinib in the front-line had estimated 80 percent overall survival (OS) at three years, as published in The Lancet Oncology1.
About Iclusig (ponatinib) tablets
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD’s computational and structure-based drug-design platform specifically to inhibit the activity of BCR-ABL. Iclusig targets not only native BCR-ABL but also its isoforms that carry mutations that confer resistance to treatment, including the T315I mutation, which has been associated with resistance to other approved TKIs. Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel, Canada and Japan.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL.
Limitations of use:

Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML.

IMPORTANT SAFETY INFORMATION
Based on the Phase 2 48 mo. follow-up analysis (N=449), except where noted

IMPORTANT U.S. SAFETY INFORMATION, INCLUDING THE BOXED WARNING
WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Arterial occlusion has occurred in at least 35% of Iclusig (ponatinib)-treated patients including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Interrupt or stop Iclusig immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart Iclusig.
Venous Thromboembolism has occurred in 6% of Iclusig-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.
Heart Failure, including fatalities occurred in 9% of Iclusig treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.
Warnings and Precautions

Arterial Occlusions: Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease have occurred in at least 35% of Iclusig-treated patients from the phase 1 and phase 2 trials. In the phase 2 trial, 33% (150/449) of Iclusig-treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of event. Fatal and life-threatening events have occurred within 2 weeks of starting treatment, with doses as low as 15 mg per day. Iclusig can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures. The median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193, 526, and 478 days, respectively. Patients with and without cardiovascular risk factors, some age 50 years or younger, experienced these events. The most common risk factors observed with these events were hypertension, hyperlipidemia, and history of cardiac disease. Arterial occlusive events were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hyperlipidemia. In patients suspected of developing arterial occlusive events, interrupt or stop Iclusig.

Venous Thromboembolism: Venous thromboembolic events occurred in 6% (25/449) of Iclusig-treated patients with an incidence rate of 5% (13/270 CP-CML), 4% (3/85 AP-CML), 10% (6/62 BP-CML) and 9% (3/32 Ph+ ALL). Events included: deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis with vision loss. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure: Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of Iclusig-treated patients (29/449). Nine percent of patients (39/449) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (14 patients each; 3%). Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation if serious heart failure develops.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in a patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ ALL. Severe hepatotoxicity occurred in all disease cohorts, with 11% (50/449) experiencing grade 3 or 4 hepatotoxicity. The most common forms of hepatotoxicity were elevations of AST or ALT (54% all grades, 8% grade 3 or 4, 5% not reversed at last follow-up), bilirubin, and alkaline phosphatase. Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of Iclusig-treated patients. Fifty-three patients (12%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension, 37% developed Stage 2 hypertension. In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

Pancreatitis: Pancreatitis occurred in 7% (31/449, 6% serious or grade 3/4) of Iclusig-treated patients. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater). Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449). The median time to onset of pancreatitis was 14 days. Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with chronic phase (CP) CML, single agent Iclusig 45 mg once-daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once-daily. The median exposure to treatment was less than 6 months. The trial was halted for safety in October 2013. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 20% (90/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%, 19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, 10/449), muscular weakness (2% 10/449) and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 2% (10/449) of Iclusig-treated patients (<1%, 3/449 – grade 3/4). Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of Iclusig-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with Iclusig. Hemorrhage occurred in 28% (124/449) of patients. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449) each. Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with Iclusig. One instance of brain edema was fatal. For fluid retention events occurring in >2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, <1%).

In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac arrhythmias: Arrhythmias occurred in 19% (86/449) of Iclusig-treated patients, of which 7% (33/449) were grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being grade 3 or greater. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients.

Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%). For 27 patients, the event led to hospitalization.

In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt Iclusig and evaluate.

Myelosuppression: Myelosuppression was reported as an adverse reaction in 59% (266/449) of Iclusig-treated patients and grade 3/4 myelosuppression occurred in 50% (226/449) of patients. The incidence of these events was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML.
Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range <1-40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%, one with AP-CML and one with BP-CML) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (31/449) of patients. Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Postmarketing cases of reversible posterior leukoencephalopathy syndrome (RPLS—also known as Posterior Reversible Encephalopathy Syndrome (PRES)) have been reported in Iclusig-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present and diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. If RPLS is diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, Iclusig can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose.

Most Common Adverse Reactions: Overall, the most common non-hematologic adverse reactions (≥20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.

Please see the full U.S. Prescribing Information for Iclusig, including the Boxed Warning.

Iclusig is a registered trademark of ARIAD Pharmaceuticals, Inc.

On December 6, 2016 Celgene Corporation (NASDAQ:CELG) reported interim results from the ABOUND clinical trial program evaluating the use of ABRAXANE (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) in patients with advanced non-small cell lung cancer (NSCLC) (Press release, Celgene, DEC 6, 2016, View Source [SID1234516944]). Interim data being presented from the ABOUND trials during the IASLC 17th World Conference on Lung Cancer (WCLC) reinforces the benefit of ABRAXANE/carboplatin doublet therapy in first-line NSCLC.

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Interim ABOUND.70+ data in 128 elderly patients (≥ 70 years old) receiving first-line treatment with ABRAXANE/carboplatin for advanced NSCLC found that 91 (73%) patients experienced grade ≥2 peripheral neuropathy (PN) or grade ≥3 myelosuppression [primary endpoint]. At the time of the analyses, the median overall survival was 14.6 months and the median progression-free survival was 6.2 months, pooled across the two treatment arms [secondary endpoints]. Patients were randomized to receive first-line treatment with ABRAXANE/carboplatin either continuous weekly or weekly every three weeks with a one-week break.i Overall, 80 percent of patients discontinued treatment and the majority did so due to adverse events (24 percent) or disease progression (34 percent). Grade ≥2 PN was reported in 34% of patients, and grade ≥3 neutropenia, anemia, and thrombocytopenia was observed in 52%, 21% and 21% of patients, respectively. i

The interim ABOUND.sqm data in 284 patients receiving first-line induction treatment with ABRAXANE/carboplatin for stage IIIB/IV squamous NSCLC showed that the safety profile was consistent with that previously reported for the squamous subset in the pivotal Phase III trial.ii,iii During the induction phase, all patients received four 21-day cycles of standard ABRAXANE/carboplatin therapy.ii Overall, 119 patients (42 percent) discontinued treatment during the induction phase. The majority of patients discontinued treatment due to disease progression (34 percent) or adverse events (24 percent). The most common grade 3/4 treatment emergent adverse events (TEAEs) were hematologic and included anemia (26 percent), neutropenia (43 percent) and thrombocytopenia (15 percent).ii

Both ABOUND trials also evaluated quality of life utilizing the Lung Cancer Symptom 3-item index Scale (LCSS), Symptom Burden Index, Lung Cancer Symptom and Pulmonary Symptom Scores and the EuroQol five dimensions, five level questionnaire (EQ-5D-5L). These interim analyses suggest that quality of life was generally maintained or improved in both patient populations.iv,v

"These early data from the ABOUND clinical trial program are very encouraging, as they are consistent with the findings related to these hard to treat non-small cell lung cancer patient subgroups seen in the pivotal ABRAXANE Phase III trial," said Michael Pehl, President, Hematology and Oncology for Celgene. "These data, coupled with the ongoing studies of ABRAXANE in combination with novel agents and immunotherapies, provide us with a deeper understanding of how to treat challenging patient populations and will help us continue to develop future treatment options."

With the rapidly evolving lung cancer treatment landscape, Celgene remains committed to continuing to explore new combinations that will benefit those living with lung cancer, including patients who may not benefit from immunotherapy and targeted therapy. ABRAXANE is being actively evaluated as a foundation therapy in these patients.

Interim results of the phase I study of the immunotherapy agent nivolumab in combination with ABRAXANE/carboplatin in 22 patients with Stage IIIB/IV NSCLC will also be presented at WCLC. Patients received four cycles of standard ABRAXANE/carboplatin therapy in combination with nivolumab, followed by nivolumab monotherapy starting at cycle 5. The primary endpoints were number of patients with dose limiting toxicity and percentage of patients with grade 3/4 TEAEs or treatment discontinuation due to a TEAE. The interim data suggests that combining ABRAXANE/carboplatin with nivolumab may have promising anti-tumor activity in patients with advanced NSCLC with no unexpected adverse events (AEs).vi

The most common grade 3/4 AEs observed during the study included neutropenia (45 percent), anemia (35 percent), hypokalemia (15 percent), and vomiting (15 percent).vi The study has been expanded and patients are currently enrolling in part 2. Additional data on the safety and efficacy of this combination in multiple tumor types will be presented at a future medical meeting.

Additional ABRAXANE Data Presented at WCLC

There will also be an oral presentation at WCLC focused on new findings from the phase III registration study for ABRAXANE (Abstract 4460), which reports on the impact of depth of response on survival in patients with advanced NSCLC treated with first-line chemotherapy. Real-world analyses of US veterans with NSCLC are also being presented at WCLC, evaluating prevalence of squamous NSCLC in veterans vs. the general population (Abstract 4737) and the prevalence of autoimmune disease in veterans with NSCLC (Abstract 4745).

Additional investigator initiated studies presented at WCLC also evaluated ABRAXANE as first-line (Posters P2.03a-028 and P2.06-018), second-line (Posters P2.03a-040, P2.03a-054 and P2.03a-056) or third-line (Poster P2.06-015) treatment for advanced NSCLC patients, as well as in the adjuvant (Poster P2.03a-070) and neoadjuvant (Poster P2.04-034) settings and in chemo-naïve patients with an EGFR mutation (Poster P3.02b-061).

ABOUT ABOUND

ABOUND is a multi-phase, open-label, multicenter clinical trial program evaluating the use of ABRAXANE in combination with carboplatin or other novel agents, including immunotherapy, as first- or second-line treatment of patients with advanced non-small cell lung cancer (NSCLC). The ABOUND trials included patients 70 years and older, as well as those with poorer performance status or squamous disease and those receiving second-line+ treatment.vii,viii,ix,x

ABOUT THE ABRAXANE/NIVOLUMAB STUDY

This is a phase I, open-label, multicenter, safety study of ABRAXANE-based chemotherapy regimens administered prior to and/or in combination with nivolumab in pancreatic cancer, NSCLC and metastatic breast cancer. This is a six arm study assessing two treatment arms per tumor-type/indication.

About ABRAXANE (nab-paclitaxel)

ABRAXANE is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.

Important Safety Information

WARNING – NEUTROPENIA

Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE
Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS
CONTRAINDICATIONS

Neutrophil Counts

ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1500cells/mm3
Hypersensitivity

Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug
WARNINGS AND PRECAUTIONS

Hematologic Effects

Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 47% of patients with non-small cell lung cancer (NSCLC)
Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15
Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3
In the case of severe neutropenia ( < 500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, reduce the dose of ABRAXANE in subsequent courses in patients with NSCLC
Resume treatment if recommended at permanently reduced doses for both weekly ABRAXANE and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle
Nervous System

Sensory neuropathy is dose- and schedule-dependent
The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification
If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE
Hypersensitivity

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported
Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug
Hepatic Impairment

Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution
Patients with hepatic impairment may be at an increased risk of toxicity, particularly from myelosuppression, and should be monitored for development of profound myelosuppression
For NSCLC, the starting dose should be reduced for patients with moderate or severe hepatic impairment
Albumin (Human)

ABRAXANE contains albumin (human), a derivative of human blood
Use in Pregnancy: Pregnancy Category D

ABRAXANE can cause fetal harm when administered to a pregnant woman
If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE
Use in Men

Men should be advised not to father a child while receiving ABRAXANE
ADVERSE REACTIONS

Non-Small Cell Lung Cancer (NSCLC) Study

The most common adverse reactions (≥20%) of ABRAXANE in combination with carboplatin are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue
The most common serious adverse reactions of ABRAXANE in combination with carboplatin for NSCLC are anemia (4%) and pneumonia (3%)
The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%)
The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (24%), thrombocytopenia (13%), and anemia (6%)
The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%)
The following common (≥10% incidence) adverse reactions were observed at a similar incidence in ABRAXANE plus carboplatin-treated and paclitaxel injection plus carboplatin-treated patients: alopecia (56%), nausea (27%), fatigue (25%), decreased appetite (17%), asthenia (16%), constipation (16%), diarrhea (15%), vomiting (12%), dyspnea (12%), and rash (10%); incidence rates are for the ABRAXANE plus carboplatin treatment group
Adverse reactions with a difference of ≥2%, Grade 3 or higher, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (28%, 7%), neutropenia (47%, 58%), thrombocytopenia (18%, 9%), and peripheral neuropathy (3%, 12%), respectively
Adverse reactions with a difference of ≥5%, Grades 1-4, with combination use of ABRAXANE and carboplatin vs combination use of paclitaxel injection and carboplatin in NSCLC are anemia (98%, 91%), thrombocytopenia (68%, 55%), peripheral neuropathy (48%, 64%), edema peripheral (10%, 4%), epistaxis (7%, 2%), arthralgia (13%, 25%), and myalgia (10%, 19%), respectively
Neutropenia (all grades) was reported in 85% of patients who received ABRAXANE and carboplatin vs 83% of patients who received paclitaxel injection and carboplatin
Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied
There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs
There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration
DRUG INTERACTIONS

Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4
USE IN SPECIFIC POPULATIONS

Nursing Mothers

It is not known whether paclitaxel is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
Pediatric

The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated
Geriatric

Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients ≥65 years of age treated with ABRAXANE and carboplatin in NSCLC
Renal Impairment

There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance < 30 mL/min)
DOSAGE AND ADMINISTRATION

Do not administer ABRAXANE to any patient with total bilirubin greater than 5 x ULN or AST greater than 10 x ULN
Reduce starting dose in NSCLC patients with moderate to severe hepatic impairment
Dose reductions or discontinuation may be needed based on severe hematologic or neurologic toxicity
Monitor patients closely
Please see full Prescribing Information, including Boxed WARNING.

Please refer to the Summary of Product Characteristics for full European prescribing information.