On September 27, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported positive results from two phase II studies that evaluated the investigational cancer immunotherapy atezolizumab (anti-PDL1; MPDL3280A) in people with advanced non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche , SEP 27, 2015, View Source [SID:1234507566]). In the randomised phase II study, POPLAR, atezolizumab met its primary endpoint and showed a statistically significant survival benefit compared to chemotherapy (HR=0.54; p=0.014) in people with recurrent NSCLC whose tumours expressed medium and high levels of PD-L1, which corresponded with people living 7.7 months longer than people who received docetaxel chemotherapy. A separate, single-arm phase II study, BIRCH, met its primary endpoint and showed that atezolizumab shrank tumours (objective response rate, ORR) in up to 27 percent (p=0.0001) of people whose disease had progressed on prior medicines and also expressed the highest levels of PD-L1. Median survival had not yet been reached. In both studies of atezolizumab, adverse events (AEs) were consistent with those observed in previous studies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Results from both of our studies in non-small cell lung cancer showed that measuring PD-L1 may help identify people most likely to respond to atezolizumab, and the majority of responses continued when these data were assessed," said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development. "Durable responses are meaningful for people whose cancer has progressed on other medicines, and we plan to submit these results to global health authorities to bring this potential new option to people as soon as possible".

In February 2015, atezolizumab received Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) for the treatment of people whose NSCLC expresses PD-L1 and whose disease worsened during or after standard treatments (e.g. platinum-based chemotherapy and appropriate targeted therapy for EGFR mutation-positive or ALK-positive disease). Roche is discussing these NSCLC data from POPLAR and BIRCH with the FDA as part of its Breakthrough Therapy Designation and with other health authorities around the world. Roche currently has seven ongoing phase III studies of atezolizumab alone or in combination with other medicines for various types of lung cancer.

About the POPLAR study
Full results of the POPLAR study will be presented by Johan Vansteenkiste, University Hospital Leuven, Leuven, Belgium (Abstract #14LBA) on Sunday, 27 September, 09:15 CET.

Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR)

POPLAR is a multicentre, open-label, randomised phase II study evaluating the efficacy and safety of atezolizumab compared with docetaxel in people with recurrent locally advanced or metastatic NSCLC. Patients were randomised to receive either atezolizumab 1200 mg intravenously every three weeks or docetaxel 75 mg/m2 intravenously every three weeks. Treatment with atezolizumab may have been continued as long as people were experiencing clinical benefit as assessed by the investigator, i.e. in the absence of unacceptable toxicity or symptomatic deterioration attributed to disease progression. The study enrolled 287 people with previously treated, advanced NSCLC. The primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), 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 an immunohistochemistry (IHC) test being developed by Roche Diagnostics.

About the BIRCH study
Interim results of the BIRCH study will be presented by Benjamin Besse, Institut Gustave Roussy, Villejuif France and Paris Sud University, France (Abstract #16LBA) on Sunday, 27 September, 09:35 Central European Time (CET).

Phase II, single-arm trial (BIRCH) of atezolizumab as first-line or subsequent therapy for locally advanced or metastatic, PDL1-selected NSCLC

BIRCH is an open-label, multicentre, single-arm phase II study that evaluated the safety and efficacy of atezolizumab in 667 people with locally advanced or metastatic NSCLC whose disease expressed

PD-L1. PD-L1 expression was assessed for both TCs and tumour-infiltrating ICs with an investigational immunohistochemistry test (IHC) being developed by Roche Diagnostics. Eligibility criteria included people whose tumours were determined to express PD-L1 with an IHC score of TC2/3 or IC2/3. People in the study received a 1200 mg intravenous dose of atezolizumab every three weeks. The primary endpoint of the study was the ORR assessed by independent review facility per RECIST v1.1. Secondary endpoints included duration of response, OS, PFS and safety.

About atezolizumab
Atezolizumab (anti-PDL1; MPDL3280A) is an investigational monoclonal antibody designed to interfere with a protein called PD-L1. Atezolizumab is designed to target PD-L1 expressed on TCs and tumour-infiltrating ICs, preventing it from binding to PD-1 and B7.1 on the surface of T cells. By inhibiting PDL1, atezolizumab may activate T cells.

All studies of atezolizumab include the evaluation of an investigational IHC test that uses the antibody SP142 to measure PD-L1 expression on both TCs and tumour-infiltrating ICs. The goal of PD-L1 as a biomarker is to identify those people most likely to benefit when treated with atezolizumab alone, and to determine which people may benefit most from a combination of atezolizumab and another medicine. There are 11 ongoing or planned phase III studies of atezolizumab across certain kinds of lung, kidney, breast and bladder cancers.

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 percent of all cases.

On September 27, 2015 Bristol-Myers Squibb Company (NYSE:BMY) reported longer term (18 month) survival data from CheckMate -057, an open-label, randomized Phase 3 study evaluating Opdivo (n=292) versus docetaxel (n=290) in previously treated patients with advanced, non-squamous (NSQ) non-small cell lung cancer (NSCLC) (Press release, Bristol-Myers Squibb, SEP 27, 2015, View Source [SID:1234507560]). Opdivo continued to demonstrate superior overall survival (OS) – the study’s primary endpoint – with an estimated 39% of patients alive at 18 months (95% CI, 34-45) versus 23% for docetaxel, based on a minimum follow-up of 17.1 months. Opdivo also continued to demonstrate a reduction in the risk of death by 28% (a hazard ratio of 0.72; 95% CI, 0.60 – 0.88). In the study, Grade 3-4 treatment-related adverse events were reported in 10% of patients treated with Opdivo versus 54% in the docetaxel arm. These data will be presented on Monday, September 28 during the 2015 European Cancer Congress (ECC 2015) (Abstract # 3010) and published in the New England Journal of Medicine.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These longer term survival results for nivolumab in advanced, non-squamous non-small cell lung cancer support the potential for this Immuno-Oncology agent in treating lung cancer patients," said Leora Horn, M.D., Vanderbilt-Ingram Cancer Center. "CheckMate -057 builds upon its critical findings and now, data show a sustained survival benefit for nivolumab in this hard-to-treat disease that is incredibly encouraging for oncologists, and most importantly, for our patients."

CheckMate -057 clinical results were first reported at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), marking the first time a PD-1 inhibitor demonstrated superior OS versus docetaxel in previously treated patients with NSQ NSCLC. Data from this trial have been accepted for regulatory review by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency to expand the respective Opdivo indications to include previously treated patients with NSQ NSCLC. This application has also been granted Priority Review in the U.S., and Opdivo has received Breakthrough Therapy Designation for this indication.

"At the core of our Immuno-Oncology approach is an unrelenting focus to fundamentally change survival expectations for all cancer patients. Today, we are driving insights into how advanced lung cancer may be treated – from defining the role of PD-L1 expression to showing clinical efficacy resulting in deep and durable responses for these patients," said Michael Giordano, senior vice president, head of Development, Oncology. "The 18-month data from CheckMate -057 reinforce the potential for Opdivo, across PD-L1 expression levels, to offer patients durable overall survival benefit with lower incidence of serious adverse events versus chemotherapy."

About CheckMate -057

CheckMate -057 is a Phase 3, open-label, randomized clinical trial that evaluated patients with advanced NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The trial included patients regardless of their PD-L1 status. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Patients enrolled in the trial received Opdivo 3 mg/kg every two weeks versus standard of care, docetaxel, at 75 mg/m2 every three weeks. In the trial, Opdivo demonstrated continued superior OS benefit, with an estimated 51% of patients alive at one year versus 39% for docetaxel, and an estimated 39% of patients alive at 18 months (95% CI, 34-45) versus 23% for docetaxel, based on a minimum follow-up of 17.1 months.

CheckMate -057 also evaluated the efficacy of Opdivo by tumor PD-L1 expression. Of randomized patients, 78% (455/582) had tumor samples evaluable for PD-L1 expression. Rates of PD-L1 expressing tumors were balanced between groups. PD-L1 status was predictive for benefit from Opdivo, across pre-specified 1%, 5%, and 10% expression levels. In PD-L1 non-expressors, OS was similar between Opdivo and docetaxel, with improved durability of responses seen in patients treated with Opdivo versus docetaxel.

In addition, clinical results showed confirmed ORR was significantly higher for Opdivo (19%) than docetaxel (12%). For patients administered Opdivo, median duration of response was 17.2 months and 5.6 months for docetaxel. One-year PFS was 19% for Opdivo (95% CI, 14-23) and 8% for docetaxel (95% CI, 5-12). Median PFS was 2.3 months for Opdivo (95% CI, 2.2-3.3) and 4.2 months for docetaxel (95% CI, 3.5-4.9).

The safety profile of Opdivo in CheckMate -057 was consistent with prior studies and similar across expressors and non-expressors. Treatment-related adverse events were low in severity with Opdivo and occurred less frequently (any grade: 69%; grade 3-4: 10%) than docetaxel (any grade: 88%; grade 3-4: 54%), including both hematologic and non-hematologic toxicities. Treatment-related serious adverse events were reported less frequently with Opdivo (any grade: 7%; grade 3-4: 5%) than docetaxel (any grade: 20%; grade 3-4: 18%). Discontinuation due to treatment–related adverse events was less frequent with Opdivo (5%) than docetaxel (15%).

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year, according to the World Health Organization. Lung cancer results in more deaths worldwide than colorectal, breast and prostate cancers combined. Non-small cell lung cancer is one of the most common types of the disease and accounts for approximately 85% of cases.

On September 27, 2015 Novartis reported results of a Phase III pivotal study showing Afinitor (everolimus) tablets reduced the risk of progression by 52% (hazard ratio [HR] = 0.48; 95% confidence interval [CI], 0.35-0.67; p<0.00001) vs placebo in patients with advanced, progressive, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin (Press release, Novartis, SEP 26, 2015, View Source [SID:1234507579]). The study, RADIANT-4, will be presented at the European Cancer Congress (ECC) 2015 in Vienna, Austria, and was highlighted in the ECC press conference on Saturday, September 26[1].

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Additionally, the data show everolimus, a mammalian target of rapamycin (mTOR) inhibitor, extended median progression free survival (PFS) by 7.1 months: median PFS by central review was 11.0 months (95% CI, 9.23-13.3) in the everolimus arm and 3.9 months (95% CI, 3.58-7.43) in the placebo arm. Overall survival (OS) was a key secondary endpoint of the trial. While the OS data are not mature, the first interim analysis showed a trend favoring the everolimus arm. Additional OS analyses are planned. Another secondary endpoint was best overall response rate; the study found that 64% of patients receiving everolimus experienced at least some degree of tumor shrinkage compared to 26% of those on placebo[1].

Safety was also a secondary endpoint of the trial and adverse events (AEs) were consistent with the known safety profile of everolimus. The most common treatment-related grade 3/4 AEs (>5%) for everolimus and placebo, respectively, were stomatitis (9.0% vs 0.0%), diarrhea (7.0% vs 2.0%) and infections (7.0% vs 0.0%)[1].

"Advanced, progressive, nonfunctional NET of GI or lung origin are rare and aggressive cancers, with limited treatment options," said James Yao, MD, Professor of Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, and the study’s principal investigator. "These pivotal trial results demonstrate strong evidence for the efficacy of the mTOR inhibitor everolimus in this patient population."

NET are a rare type of cancer that originate in neuroendocrine cells found throughout the body, and are most often found in the GI tract, lungs or pancreas[5]. NET can be functional or nonfunctional: functional NET produce symptoms caused by the secretion of hormones and other substances; nonfunctional NET may produce symptoms caused by the tumor’s growth, such as intestinal blockage, pain and bleeding[5],[6],[7],[8]. At time of diagnosis, 5%-44% of patients with NET in the GI system and 28% of patients with lung NET have advanced disease, meaning the cancer has spread to other parts of the body and is more difficult to treat[5].

"These results show that everolimus has the potential to be a new, clinically meaningful therapy for patients with advanced, progressive, nonfunctional GI or lung NET, which typically have poor prognoses," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Our work with the RADIANT clinical program demonstrates our long-term commitment to NET and has yielded important data that have led to improved outcomes for patients with different types of NET."

The results of the RADIANT-4 study-part of the largest clinical trial program in patients with advanced NET-will serve as the basis of worldwide regulatory submissions for Afinitor for the treatment of advanced, progressive, nonfunctional GI and lung NET. Afinitor is already approved in more than 95 countries worldwide for locally advanced, metastatic or unresectable progressive NET of pancreatic origin.

About RADIANT-4
RADIANT-4 (RAD001 In Advanced Neuroendocrine Tumors) is a Phase III prospective, double-blind, randomized, parallel group, placebo-controlled, multicenter study. The trial examined the efficacy and safety of everolimus plus best supportive care (BSC) vs placebo plus BSC in 302 patients with progressive, well-differentiated, nonfunctional, advanced NET of GI or lung origin. All patients received BSC during treatment, which excluded antitumor agents such as somatostatin analogues (SSAs). Patients were required to have ceased treatment with SSAs for 4 weeks before study entry. Everolimus demonstrated similar efficacy regardless of whether the patient had prior SSA therapy or not. Patients had no history or active symptoms of carcinoid syndrome, and had documented disease progression within the previous 6 months. Patients were randomized 2:1 to receive either daily everolimus 10 mg or daily placebo orally[1].

The primary endpoint of RADIANT-4 was PFS by central radiology review. Secondary endpoints included safety, OS, best overall response rate (defined as complete response plus partial response) and disease control rate[1].

The safety profile of everolimus was consistent with what has been observed in previous studies of this drug. The most common treatment-related AEs included stomatitis, diarrhea, peripheral edema, fatigue, and rash. At the time of the data analysis cutoff date, the primary reasons for treatment discontinuation were disease progression (37% in the everolimus arm vs 72% in the placebo arm) and adverse events (29% in the everolimus arm vs 7% in the placebo arm). A trend towards improved survival was observed at the time of interim OS analysis [HR=0.64; 95% CI, 0.40-1.05; p=0.037], with a total of 70 deaths recorded at the time of the data cutoff (42 [20.5%] in the everolimus arm and 28 [28.6%] in the placebo arm). The result was not statistically significant, since interim analysis significance threshold was p=0.000213[1].

About Afinitor (everolimus) tablets
Afinitor (everolimus) is approved in more than 95 countries, including the United States and throughout the European Union, for locally advanced, metastatic or unresectable progressive neuroendocrine tumors of pancreatic origin. It is also approved in 121 countries including the United States and European Union for advanced renal cell carcinoma following progression on or after vascular endothelial growth factor (VEGF)-targeted therapy.

Afinitor is also approved in more than 100 countries including the United States and European Union for advanced HR+/HER2- breast cancer in combination with exemestane, after prior endocrine therapy.

Everolimus is also available from Novartis for use in certain non-oncology patient populations under the brand names Afinitor or Votubia, Certican and Zortress and is exclusively licensed to Abbott and sublicensed to Boston Scientific for use in drug-eluting stents.

Indications vary by country and not all indications are available in every country. The safety and efficacy profile of everolimus has not yet been established outside the approved indications. Because of the uncertainty of clinical trials, there is no guarantee that everolimus will become commercially available for additional indications anywhere else in the world.

Important Safety Information about Afinitor (everolimus) tablets
Afinitor/Votubia can cause serious side effects including lung or breathing problems, infections (including sepsis), and kidney failure, which can lead to death. Patients taking concomitant angiotensin-converting enzyme (ACE) inhibitors may be at an increased risk for angioedema. Mouth ulcers and mouth sores are common side effects. Afinitor/Votubia can affect blood cell counts, kidney and liver function, and blood sugar, cholesterol, and triglyceride levels. Afinitor/Votubia may cause fetal harm in pregnant women. Highly effective contraception is recommended for women of child-bearing potential while receiving Afinitor/Votubia and for up to eight weeks after ending treatment. Women taking Afinitor/Votubia should not breast feed. Fertility in women and men may be affected by treatment with Afinitor/Votubia.

The most common adverse drug reactions (incidence >=10 percent) are mouth ulcers, skin rash, feeling tired or weak, diarrhea, infections (including upper respiratory tract infection, sore throat and runny nose, sinusitis, middle ear infection and pneumonia), absence of menstrual periods, high levels of cholesterol, nausea, decreased appetite, low level of red blood cells, acne, abnormal taste, irregular menstrual periods, inflammation of lung tissue, swelling of extremities or other parts of the body, high level of blood sugar, itching, weight loss, nose bleeds, cough and headache. The most common grade 3-4 adverse drug reactions (incidence >=2 percent) are mouth ulcers, infections (including pneumonia), low level of red blood cells, absence of menstrual periods, high level of blood sugar, feeling tired or weak, diarrhea, low white blood cells, inflammation of lung tissue and spontaneous bleeding or bruising. Cases of hepatitis B reactivation, blood clots in the lung or legs, and pneumocystis jirovecii pneumonia (PJP) have been reported. Abnormalities were observed in hematology and clinical chemistry laboratory tests.

On September 26, 2015 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company at the forefront of developing and commercializing novel immuno-oncology product candidates to improve the lives of patients with cancer, reported promising early-stage clinical data from a Phase 1b study of indoximod, its wholly owned indoleamine 2,3 dioxygenase (IDO) pathway inhibitor, in combination with ipilimumab for the treatment of patients with unresectable stage 3 or 4 melanoma at the European Cancer Congress 2015 (ECC) in Vienna, Austria (Press release, NewLink Genetics, SEP 26, 2015, View Source [SID:1234507577]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The data reported today are from a Phase 1b safety study of nine patients to determine the safety of indoximod and to establish the dose for a Phase 2 study of indoximod in combination with ipilimumab, which is currently enrolling patients.

Indoximod is an orally available, small molecule, broad IDO pathway inhibitor that has shown the potential to interfere with multiple targets within the IDO pathway. IDO pathway inhibitors, such as indoximod, are designed to be used in combination with other therapeutic agents to maximize the body’s immune response against tumors.

Combination therapy with indoximod and ipilimumab showed encouraging clinical activity in some patients. Of the seven patients evaluable for a response, one patient had a complete response and one patient had a partial response by RECIST criteria. Five patients in the study had progressive disease, and two patients are still awaiting follow up.

"We are pleased to present data from the successful completion of our Phase 1b trial evaluating the combination of indoximod and ipilimumab in patients with advanced melanoma," said Nicholas Vahanian, M.D., President and Chief Medical Officer. "The combination was well-tolerated and did not demonstrate any regimen-limiting immune-based toxicities, abnormalities in liver function tests or other toxicities that have been reported with this class of drugs. Based on these promising clinical results, we are already enrolling patents in the Phase 2 combination study."

The Phase 2 study, currently enrolling 38 patients, will utilize a revised study design with standard of care immune checkpoint inhibition (consisting of four cycles of concomitant ipilimumab, repeat cycles of nivolumab or repeat cycles of pembrolizumab) being given in combination with indoximod. The Phase 2 dose for indoximod has been established at 1,200 mg BID (twice daily), and the primary endpoint will be preliminary efficacy as measured by median progression-free survival.

On September 26, 2015 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the first-time presentation of findings investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy in patients with advanced unresectable nasopharyngeal carcinoma (NPC) – a type of head and neck cancer – whose tumors express PD-L1 (≥1% of cells in tumor nests or PD-L1+ bands in stroma) (Press release, Merck & Co, SEP 26, 2015, View Source [SID:1234507575]). Data were from a Phase 1b study (KEYNOTE-028) and showed an overall response rate (ORR) (confirmed and unconfirmed) of 22.2 percent (95% CI, 8.6-42.3) in evaluable patients (n=27) who were treated with KEYTRUDA. Results were presented in an oral session by Dr. Chiun Hsu, National Taiwan University Hospital, at the European Cancer Congress (ECC) in Vienna (Abstract #2801).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Advanced nasopharyngeal carcinoma is a severe form of head and neck cancer often associated with a poor prognosis," said Dr. Hsu. "These data presented at ECC represent the potential for new approaches to treat this type of cancer, for which there are currently limited treatment options, and further support the need for additional research into how KEYTRUDA may work for certain types of head and neck cancer."

Merck has initiated a comprehensive clinical development program evaluating KEYTRUDA in head and neck cancer across multiple lines of therapy as monotherapy and in combination with chemotherapy as well as other agents. In KEYNOTE-028, KEYTRUDA is being evaluated in patients with advanced unresectable NPC that is not responding to current therapy or for which current therapy is not appropriate. This is the second study to show early activity of KEYTRUDA in patients with head and neck cancer and the first study of an anti-PD-1 therapy to demonstrate clinical activity in patients with recurrent or metastatic NPC. For more information about our oncology clinical trials, visit www.keynoteclinicaltrials.com.

"The findings emerging from this trial again demonstrate that KEYTRUDA is active across a broad range of cancers, including those that are difficult to treat with standard treatments," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "Based on these and other results to date, we are continuing to advance a comprehensive head and neck clinical program for KEYTRUDA, and we remain focused on realizing its full potential to address the unmet treatment needs for patients with difficult-to-treat cancers such as nasopharyngeal carcinoma."

Additional Nasopharyngeal Carcinoma Results from KEYNOTE-028

KEYNOTE-028 is an ongoing multi-cohort, non-randomized Phase 1b basket trial (a trial design that allows for the study of multiple sub-populations of different tumor or histological types within one study) evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy (10 mg/kg dosed every two weeks) in more than 450 patients across 20 different types of cancer. The study was designed to evaluate patients with advanced solid tumors that express PD-L1 and which have not responded to current therapy or for which current therapy is not appropriate.

These early findings from 27 heavily pre-treated patients with advanced NPC demonstrated an ORR of 22.2 percent (n=6/27) (per RECIST v1.1), including six partial responses (95% CI, 8.6-42.3). Additionally, 55.6 percent of patients had stable disease (n=15/27) (95% CI, 35.3-74.5), the disease control rate (DCR) was 77.8 percent (n=21/27) (95% CI, 57.7-91.4), and tumor shrinkage was achieved in 67 percent of patients. The 6-month progression-free survival (PFS) rate was 49.7 percent and the 12-month PFS rate was 28.9 percent. The median follow-up duration for evaluable patients was 12.9 months (range, 2.2−15.0) and the median response duration was 10.8 months (range, 4.8- 10.8).

Adverse events were generally consistent with previously reported safety data for KEYTRUDA. Grade 3-5 investigator-assessed, treatment-related adverse events were hepatitis (n=2), pneumonitis (n=2), anemia (n=1), facial pain (n=1), increased blood creatine phosphokinase (n=1), proteinuria (n=1), and sepsis (n=1). Immune-mediated adverse events were hypothyroidism (n=5), hepatitis (n=4), and pneumonitis (n=3). There was one treatment-related death due to bacterial sepsis.

About PD-L1 and PD-L1 Expression

PD-L1, also called programmed death-ligand 1, is a protein expressed on many types of cells, including some cancer cells. Under normal conditions, the interaction of PD-L1 with another protein, called programmed death receptor-1 (PD-1), serves as an important immune system checkpoint, keeping the immune system in balance and preventing the body from attacking its own cells when inflammation or an infection is present. When cancerous tumors express PD-L1, however, they are able to escape detection and destruction by cytotoxic T-cells – a type of cancer-killing immune cell – allowing the tumor to survive and grow. Tumor PD-L1 expression has been observed at varying levels across many tumor types, including breast, lung, bladder cancer, and nasopharyngeal carcinoma. High levels of PD-L1 expression, called overexpression, are under investigation for potential use as a way to help identify patients with an enhanced likelihood to respond to certain immune-based treatment approaches.

About Nasopharyngeal Cancer

Nasopharyngeal cancer (NPC) is a type of head and neck cancer that starts in the epithelial cells that line the surface of the nasopharynx, the upper part of the throat behind the nose and near the base of skull.1 There are three types of NPC, based on how the cancer cells look under the microscope: keratinizing squamous cell carcinoma, non-keratinizing differentiated carcinoma, and undifferentiated carcinoma.1 Leading risk factors for NPC include Chinese or Asian ancestry, being exposed to the Epstein-Barr virus, and drinking large amounts of alcohol.2 In most parts of the world (including the United States), there is less than one case of NPC for every 100,000 people each year.3 In 2015, about 3,200 cases of NPC are expected to occur in the United States.3

About KEYTRUDA (pembrolizumab)

KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 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.

The KEYTRUDA clinical development program has rapidly expanded to encompass more than 30 tumor types in more than 130 clinical trials, of which more than 70 trials combine KEYTRUDA with other cancer treatments. Registration-enabling trials of KEYTRUDA monotherapy are currently enrolling patients in melanoma, NSCLC, head and neck cancer, bladder cancer, gastric cancer, colorectal cancer, and Hodgkin Lymphoma, with further trials in planning for other cancers.

Selected Important Safety Information for KEYTRUDA

Pneumonitis occurred in 12 (2.9%) of 411 patients, including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. 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 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving KEYTRUDA. 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.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, 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 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. 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 corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Type 1 diabetes mellitus, including diabetic ketoacidosis, has occurred in patients receiving KEYTRUDA. Monitor patients for hyperglycemia and other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA in cases of severe hyperglycemia until metabolic control is achieved.

Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. 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. The following clinically significant immune-mediated adverse reactions occurred in patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, severe dermatitis including bullous pemphigoid, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

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 of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Infusion-related reactions, including severe and life-threatening reactions, have occurred in patients receiving KEYTRUDA. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For severe or life-threatening reactions, stop infusion and permanently discontinue KEYTRUDA.

Based on its mechanism of action, KEYTRUDA may 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 for adverse reactions in 9% of 411 patients. Adverse reactions, reported in at least two patients, that led to discontinuation of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients. The most frequent serious adverse reactions, reported in 2% or more of patients, were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in at least 20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. 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. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.