On June 5, 2017 Lion Biotechnologies, Inc. (NASDAQ: LBIO), a biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported a poster presentation of additional data from 16 patients enrolled in the first cohort of its ongoing Phase 2 study of LN-144 for the treatment of metastatic melanoma at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Lion Biotechnologies, JUN 5, 2017, View Source [SID1234519429]).

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"The data presented today demonstrate that we can manufacture TIL at our central GMP facilities and treat a patient population with a high unmet need at multiple clinical sites," said Dr. Maria Fardis, PhD, MBA, Chief Executive Officer of Lion Biotechnologies. "These initial data show clinically-meaningful outcomes, as assessed both by ORR and DCR, in a heavily pre-treated patient group, all of which had received prior anti-PD-1 and over 80% with prior anti-CTLA-4 checkpoint inhibitors."

This Phase 2, multicenter, three-cohort study is designed to assess the safety and efficacy of LN-144 for treatment of patients with metastatic melanoma. Cohorts one and two will now enroll up to 30 patients each and cohort three is a re-treatment cohort for a second LN-144 infusion in up to ten patients. The first two cohorts are evaluating two different manufacturing processes for LN-144. Patients in cohort one are receiving fresh, non-cryopreserved TIL and cohort two patients are receiving product manufactured through a more streamlined and rapid three-week procedure yielding a cryopreserved product.

In the poster presentation entitled, "Efficacy of Single Administration of Tumor Infiltrating Lymphocytes (TIL) in Heavily Pre-treated Metastatic Melanoma Patients Following Checkpoint Therapy," Amod Sarnaik, MD, a surgical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and a member of the Immunology Program provided updated data from 16 patients in cohort one who were infused as of April 24, 2017. These advanced metastatic melanoma patients were a median age of 55 and were highly refractory to multiple prior lines of therapy with significant tumor burden at baseline. All had prior anti-PD-1 therapy, 88 percent had anti-CTLA4 therapy and 64 percent had received three or more prior therapies. The results show:

Of the evaluable patients, a 29 percent objective response rate was reported including one complete response (CR) continuing beyond 15 months post-administration of a single TIL treatment
77 percent of patients had reduction in target tumor size
Mean time to first response of 1.6 months, with the CR developing at 6 months
Responses were observed in patients with tumors carrying wild type or BRAF mutations
The protocol allows for administration of up to 6 doses of IL-2. The median number of IL-2 administrations was six.
Additionally, the protocol for this study was amended to both increase the sample size for the study as well as further define the patient population to patients with unresectable or metastatic melanoma who have progressed after immune checkpoint inhibition therapy (e.g., anti-PD-1), and if BRAF mutation-positive, after BRAF targeted therapy.

On June 5, 2017 VBL Therapeutics (Nasdaq:VBLT), reported the presentation of new data demonstrating that treatment with VB-111 (ofranergene obadenovec) induced durable tumor regression and attenuation of tumor growth in patients with recurrent glioblastoma (rGBM) (Press release, VBL Therapeutics, JUN 5, 2017, View Source [SID1234519427]). Data from the company’s prior Phase 2 study in rGBM, will be presented today at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, taking place in Chicago. They will be presented by Andrew Brenner, MD, PhD, the principal investigator of the Phase 2 study and associate professor in medicine, neurology and neurosurgery at the Cancer Therapy and Research Center (CTRC), University of Texas Health Science Center San Antonio.

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VBL’s Phase 2 multi-center study for VB-111 was designed to determine the safety, tolerability and efficacy of VB-111 in patients with rGBM. A total of 46 patients were enrolled in two sequential cohorts. In the first cohort, patients were treated with VB-111 as monotherapy for a median of only one dose and, upon disease progression, switched to Avastin (bevacizumab) alone as standard of care (Limited Exposure cohort). This cohort behaved like an Avastin historical control with a median Overall Survival (mOS) of 8 months.

In the second cohort, patients continued to receive treatment with VB-111 after progression, in combination with Avastin as the standard of care (Treatment Through Progression cohort). This cohort received in median 4 doses of VB-111, about 8 months of treatment.

VBL previously reported that the study met the primary endpoint of statistically-significant increase in median overall survival, with 59 weeks in patients treated continuously with VB-111, compared to 32 weeks in patients with only one dose (in median) of VB-111 (p=0.048), both groups having received Avastin upon progression after a short course of VB-111. 12-Month overall survival was 57% in the VB-111 continuous exposure cohort, compared with only 24% in historical pooled Avastin trials (p=0.03), consistent with data indicating that Avastin monotherapy does not improve OS in rGBM patients.

To further understand the why treatment with VB-111 was associated with prolonged survival, VBL analyzed the tumor growth kinetics in all rGBM patients who participated in the VB-111 Phase 2 trial. These new data demonstrate that tumor growth kinetics was significantly attenuated upon longer treatment with VB-111.

Whereas brief exposure to VB-111 was associated with tumor progression in most patients, longer exposure to VB-111 (median= 4, mean=4.7 doses) led to attenuation of tumor growth kinetics (median % increase (MPI) per 30 days: 0.6 vs 14.1, p=0.0032). Furthermore, tumor regression was more frequent upon longer exposure to VB-111; only 16% of patients with limited exposure to VB-111 had tumors shrink below baseline dimensions during the first 100 days, compared to 61% of patients who continued to receive VB-111 through progression (p=0.002; McNemar’s test). Except for longer treatment with VB-111 leading to favorable OS, there was no evidence for difference between the two cohorts in any of the criteria tested, including patient characteristics, initial tumor growth kinetics, and Avastin treatment of both groups.

Overall, VBL’s Phase 2 data point to a favorable anti-tumor effect of VB-111 in rGBM, in terms of both regression rate and overall survival following treatment through progression, compared to both brief exposure to VB-111 with subsequent Avastin monotherapy and to historical data of Avastin monotherapy. Notably, responses were seen even with VB-111 monotherapy, including a patient who remains in complete remission after over 3 years.

"The new analysis supports the benefit of continuous exposure to VB-111 in combination with Avastin, on both inhibition of tumor growth and survival in rGBM patients," said Dr. Andrew Brenner, CTRC, University of Texas Health Science Center San Antonio, principal investigator in the VB-111 Phase 2 study.

Yael Cohen, MD, Vice President of Clinical Development at VBL Therapeutics, said, "We are encouraged by these Phase 2 results in rGBM, which also are consistent with the findings from our trials of VB-111 in ovarian cancer and thyroid cancer. The current data support the design of our ongoing Phase 3 GLOBE study in rGBM."

VBL’s pivotal Phase 3 GLOBE study in rGBM, comparing VB-111 in combination with Avastin to Avastin alone, is currently being conducted in the US, Canada and Israel. Enrollment in the study, 256 patients in total, was completed in December 2016, five months ahead of schedule. The study is proceeding under a Special Protocol Assessment (SPA) granted by the U.S. Food and Drug Administration (FDA), with full endorsement by the Canadian Brain Tumor Consortium (CBTC). The company expects an interim analysis of the GLOBE trial to occur in the third quarter of 2017, with top-line results from the full dataset expected in early 2018.

The new Phase 2 data will be presented in a poster session at ASCO (Free ASCO Whitepaper) today at 1:15 PM – 4:45 PM CDT, Hall A, poster board # 297. The poster will be also available on the company’s website, at ir.vblrx.com.

About Ofranergene Obadenovec (VB-111)
Ofranergene obadenovec is a unique biologic agent that uses a dual mechanism to target solid tumors. Based on a non-integrating, non-replicating, Adeno 5 vector, ofranergene obadenovec utilizes VBL’s proprietary Vascular Targeting System (VTS) to target the tumor vasculature for cancer therapy. Unlike anti-VEGF or TKIs, ofranergene obadenovec does not aim to block a specific pro-angiogenic pathway; instead, it uses an angiogenesis-specific sensor (VBL’s PPE-1-3x proprietary promoter) to specifically induce cell death in angiogenic endothelial cells in the tumor milieu. This mechanism retains activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and shows activity even after failure of prior treatment with other anti-angiogenics. Moreover, ofranergene obadenovec induces specific anti-tumor immune response, which is accompanied by recruitment of CD8 T-cells and apoptosis of tumor cells.

Ofranergene obadenovec completed a Phase 2 study in rGBM, which showed a statistically significant improvement in overall survival in patients treated with ofranergene obadenovec through progression, compared to either patients treated with ofranergene obadenovec followed by bevacizumab alone, or to historical bevacizumab data. In a Phase 2 trial for recurrent platinum-resistant ovarian cancer, ofranergene obadenovec demonstrated a statistically significant increase in overall survival and 60% durable response rate (as measured by reduction in CA-125), approximately twice the historical response with bevacizumab plus chemotherapy in ovarian cancer. In a Phase 2 study in recurrent, iodine-resistant differentiated thyroid cancer, ofranergene obadenovec met the primary endpoint demonstrating disease stabilization with a positive safety profile, along with a dose-response and evidence of an overall survival benefit. Ofranergene obadenovec has received Fast Track Designation for recurrent glioblastoma in the U.S. and orphan drug status for glioblastoma in both the U.S. and EU.

Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported updated overall survival (OS) findings from KEYNOTE-024, the phase 3 study evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy compared to platinum-containing chemotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors express high levels of PD-L1 (tumor proportion score [TPS] of 50 percent or more). The study included patients with squamous and non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations and demonstrated a reduction in the risk of death by 37 percent for KEYTRUDA compared to chemotherapy based on 19 months of median follow-up (HR, 0.63 [95% CI, 0.46-0.88]; p = 0.003). Additionally, in an exploratory analysis, progression-free survival 2 (PFS2) – a clinical endpoint used to assess the impact of next-line treatment on disease control – was substantially improved for patients in the KEYTRUDA group compared to the chemotherapy group. These data are being presented in an oral session at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Tuesday, June 6, from 9:45 – 9:57 a.m. CDT (Location: Hall D1) (Abstract #9000).

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With approximately eight additional months of follow-up, data showed continued OS benefit with KEYTRUDA over chemotherapy in the first-line treatment of patients with advanced NSCLC whose tumors expressed high levels of PD-L1 – showing an 18-month OS rate of 61.2 percent in the KEYTRUDA group compared to 43.0 percent in the chemotherapy group; the 12-month OS rate was 70.3 percent in the KEYTRUDA group compared to 54.8 percent in the chemotherapy group.

For PFS2, findings based on 19 months of median follow-up showed a 46 percent reduction in the risk of progression after the start of the second-line regimen or death in patients initially randomized to KEYTRUDA compared to patients initially randomized to chemotherapy (HR, 0.54 [95% CI, 0.40-0.72]; p < 0.001]).

"From the start of the KEYTRUDA program in non-small cell lung cancer, one of our goals has been to demonstrate the value of KEYTRUDA monotherapy in appropriate patient populations," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "With updated data from KEYNOTE-024, as well as from other studies in our clinical development program, we are establishing the role of KEYTRUDA in the treatment of advanced non-small cell lung cancer."

Merck has a robust clinical development program for KEYTRUDA in lung cancer, with multiple registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 500 clinical trials, including more than 300 trials that combine KEYTRUDA with other cancer treatments.

"These results from additional follow-up in KEYNOTE-024 – including improved overall survival despite significant crossover – give us further confidence in KEYTRUDA as a first-line treatment for patients with non-small cell lung cancer whose tumors express high levels of PD-L1," said Prof. Martin Reck, head of the department of thoracic oncology, LungenClinic Grosshansdorf, Germany.

Key Findings from the KEYNOTE-024 Study

KEYNOTE-024 is a randomized, phase 3 study of 305 patients with metastatic NSCLC who were assigned either KEYTRUDA (pembrolizumab) as monotherapy (n=154) or standard of care platinum-based chemotherapy (n=151). Enrollment criteria included: having no prior systemic chemotherapy treatment for their advanced disease, tumors without an EGFR sensitizing mutation or ALK translocation, and tumors expressing high levels of PD-L1 (TPS of 50 percent or more) as determined by a central laboratory using the Dako PD-L1 IHC 22C3 PharmDx test, from Agilent Technologies. The primary endpoint was progression-free survival (PFS) and the key secondary endpoint was OS. Other secondary endpoints include overall response rate (ORR) and safety. Exploratory endpoints include PFS2 and duration of response.

Data presented at ASCO (Free ASCO Whitepaper) are based on a median follow-up of 19.1 months (range: 14.3-27.6) and include findings from 79 patients who crossed over from the chemotherapy arm to receive KEYTRUDA, per study protocol, and 12 patients who received anti-PD-1 therapy outside of study crossover. Results show that KEYTRUDA maintained an OS benefit over chemotherapy in patients whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more), with a 37 percent reduction in the risk of death (HR, 0.63 [95% CI, 0.46-0.88]; p = 0.003). The 12-month OS rate was 70.3 percent in the KEYTRUDA group compared to 54.8 percent in the chemotherapy group; at 18 months, the OS rate was 61.2 percent in the KEYTRUDA group compared to 43.0 percent in the chemotherapy group. The median OS had not yet been reached in the KEYTRUDA group (95% CI, 19.4-NE), compared to 14.5 months in the chemotherapy group (95% CI, 9.8-19.6).

In an exploratory analysis of PFS2 – a clinical endpoint used to assess the impact of next-line treatment on disease control – findings showed a 46 percent reduction in the risk of progression after initiation of the second-line regimen or death in patients initially randomized to KEYTRUDA compared to patients initially randomized to chemotherapy (HR, 0.54 [95% CI, 0.40-0.72]; p < 0.001]). The 12-month PFS2 rate was 59.7 percent in the KEYTRUDA group and 38.5 percent in the chemotherapy group; the 18-month PFS2 rate was 51.0 percent in the KEYTRUDA group and 24.6 percent in the chemotherapy group. The median PFS2 was 18.3 months in the KEYTRUDA group (95% CI, 12.7-NE) compared to 8.4 months in the chemotherapy group (95% CI, 6.8-9.8).

A safety analysis was not performed for this data set.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be two percent.

About KEYTRUDA (pembrolizumab) Injection

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.

Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

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-dose vial.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, 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, as a single agent, 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.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

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.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

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 (pembrolizumab) 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.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines of therapy. 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 adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is also indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

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

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, 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. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or 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 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 (pembrolizumab) 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. 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. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (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. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA (pembrolizumab). Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, 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.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

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 monotherapy 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%).

It is not known whether KEYTRUDA (pembrolizumab) 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.

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 more than 500 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.

– See more at: View Source

On June 5, 2017 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that results from its pivotal Phase III trial with fruquintinib, its novel vascular endothelial growth factor receptor ("VEGFR") kinase inhibitor, were highlighted in an oral presentation today during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting ("ASCO"), held in Chicago (Press release, Hutchison China MediTech, JUN 5, 2017, http://www.chi-med.com/highlights-fruquintinib-ph3-data-at-asco/ [SID1234519422]). Results showed that FRESCO, a randomized, double-blind, placebo-controlled, multi-centered Phase III trial assessing fruquintinib in patients with locally advanced or metastatic colorectal cancer ("CRC") in China, met all primary and secondary endpoints including significant improvements in overall and progression-free survival with a manageable safety profile and lower off-target toxicities compared to other targeted therapies.

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"Data from this 416-patient trial showed that treatment with fruquintinib resulted in statistically significant and clinically meaningful survival benefits in colorectal cancer patients who failed two previous lines of systemic therapy," said Dr. Jin Li, Director of the Department of Oncology, Tongji University affiliated Shanghai East Hospital. "Importantly, adverse events associated with fruquintinib therapy were manageable and controllable. Particularly encouraging was that fruquintinib showed relatively low frequency and less severe liver function abnormalities as compared with other targeted therapies used in this disease setting."

"The totality of safety and efficacy data suggest fruquintinib can be an important new treatment option for patients whose colorectal cancer continues to progress," he concluded.

Efficacy Results

The FRESCO trial is a randomized, double-blind, placebo-controlled, multicenter, Phase III pivotal trial in patients with locally advanced or metastatic CRC who have failed at least two prior systemic antineoplastic therapies, including fluoropyrimidine, oxaliplatin and irinotecan. No drugs have been approved in third-line CRC in China, with best supportive care ("BSC") being the general standard of care. Enrollment was completed in May 2016. 519 patients were screened. The intention-to-treat (ITT) population of 416 patients was randomized at a 2:1 ratio to receive either: 5mg of fruquintinib orally once per day, on a three-weeks-on / one-week-off cycle, plus BSC (278 patients); or placebo plus BSC (138 patients). Randomization was stratified for prior anti-VEGF therapy and K-Ras gene status. The trial was concluded on January 17, 2017.

The primary endpoint of median overall survival (OS) was 9.30 months [95% CI 8.18–10.45] in the fruquintinib group vs. 6.57 months [95% CI 5.88–8.11] in the placebo group, with a hazard ratio of 0.65 [95% CI: 0.51–0.83; two-sided p<0.001].

The secondary endpoint of median progression-free survival (PFS) was 3.71 months [95% CI 3.65–4.63] in the fruquintinib group vs. 1.84 months [95% CI 1.81–1.84] in the placebo group, with a hazard ratio of 0.26 [95% CI: 0.21–0.34; two-sided p<0.001].

Significant benefits were also seen in other secondary endpoints. The fruquintinib group disease control rate (DCR) was 62.2% vs. 12.3% for placebo (p<0.001), while the overall response rate (ORR) was 4.7% vs. 0% for placebo (p=0.012).



Safety and Tolerability Results

Results showed that fruquintinib had a manageable safety profile with lower off-target toxicities compared to other targeted therapies, and did not demonstrate the sometimes severe and fatal hepatotoxicity (liver toxicity) observed with other therapies in this disease setting. The most frequently reported fruquintinib-related grade ≥3 adverse events included hypertension (21.2%), hand-foot skin reaction (10.8%), proteinuria (3.2%) and diarrhea (2.9%), all associated with VEGFR inhibition. No other grade ≥3 adverse events exceeded 1.4% in the fruquintinib population, including hepatic function adverse events such as elevations in bilirubin (1.4%), alanine aminotransferase (ALT) (0.7%) or aspartate aminotransferase (AST) (0.4%).

Dose interruptions or reductions occurred in only 35.3% and 24.1% of patients in the fruquintinib arm, respectively, and only 15.1% of patients discontinued treatment vs. 5.8% for placebo.

The FRESCO study may be found at clinicaltrials.gov using identifier NCT02314819. The presentation will be available at chi-med.com/wp-content/uploads/2017/06/pre170605-013asco.pdf.

Chi-Med expects to complete the New Drug Application (NDA) submission for fruquintinib to the China Food and Drug Administration imminently. The Company also expects to initiate U.S. clinical studies in 2017.



About Fruquintinib
Fruquintinib is a highly selective small molecule drug candidate that has been shown to inhibit VEGFR 24 hours a day via an oral dose, with lower off-target toxicities compared to other targeted therapies. Its tolerability, along with its clean drug-drug interaction profile demonstrated to date, may enable rational combination with other cancer therapies such as in our ongoing clinical trials of fruquintinib in combination with chemotherapy and targeted therapy.

At an advanced stage, tumors secrete large amounts of VEGF, a protein ligand, to stimulate formation of excessive vasculature (angiogenesis) around the tumor to provide greater blood flow, oxygen, and nutrients to the tumor. VEGF and VEGFR play pivotal roles in tumor-related angiogenesis, and fruquintinib inhibits the VEGF/VEGFR pathway. This represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

Fruquintinib is currently under joint development in China by Chi-Med and its partner Eli Lilly and Company ("Lilly"). Chi-Med and Lilly jointly announced top-line results from the FRESCO CRC trial on March 3, 2017. In addition, fruquintinib is being studied in China in a Phase III pivotal trial in non-small cell lung cancer ("NSCLC"), known as FALUCA; and a Phase II study using fruquintinib combined with Iressa (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC. Other studies currently being planned, and soon to be initiated, include a Phase III study in gastric cancer in combination with paclitaxel in China, new studies in the United States, and certain exploratory studies in combination with other oncology agents.

About Chi-Med
Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 0001). For more information, please visit: www.chi-med.com.

On June 5, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported on the initial progress of the two ongoing Phase 1 trials of its Chk1 inhibitor, SRA737. In addition, today Sierra is presenting two posters describing the innovative clinical designs of these trials at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, being held in Chicago (Press release, Sierra Oncology, JUN 5, 2017, View Source [SID1234519421]).

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"The Dose Escalation Phase of our monotherapy study for SRA737 employs an accelerated titration design which has allowed us to rapidly and efficiently advance through several 100% dose escalations with single patient cohorts," said Dr. Barbara Klencke, Chief Development Officer of Sierra Oncology. "We have not yet observed any dose limiting toxicity and are achieving excellent exposure with several cohorts having surpassed the proposed minimum efficacious plasma concentration for SRA737 based on preclinical modelling. This has enabled the commencement of the parallel Cohort Expansion Phase of the study, described in detail in one of our posters presented at ASCO (Free ASCO Whitepaper) today. This innovative clinical trial design will enroll prospectively-selected genetically-defined patients into five indication-specific cohort expansions at potentially active dose levels."

The SRA737 Phase 1 monotherapy trial has advanced through six single patient dose cohorts of 20, 40, 80, 160, 300 and 600 mg/day, administered under a continuous daily oral dosing regimen in 28-day cycles. Dose escalation will continue until a maximum tolerated dose (MTD) is reached, in parallel with ongoing Cohort Expansion enrollment.
Preliminary observations from the ongoing monotherapy study are as follows:
SRA737 has been well-tolerated to date: No Grade 2 or higher SRA737-related Adverse Events have been reported.
No dose-limiting toxicities have been observed and an MTD has not been reached.

Dose-proportional exposure: Pharmacokinetic (PK) parameters for SRA737 have been generally linear across the dose range tested to date.

Plasma concentrations of SRA737 exceeding the proposed minimum efficacious threshold (Cmin) of 100 nM were maintained for 24 hours post-dose at the 160 mg/day dose level and above.

Having successfully surpassed the proposed minimum efficacious exposure threshold, the Cohort Expansion Phase of the trial has commenced and is enrolling patients with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition via synthetic lethality into five indication-specific cohorts: colorectal, head and neck, non-small cell lung, ovarian, and prostate cancers.

For the Phase 1 Chemotherapy Combination study, Stage 1, which is evaluating SRA737 in combination with gemcitabine and cisplatin, has concluded enrolment and the study has transitioned to Stage 2. This stage is seeking to establish the safety profile, determine the MTD and to propose a recommended dose for further development of SRA737 in combination with low-dose gemcitabine. Once an MTD and dosing schedule have been determined, the study will also evaluate the preliminary efficacy of SRA737 in combination with low-dose gemcitabine in indication-specific cohorts of prospectively-selected, genetically-defined subjects with bladder or pancreatic cancer.

"In addition to advancing our novel synthetic lethality-oriented monotherapy study, we are also excited by the potential for SRA737 to combine synergistically with other agents. Gemcitabine is a potent inducer of replication stress and DNA damage via multiple mechanisms, and represents a rational drug combination for SRA737, given Chk1’s fundamental biological role in responding to such stressors. Our preclinical modeling demonstrates robust synergistic anti-tumor activity of SRA737 in combination with low-dose gemcitabine," added Dr. Nick Glover, President and CEO of Sierra Oncology. "We expect to accrue a solid understanding of dose, schedule, pharmacodynamic and pharmacokinetic parameters for SRA737 from these two studies, and the data observed to date are encouraging and consistent with our preclinical research. Our SRA737 development program remains on track and we expect to provide an update from these studies, including potential preliminary activity data, in early 2018."

About SRA737
SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of important cell cycle checkpoints and a central mediator of the DDR network. In cancer cells, replication stress induced by oncogenes (e.g., MYC or RAS) or genetic mutations in DNA repair machinery (e.g., BRCA1 or FA) combined with loss of function in tumor suppressors (e.g., TP53 or ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition by SRA737 may therefore be synthetically lethal to these cancer cells and have utility as a monotherapy in a range of tumor indications.

Profound mechanistic potentiation has also been reported when Chk1 inhibition is combined with DNA damaging cytotoxic agents or radiation. The widely-used chemotherapy gemcitabine is a strong exogenous inducer of replication stress and preclinical modeling demonstrates robust synergistic anti-tumor activity for SRA737 potentiated by gemcitabine.

SRA737 was discovered and initially developed at the Cancer Research UK (CRUK) Cancer Therapeutics Unit at the Institute of Cancer Research (ICR).

About the SRA737 Monotherapy Trial Design
This first-in-human, multicenter, Phase 1 Monotherapy study consists of two phases, a Dose Escalation Phase and a Cohort Expansion Phase, being run concurrently.

The Dose Escalation Phase of the SRA737 Phase 1 monotherapy trial is investigating the safety and tolerability of SRA737 and seeking to identify its optimal dose, schedule, and maximum tolerated dose (MTD). Single patient cohorts will receive escalating doses of SRA737, starting at 20 mg, administered orally on a continuous daily dosing schedule in 28-day cycles until SRA737-related Grade 2 toxicity is observed in a dose escalation subject during Cycle 1. At that point, that dose level and all subsequent dose level cohorts will be expanded to three to six subjects, following a rolling six design. Intensive PK and pharmacodynamic assessments will be obtained on all subjects.
In the Cohort Expansion Phase, enrollment into five indication-specific cohort expansions was initiated once the minimum efficacious dose level was reached. Subjects with colorectal, head and neck, non-small cell lung, ovarian, and prostate cancer will be selected based on prospective, tumor tissue genetic profiling using Next Generation Screening (NGS) and must have tumors that harbor a minimum of two genomic alterations hypothesized to confer sensitivity to Chk1 inhibition. The Dose Escalation Phase will continue concurrently until the MTD and Recommended Phase 2 Dose are identified.

About the SRA737 Chemotherapy Combination Trial Design
This first-in-human Phase 1, multicenter study consists of two stages:
In Stage 1, a triplet combination (SRA737 with gemcitabine and cisplatin) is being evaluated in subjects with solid tumors. Cohorts consisting of three to six subjects will receive escalating doses of SRA737. Intensive PK and pharmacodynamic assessments will be obtained on all subjects. Enrolment for this stage has concluded and the study has transitioned to Stage 2.

In the Dose Escalation Phase of Stage 2, cohorts of three to six subjects will be given escalating doses of SRA737 on an intermittent schedule in addition to low-dose gemcitabine until the combination MTD is reached. The starting dose of SRA737 for the first cohort was 40 mg. SRA737 will be administered orally on days 2, 3, 9, 10, 16 & 17 of a 28-day cycle; 300 mg/m2 of gemcitabine will be administered intravenously on days 1, 8, & 15.

Once the MTD of SRA737 in combination with gemcitabine has been identified, the Cohort Expansion Phase of Stage 2 will begin. Qualifying patients will be enrolled into two indication-specific cohort expansions, bladder cancer and pancreatic cancer. To qualify for enrolment into these cohorts, the subject’s tumor must have a confirmed minimum of two genomic alterations hypothesized to confer sensitivity to Chk1 inhibition, determined using NGS.
About the SRA737 ASCO (Free ASCO Whitepaper) 2017 Poster Presentations

Two "Trials in Progress" posters describing the innovative Phase 1 clinical designs for SRA737 are being presented today at the 2017 ASCO (Free ASCO Whitepaper) Annual Meeting. The posters are available on the company’s website at www.sierraoncology.com

SRA737 Monotherapy Poster
Title: A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.
Trials in Progress Abstract: #TPS2607
Poster: #93b
Poster Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics
Date and Time: Monday, June 5, 2017, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr., Chicago, Illinois

SRA737 Chemotherapy Combination Poster
Title: A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.
Trials in Progress Abstract: #TPS2613
Poster: #96b
Poster Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics
Date and Time: Monday, June 5, 2017, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr., Chicago, Illinois