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Momenta Pharmaceuticals Announces Presentation of Final Data from Phase 1 Trial of Necuparanib in Patients with Pancreatic Cancer at ASCO

On June 04, 2016 Momenta Pharmaceuticals, Inc. (NASDAQ:MNTA), a biotechnology company specializing in the characterization and engineering of complex drugs, reported final data from the Phase 1 trial evaluating necuparanib in combination with nab-paclitaxel (nabP; Abraxane) and gemcitabine (gem) in patients with advanced metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) at the 2016 ASCO (Free ASCO Whitepaper) Annual Meeting, from 8:00 to 11:30 am CDT (Abstract #4117 / Poster #109) in Chicago, IL (Press release, Momenta Pharmaceuticals, JUN 4, 2016, View Source [SID:1234513080]).

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"The final data read out from the Phase 1 study continues to show favorable tolerability and promising antitumor activity as assessed by survival and response data," said Eileen O’Reilly, MD of David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center and lead author on the poster. "We also continued to see a clinically meaningful reduction in levels of CA19.9, a predictive biomarker that often correlates with the long-term outcome and response to treatment in pancreatic cancer patients."

Necuparanib was administered daily in combination with 125 mg/m2 nabP and 1000 mg/m2 gem (Days 1, 8, and 15 of each 28-day cycle). The necuparanib starting dose was 0.5 mg/kg, which was increased until the maximum tolerated dose of 5 mg/kg was determined. nabP was added to the treatment regimen starting with the third cohort. Thirty-nine patients (12 patients in the first two cohorts and 27 patients in the five subsequent cohorts) received necuparanib and were included in the analyses. Top-line results included:

Necuparanib was well tolerated when added to standard of care; no increases in incidence, severity, or duration for known adverse events of gem or nabP + gem were observed when combined with necuparanib.
Measurable levels of necuparanib were seen starting at the 2 mg/kg dose group. Release of heparin-binding protein (a pharmacodynamic marker) increased with increasing doses and plateaued at 4-5 mg/kg.
Encouraging signals of activity were observed:
16 patients treated with necuparanib + nabP + gem completed Cycle 1 and had ≥1 scan on treatment; 9 (56%) achieved RECIST partial response (PR) and 5 (31%) achieved stable disease, for a disease control rate (DCR) of 14/16 (88%); median OS in this subset was 15.6 months. Median OS of patients treated with ≥1 dose of necuparanib + nabP + gem (n=24) was 13.1 months.
24-month survival rates for patients treated with ≥1 cycle and ≥1 dose of necuparanib + nabP + gem were 25% and 21%, respectively.
Of 15 CA19.9 evaluable patients, 15 (100%) had ≥20%, 14 (93%) had ≥50%, and 7 (47%) had ≥90% decreases from baseline.
"We continue to be encouraged by these data from our lead novel drug candidate, and look forward to completing enrollment of the Phase 2 study over the next several months," said Jim Roach, M.D., Senior Vice President of Development and Chief Medical Officer of Momenta Pharmaceuticals. "We expect to report key results from the Phase 2 study in the second half of 2017."

About Necuparanib
Necuparanib (M402) is a novel oncology drug candidate engineered to have a broad range of effects on tumor cells. The use of heparins to treat venous thrombosis in cancer patients has generated numerous reports of antitumor activity; however, the dose of these products has been limited by their anticoagulant activity. Leveraging its experience in deciphering the structure-function relationships of complex therapeutics, Momenta engineered necuparanib from unfractionated heparin to have significantly reduced anticoagulant activity while preserving relevant antitumor properties associated with heparins. A Phase 2, randomized, double-blind, controlled study in pancreatic cancer is ongoing, which will evaluate the antitumor activity of necuparanib in combination with nab-paclitaxel (Abraxane) plus gemcitabine, versus nab-paclitaxel plus gemcitabine alone. Necuparanib has received Orphan Drug and Fast Track designations from the U.S. Food and Drug Administration (FDA) for the treatment of pancreatic cancer.

Novartis data show more than 50 percent of eligible Ph+ CML patients maintain Treatment-free Remission (TFR) after stopping Tasigna®

On June 4, 2016 Novartis reported at the 52nd American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, the first results from the Tasigna (nilotinib) Treatment-free Remission (TFR) clinical trial program (Press release, Novartis, JUN 4, 2016, View Source [SID:1234513052]). These studies evaluated the potential to maintain molecular response (MR) after stopping therapy in adult patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase who achieved a sustained deep level of molecular response with Tasigna – a concept called TFR[3]. Findings from two open label trials, ENESTfreedom and ENESTop, showed that more than 50% of Ph+ CML patients who met the rigorous predefined response criteria of the trials were able to maintain TFR after stopping Tasigna both in the first-line setting and after switching from Glivec (imatinib)*[1],[2]. Discussions with regulatory authorities are underway with potential submissions in 2016.

Results from the ENESTfreedom study found that more than half (51.6%) of 190 CML patients (confidence interval [CI] 95%: 44.2%-58.9%) who achieved a sustained deep molecular response following at least three years of first-line treatment with Tasigna were able to discontinue therapy and remain in TFR for 48 weeks[1]. ENESTfreedom did not meet its primary objective, the percentage of patients in major molecular response (MMR; BCR-ABL1 International Scale [IS] <= 0.1%) at 48 weeks in the TFR phase, per the original statistical assumption that the lower limit of the 95% CI will be equal to or greater than 50%[1]. The median treatment duration in this trial was 3.6 years which is a short length of tyrosine kinase inhibitor (TKI) exposure prior to attempting TFR. Of the 86 patients who restarted treatment with Tasigna due to loss of MMR, 98.8% were able to regain MMR (n=85) and 88.4% were able to regain MR4.5 (BCR-ABL1 IS <= 0.0032%; n=76) [1]. By weeks 7.9 and 15.0 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MMR and MR4.5, respectively1. One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with Tasigna[1].

"ENESTfreedom is the first trial to show that, after a short treatment duration with nilotinib of 3.6 years, more than 50 percent of patients who stopped therapy were able to remain treatment-free at 48 weeks," said Dr. Andreas Hochhaus, Head of the Department of Hematology and Medical Oncology, Jena University Hospital, Germany, and primary investigator for the ENESTfreedom study. "Findings from the nilotinib TFR trials add to the existing body of research exploring the discontinuation of tyrosine kinase inhibitor treatment in CML and may help to establish safe and appropriate criteria for eligible patients to stop treatment[1],[2],[3]."

ENESTop, the second Novartis TFR trial at ASCO (Free ASCO Whitepaper), evaluated 126 patients who were able to achieve a sustained deep molecular response with Tasigna, but not with prior Glivec therapy[2]. In this trial, nearly 6 out of 10 (57.9%) patients (95% CI: 48.8%-66.7%) who achieved a sustained deep molecular response following at least three years of Tasigna therapy maintained a molecular response 48 weeks after stopping treatment[2]. The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 (BCR-ABL1 IS <= 0.01%) or loss of MMR within 48 weeks of Tasigna discontinuation in the TFR phase[2]. In the study, 51 patients with confirmed loss of MR4.0 or loss of MMR restarted Tasigna[2]. Of these patients, 98.0% (n=50) regained at least MMR, with 94.1% (n=48) and 92.2% (n=47) regaining MR4.0 and MR4.5, respectively[2]. By weeks 12.0 and 13.1 of treatment reinitiation with Tasigna, 50% of retreated patients already achieved MR4.0 and MR4.5, respectively[2]. One patient entered the treatment reinitiation phase but did not regain MMR by 20 weeks and discontinued the study. The BCR-ABL1 for this patient was 62.2% at the start of Tasigna retreatment and 9.8% at study exit[2].

"Novartis has been at the forefront of advancements in the treatment and understanding of CML for 20 years," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "The exploration of TFR in patients treated with Tasigna, which includes Novartis support of eight TFR studies, is the next step in our commitment to advancing care for patients living with this disease."

Results from ENESTfreedom were presented today in an oral session (Abstract #7001, 3:12 p.m. CDT) at ASCO (Free ASCO Whitepaper) in Chicago. Data from ENESTop will be presented in a poster session on June 6 (Abstract #7054, 8:00-11:00 a.m. CDT). Both studies are ongoing, with planned follow-up to evaluate the ability of patients to sustain remission for longer durations following discontinuation of Tasigna. These are the first presentations of data from the Novartis Tasigna TFR clinical trial program.

An important part of the Tasigna TFR studies is regular and frequent molecular monitoring with a well-validated assay able to measure BCR-ABL transcript levels down to MR4.5. Frequent patient monitoring during TFR allows timely determination of loss of MR4.0 and MMR and need for treatment initiation[1],[2].

No new major safety findings were observed in these studies in patients treated with Tasigna beyond those in the known safety profile of Tasigna[1],[2]. In ENESTfreedom, 24.7% of patients experienced musculoskeletal pain during the first year of the TFR phase versus 16.3% while still taking Tasigna in the one-year consolidation phase[1]. In ENESTop, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking Tasigna in the consolidation phase[2]. No patients progressed to advance phase/blast crisis in the two studies[1],[2].

Stopping CML treatment is currently not a clinical recommendation and should only be attempted in the context of a clinical study. Discontinuation of treatment in ENESTfreedom and ENESTop was conducted under the conditions of the trials and in patients who met the rigorous predefined criteria of the trials[1],[2].

Novartis commitment to CML
Novartis is supporting eight studies as part of its TFR clinical trial program, which includes ENESTfreedom and ENESTop, as well as two other ongoing company-sponsored TFR studies and four investigator-initiated studies that are now underway in more than 100 global sites across 40 countries. Over the past several decades, Novartis research in Ph+ CML has helped transform the disease from a fatal leukemia to a chronic condition and, today, the company continues its long-standing commitment to the global CML community. Novartis follows the science and builds upon existing evidence to explore what could be the next major contribution in the treatment of Ph+ CML through these TFR trials as well as investigational compounds.

About ENESTfreedom
ENESTfreedom (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Following REsponsE in De nOvo CML-CP Patients) is an open label Phase II study involving 215 Ph+ CML patients in the chronic phase, conducted at 132 sites across 19 countries. ENESTfreedom evaluated stopping treatment in 190 adults with Ph+ CML after the patients had achieved a response of MR4.5 with Tasigna and a sustained deep molecular response for one year as a first-line treatment.

About ENESTop
ENESTop (Evaluating Nilotinib Efficacy and Safety Trial) is an open label Phase II study involving 163 Ph+ CML patients, conducted at 63 sites across 18 countries. The trial evaluated stopping treatment in 126 adults with Ph+ CML in the chronic phase after patients had achieved and sustained deep molecular response for one year with Tasigna following Glivec.

About Tasigna (nilotinib)
Tasigna (nilotinib) is approved in more than 122 countries for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to at least one prior therapy, including Glivec (imatinib), and in more than 120 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.

IMPORTANT SAFETY INFORMATION for TASIGNA (nilotinib) Capsules
Use with caution in patients with uncontrolled or significant cardiac disease and in patients who have or may develop prolongation of QTc. Low levels of potassium or magnesium must be corrected prior to Tasigna administration. Monitor closely for an effect on the QTc interval. Baseline ECG is recommended prior to initiating therapy and as clinically indicated. Cases of sudden death have been reported in clinical studies in patients with significant risk factors. Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors. Avoid food 2 hours before and 1 hour after taking dose. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Use with caution in patients with liver impairment, with a history of pancreatitis and with total gastrectomy. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not use Tasigna. Tasigna may cause fetal harm in pregnant women. Women taking Tasigna should not breastfeed.

Cases of cardiovascular events included ischemic heart disease-related events, peripheral arterial occlusive disease, and ischemic cerebrovascular events have been reported. Serious cases of hemorrhage from various sites including gastrointestinal were reported in patients receiving Tasigna. Grade 3 or 4 fluid retention including pleural effusion, pericardial effusion, ascites and pulmonary edema have been reported. Cases of tumor lysis syndrome have been reported in Tasigna-treated patients who were resistant or intolerant to prior CML therapy.

The most frequent Grade 3 or 4 adverse events are hematological (neutropenia, thrombocytopenia, anemia) which are generally reversible and usually managed by withholding Tasigna temporarily or dose reduction. Chemistry panels, including electrolytes, lipid profile, liver enzymes, and glucose should be checked prior to therapy and periodically. Tasigna can cause increases in serum lipase. The most frequent non-hematologic adverse events were rash, pruritus, nausea, fatigue, headache, alopecia, myalgia, constipation and diarrhea.

Please see full Prescribing Information including Boxed WARNING at www.tasigna.com (link is external).

About Glivec (imatinib)
Glivec (imatinib) is approved in more than 110 countries, for the treatment of adult patients in all phases of Ph+ CML, for the treatment of patients with KIT (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST.

Not all indications are available in every country.

Glivec Important Safety Information
Glivec is contraindicated in patients who are hypersensitive to imatinib or any of the excipients.

Glivec can cause fetal harm when administered to a pregnant woman. Women should not become pregnant, and should be advised of the potential risk to the unborn child.

Glivec has been associated with severe edema (swelling) and serious fluid retention. Cytopenias (anemia, neutropenia, thrombocytopenia) are common, generally reversible and usually managed by withholding Glivec or dose reduction. Monitor blood counts regularly. Severe congestive heart failure and left ventricle dysfunction, severe liver problems including cases of fatal liver failure and severe liver injury requiring liver transplants have been reported. Caution in patients with cardiac dysfunction and hepatic dysfunction. Monitor carefully. Reactivation of hepatitis B can occur in patients who are chronic carriers of this virus after receiving TKI treatment.

Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with KIT+ GIST. Skin reactions, hypothyroidism in patients taking levothyroxine replacement, GI perforation, in some cases fatal, tumor lysis syndrome which can be life threatening have also been reported with Glivec. Correct dehydration and high uric acid levels prior to treatment. Long-term use may result in potential liver, kidney, and/or heart toxicities; immune system suppression may also result from long-term use. In patients with hypereosinophilic syndrome and heart involvement, cases of heart disease have been associated with the initiation of Glivec therapy. Growth retardation has been reported in children taking Glivec. The long-term effects of extended treatment with Glivec on growth in children are unknown.

The most common side effects include fluid retention, muscle cramps or pain and bone pain, abdominal pain, loss of appetite, vomiting, diarrhea, decreased hemoglobin, abnormal bleeding, nausea, fatigue and rash. Glivec should be taken with food and a large glass of water.

Please see full Prescribing Information available at www.glivec.com (link is external).

New Data Evaluating KEYTRUDA® (pembrolizumab) in Combination with Chemotherapy for First-Line Treatment of Non-Small Cell Lung Cancer Demonstrate Response Rates Ranging from 48 to 71 Percent

On June 4, 2016 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported findings from an initial proof-of-concept study of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, combined with standard treatments, one with bevacizumab and others without, in non-small cell lung cancer (NSCLC) including chemotherapy in previously untreated patients with NSCLC; the study showed overall response rates (ORR) ranging from 48 to 71 percent, depending on the therapy used (Press release, Merck & Co, JUN 4, 2016, View Source [SID:1234513047]). These data, from the phase 1/2 KEYNOTE-021 trial, will be presented today at the 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) by Dr. Shirish Gadgeel of the Barbara Ann Karmanos Cancer Institute (Abstract #9016) from 8:00 – 11:30 a.m. CDT (Location: Hall A) and in a poster discussion from 3:00 – 4:15 p.m. CDT (Location: E354b).

"Combining KEYTRUDA and chemotherapy in the first-line lung cancer treatment setting is an important part of our effort to develop more treatment options for patients with non-small cell lung cancer," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "This study has helped us to identify chemotherapy options for combination with KEYTRUDA regardless of PD-L1 expression to take forward in phase 3 trials."

The findings presented at ASCO (Free ASCO Whitepaper) 2016 were based on 74 patients who were treated with KEYTRUDA and one of three different chemotherapy regimens in the phase 1b portion of the study. The data, across all three cohorts including patients with and without PD-L1 tumor expression, showed an ORR of 57 percent (n=42/74, 95% CI, 45-68), including one complete response and 41 partial responses. Median duration of follow-up was 12 months (range <1-21).

"These results are encouraging because they provide initial evidence that adding chemotherapy to KEYTRUDA may increase response rates and open new treatment paths for a broader range of patients with advanced non-small cell lung cancer," said Dr. Gadgeel, professor, leader of the multidisciplinary thoracic oncology team, Karmanos Cancer Institute/Wayne State University in Detroit.

The highest response rates were observed in a group of 24 patients who received KEYTRUDA (pembrolizumab) in combination with carboplatin plus pemetrexed (Cohort C), with an ORR of 71 percent (n=17/24, 95% CI, 49-87), including one complete response and 16 partial responses. In this same group, median progression-free survival (PFS) was 10.2 months (95% CI, 6.3-15.2), and median overall survival (OS) was not reached (95% CI, 13.9-NR). Median duration of follow-up was 16 months (range 4-21).

In the group that received KEYTRUDA plus carboplatin and paclitaxel (Cohort A), ORR was 52 percent (n=13/25, 95% CI, 31-72) and all responses were partial responses. Median PFS in this cohort was 10.3 months (95% CI, 3.7-NR), and median OS was not reached (95% CI, 11.0-NR). Median duration of follow-up was 13 months (range 2-21).

In the cohort that received KEYTRUDA in addition to carboplatin, paclitaxel, and bevacizumab (Cohort B), ORR was 48 percent (n=12/25, 95% CI, 28-69) and all responses were partial responses. Median PFS was not reached (95% CI, 4.1-NR), and median OS was not reached (95% CI, NR-NR). Median duration of follow-up was 9 months (range <1-17).

Overall Response Rates by Cohort

ORR (confirmed),
% (n) [95% CI]

Cohort A
(KEYTRUDA +
carboplatin and
paclitaxel)
N=25

Cohort B
(KEYTRUDA +
carboplatin,
paclitaxel, and
bevacizumab)
N=25

Cohort C
(KEYTRUDA +
carboplatin and
pemetrexed)
N=24

All Patients
N=74

Total Population 52% (13)
[31-72]
48% (12)
[28-69]
71% (17)
[49-87]
57% (42)
[45-68]
Complete
Response
0 0 4% (1) 1% (1)
Partial Response 52% (13) 48% (12) 67% (16) 55% (41)
Median duration
of follow-up
13 months
(range 2-21)
9 months
(range <1-17)
16 months
(range 4-21)
12 months
(range <1-21)
Responses were seen across all levels of PD-L1 expression, including in patients with PD-L1 negative tumors. PD-L1 levels assessed included high expression (tumor proportion score [TPS] of greater than or equal to 50 percent), any expression (TPS of greater than or equal to 1 percent), and negative expression (PD-L1 of less than 1 percent).

Overall Response Rates by PD-L1 Tumor Proportion Score

PD-L1 TPS Status
[95% CI]
Cohort A
N=25
Cohort B
N=25
Cohort C
N=24
All Patients
N=74
TPS ≥50% 56% (5/9)
[21-86]
50% (4/8)
[16-84]
75% (6/8)
[35-97]
60% (15/25)
[39-79]
TPS ≥1% 53% (8/15)
[27-79]
50% (10/20)
[27-73]
69% (11/16)
[41-89]
57% (29/51)
[42-71]
TPS <1% 44% (4/9)
[14-79]
40% (2/5)
[5-85]
75% (6/8)
[35-97]
54% (12/22)
[32-76]
The safety profile of KEYTRUDA (pembrolizumab) in combination with chemotherapy in this study was consistent with that observed previously. One dose-limiting toxicity event occurred in Cohort C, which subsequently led to discontinuation (Grade 3 toxic epidermal necrolysis). Three patients in Cohort B discontinued due to treatment-related adverse events (Grade 3 pneumonitis, drug hypersensitivity, and autoimmune colitis). No patients in Cohort A discontinued because of treatment-related adverse events. Grade 3-5 adverse events occurred in 56, 71, and 67 percent of patients in Cohorts A, B, and C, respectively. In Cohort B, the most common Grade 3-4 adverse events were drug hypersensitivity (8%), febrile neutropenia (8%), neutropenia (8%), white blood cell count decreased (8%), pneumonia (8%), and pulmonary embolism (8%). Immune-mediated adverse events, primarily Grades 1-2, were observed across cohorts. The most common Grade 3 immune-mediated adverse events were colitis (4% Cohort C), rash papular (4% Cohort A), pancreatitis (4% Cohort B), pneumonitis (4% Cohort B), and toxic epidermal necrolysis (4% Cohort C). There were no treatment-related deaths across cohorts; there was one death in Cohort B (Grade 5 pericardial effusion) which was not treatment-related.

Based on these findings, Merck has initiated two phase 3 trials in patients with previously untreated NSCLC. KEYNOTE-189 is evaluating the combination of KEYTRUDA plus a platinum/pemetrexed-based chemotherapy regimen in patients with non-squamous NSCLC. KEYNOTE-407 will study KEYTRUDA combined with carboplatin and paclitaxel or nab-paclitaxel in patients with squamous NSCLC. Merck has a robust clinical development program for KEYTRUDA in lung cancer, with five registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 270 clinical trials, including more than 100 trials that combine KEYTRUDA with other cancer treatments.

About the KEYNOTE-021 Study (Cohorts A-C)

KEYNOTE-021 is a phase 1/2 multicenter, open-label, randomized, multi-cohort trial with Cohorts A, B, and C evaluating KEYTRUDA (pembrolizumab) in combination with chemotherapy in patients with chemotherapy-naïve, EGFR- and ALK-negative unresectable or metastatic NSCLC. Patients were randomized to receive 2 mg/kg or 10 mg/kg of KEYTRUDA every three weeks plus one of several chemotherapy regimens for four cycles – Cohort A (any histology): carboplatin AUC 6 plus paclitaxel 200 mg/m2 followed by maintenance KEYTRUDA; Cohort B (non-squamous histology): carboplatin AUC 6 plus paclitaxel 200 mg/m2 plus bevacizumab 15 mg/kg followed by maintenance KEYTRUDA plus bevacizumab; or Cohort C (non-squamous histology): carboplatin AUC 5 plus pemetrexed 500 mg/m2 followed by maintenance KEYTRUDA plus pemetrexed. The primary efficacy outcome measures were ORR as assessed every six weeks for the first 18 weeks, followed by every nine weeks for the remainder of the first year, using RECIST v1.1 by a central imaging vendor. Secondary outcome measures included OS, PFS, and duration of response.

About KEYTRUDA (pembrolizumab) Injection 100 mg

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 indicated for the treatment of patients with unresectable or metastatic melanoma.

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

KEYTRUDA is administered at a dose of 2 mg/kg as an intravenous infusion over 30 minutes every three weeks for the approved indications.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

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

Immune-mediated colitis occurred in 4 (0.7%) of 550 patients, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in patients receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 1 (0.2%) of 550 patients, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 10 (1.8%) of 550 patients, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

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

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

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

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

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

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

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

No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA.

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

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

Our Focus on Cancer

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

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 270 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.

Roche’s Tecentriq® (atezolizumab) shows increasing overall survival benefit in updated clinical data analysis for people with specific type of advanced lung cancer

On June 4, 2016 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that it will present updated survival data from the phase II study POPLAR, in people with previously treated advanced non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche , JUN 4, 2016, View Source [SID:1234513042]). The study results demonstrate a clear effect of Tecentriq on the likelihood of survival (Hazard Ratios, HR) with continued improvement as data mature. The earliest data analysis showed an overall survival (OS) benefit of 11.4 months (HR=0.77. CI: 95%) for Tecentriq compared to 12.6 months (HR=0.69. CI 95%) for this updated analysis. In addition, median duration of response (mDOR) has also improved with additional follow-up, from 14.3 months (HR=0.41. CI: 95%) in the initial analysis to 18.6 months (HR 0.32, CI: 95%) in the current data analysis. There were no new or unexpected safety signals, a finding consistent with earlier study results.

"These results are very encouraging because they highlight that the benefits associated with Tecentriq have increased with time, and are not restricted to people with high levels of PD-L1 expression in this type of lung cancer," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development at Roche. "These data show that longer follow-up is necessary to fully realise the advantages of cancer immunotherapies and traditional means to describe clinical benefit, like progression free survival, may not be the most sensitive measure for this class of treatment."

The U.S. Food and Drug Administration (FDA) accepted the company’s Biologics License Application (BLA) and granted Priority Review for Tecentriq for the treatment of people with locally advanced or metastatic NSCLC whose disease expresses the protein PD-L1, as determined by an FDA-approved test, and who have progressed on or after platinum-containing chemotherapy. The FDA will make a decision on approval by 19 October, 2016.

Updated results of the POPLAR study will be presented by David Smith, Compass Oncology, Vancouver, Canada (Abstract #9028) on Saturday, 4 June, 8:00–11:30 am CDT.

Further information on Roche’s contribution to the ASCO (Free ASCO Whitepaper) 2016 scientific programme, the company’s wider progress in cancer care and key data being presented at the conference will be featured at a Roche investor briefing on Sunday 5 June between 6pm – 8pm CDT. This event is independently organised by Roche and is open to analysts attending the ASCO (Free ASCO Whitepaper) 2016 Annual Meeting. To register for the Roche investor briefing, please use the following link:
View Source
To learn more about Roche’s personalised cancer immunotherapy programme and Roche’s contribution to ASCO (Free ASCO Whitepaper) 2016, please follow Roche on Twitter via @Roche. You can keep up to date with ASCO (Free ASCO Whitepaper) 2016 Annual Meeting news and updates by using the hashtag #ASCO16.

About the POPLAR study
POPLAR is a multicentre, open-label, randomised phase II study evaluating the efficacy and safety of Tecentriq compared with chemotherapy (docetaxel) in people with previously treated recurrent locally advanced or metastatic NSCLC. Patients were randomised to receive either Tecentriq 1200 mg intravenously every three weeks or docetaxel 75 mg/m2 intravenously every three weeks. The study enrolled 287 people with previously treated, advanced NSCLC.

The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. People were stratified by PD-L1 expression on tumour-infiltrating immune cells (ICs), histology and prior lines of therapy. PD-L1 expression was assessed for both tumour cells (TCs) and ICs; people were scored as TC0, 1, 2 or 3 and IC0, 1, 2 or 3 with a companion diagnostic immunohistochemistry (IHC) test being developed by Roche Diagnostics.
Overall Survival (OS) Benefit with Tecentriq from January 2015 – December 2015:
January – OS benefit of 11.4 months (HR=0.77. CI: 0.55-1.06)
May – OS benefit of 12.6 months (HR=0.73. CI: 0.53-0.99),
December – OS benefit of 12.6 months (HR=0.69. CI: 0.52-0.92)
POPLAR updated OS data

About non-small cell lung cancer
Lung cancer is the leading cause of cancer death globally. Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day. Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.

About Tecentriq (atezolizumab)
Tecentriq is a monoclonal antibody designed to target and bind to a protein called PD-L1 (programmed death ligand-1), which is expressed on tumour cells and tumour-infiltrating immune cells. PD-L1 interacts with PD-1 and B7.1, both found on the surface of T cells, causing inhibition of T cells. By blocking this interaction, Tecentriq may enable the activation of T cells, restoring their ability to effectively detect and attack tumour cells.

About Roche in cancer immunotherapy
For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

About personalised cancer immunotherapy
The aim of personalised cancer immunotherapy (PCI) is to provide individual patients with treatment options that are tailored to their specific needs. The Roche PCI research and development programme comprises more than 20 investigational candidates, nine of which are in clinical trials. All studies include the prospective evaluation of biomarkers to determine which people may be appropriate candidates for Roche medicines. In the case of Tecentriq, PCI begins with the PD-L1 (programmed death ligand-1) IHC assay based on the SP142 antibody developed by Roche Tissue Diagnostics. The goal of PD-L1 as a biomarker is to identify those people most likely to experience clinical benefit with Tecentriq as a single agent versus those who may benefit more from combination approaches; the purpose is to inform treatment strategies which will give the greatest number of patients a chance for transformative benefit. The ability to combine Tecentriq with multiple chemotherapies may provide new treatment options to people across a broad range of tumours regardless of their level of PD-L1 expression.

PCI is an essential component of how Roche delivers on the broader commitment to personalised healthcare.

Juno Therapeutics’ Defined Composition CD19 Product Candidates Demonstrate Encouraging Clinical Outcomes and Tolerability

On June 4, 2016 Juno Therapeutics, Inc. (NASDAQ: JUNO), a biopharmaceutical company focused on re-engaging the body’s immune system to revolutionize the treatment of cancer, reported that its investigational chimeric antigen receptor (CAR) T cell product candidates are demonstrating encouraging clinical outcomes for adults and children with B-cell malignancies (Press release, Juno, JUN 4, 2016, View Source;p=RssLanding&cat=news&id=2175102 [SID:1234513025]). Data will be presented at the 52nd Annual Meeting of the American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago, including an oral presentation today on JCAR014 (Abstract #102, Hall D1, 8:48 a.m. CT) and a poster presentation tomorrow on JCAR017 (Abstract #3048, Hall A, Board #370, 8:00 a.m. CT).
"We are encouraged by the continued efficacy and duration of response that we are seeing with our defined cell products in patients with B cell malignancies. We are moving rapidly to start potential registration trials for JCAR017 across a range of B cell malignancies, including ALL, NHL, and CLL," said Mark J. Gilbert, M.D., Juno’s Chief Medical Officer. "As our understanding of JCAR017 and JCAR014 evolves, we are increasingly able to study these defined cell product candidates in the outpatient setting, which may allow for greater access to our technologies over time."
JCAR014
Updated results from a randomized Phase I/II study examining JCAR014 in patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) will be presented today by Cameron Turtle, MBBS, Ph.D., of the Fred Hutchinson Cancer Research Center. Key data include:
In efficacy-evaluable ALL patients (N=34), complete remission was reported in 34/34 (100%) patients and complete molecular remission as measured by flow cytometry (CmR) was achieved in 32/34 (94%) patients. Additionally, 13/20 (65%) had a complete molecular remission as measured by the highly sensitive technique of IGH deep sequencing. In the cohort that received fludarabine/cyclophosphamide (Flu/Cy) lymphodepletion, 22/22 (100%) patients achieved a complete remission, all of which were a CmR. Median disease free survival (DFS) and overall survival (OS) have not yet been reached with patients followed for up to 18 months. Severe cytokine release syndrome (sCRS) was observed in 14/36 (39%) patients and Grade 3 or higher neurotoxicity was observed in 14/36 (39%) patients.
In patients with multiple NHL histologies (N=20), predominantly diffuse large B-cell lymphoma, who received Flu/Cy lymphodepletion followed by JCAR014 dose level 2 (2×106/kg), 16/20 (80%) had an overall response (OR), of which 10/20 (50%) experienced a complete response (CR). CRs continue in 70% of patients, ranging from 3 to 11+ months. sCRS was observed in 2/20 (10%) patients and Grade 3 or higher neurotoxicity was observed in 2/20 (10%) patients. Notably, 16/20 (80%) patients treated with Flu/Cy lymphodepletion followed by JCAR014 dose level 2 were treated in the outpatient setting, and 6/20 (30%) did not require hospitalization during the first 30 days of treatment.
A total of 13 high-risk CLL patients (complex karyotype, del17p, ibrutinib-refractory, ibrutinib-intolerant) received JCAR014 and either non-Flu/Cy (n=2) or Flu/Cy (n=11) lymphodepleting chemotherapy. In the Flu/Cy patients, OR rate was 10/11 (91%) patients, of which 5/11 (45%) patients achieved CR. CRs are ongoing in 100% of these patients with a range of 3 to 19+ months. sCRS was observed in 3/13 (23%) patients and Grade 3 or higher neurotoxicity was observed in 3/13 (23%) patients.
JCAR017
In addition to the adult JCAR014 data presented today, Rebecca Gardner, M.D., of Seattle Children’s, announced results from Seattle Children’s Phase I study of JCAR017 in pediatric and young adults with CD19+ r/r ALL (n=42) demonstrating 39/42 (93%) patients experienced a complete remission, all of which were a CmR by flow cytometry. In patients who received the Flu/Cy preconditioning regimen, 14/14 (100%) achieved a complete remission and a CmR. sCRS was observed in 10/42 (24%) patients and Grade 3 or higher neurotoxicity was observed in 10/42 (24%) patients.
About Juno’s Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) Technologies
Juno’s CAR and TCR technologies genetically engineer T cells to recognize and kill cancer cells. Juno’s CAR T cell technology inserts a gene for a particular CAR into the T cell, enabling it to recognize cancer cells based on the expression of a specific protein located on the cell surface. Juno’s TCR technology provides the T cells with a specific T cell receptor to recognize protein fragments derived from either the surface or inside the cell. When either type of engineered T cell engages the target protein on the cancer cell, it initiates a cell-killing response against the cancer cell. JCAR014 and JCAR017 are investigational product candidates and their safety and efficacy have not been established.