On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, new data from the Phase III LUX-Lung 8 trial which further highlights the benefits of afatinib* compared to erlotinib for the treatment of patients with previously treated advanced SCC of the lung (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507556]).2 Data from the trial showed that treatment with afatinib resulted in superior progression-free survival (PFS) and superior overall survival (OS) compared to erlotinib in this patient population.2 These improved survival outcomes observed with afatinib were not driven by the presence of EGFR mutations, according to a new analysis presented at ECC.2 Furthermore, a higher number patients treated with afatinib in the LUX-Lung 8 trial reported improvements in overall health and quality of life, as well as improvements in some lung cancer-related symptoms, compared to those treated with erlotinib.3

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LUX-Lung 8 clinical trial investigator Glen D. Goss, M.D., Director of Clinical and Translational Research, The Ottawa Hospital Cancer Center, University of Ottawa, Canada, commented: "These latest data not only demonstrate benefits of afatinib compared to erlotinib for patients with SCC of the lung, but also suggest that afatinib is an effective treatment option for a broad group of patients and not just those whose tumours harbour EGFR mutations. We know that dysregulation of ErbB receptors plays a role in the underlying mechanisms of SCC of the lung and the fact that afatinib targets this family of receptors rather than only EGFR, may explain why it offered additional benefits for this patient population."

Afatinib is an oral, once daily targeted treatment which works by irreversibly blocking the ErbB family of receptors. Unlike other targeted treatments such as erlotinib which are reversible and specifically target EGFR (ErbB1), afatinib aims to provide a sustained, selective and complete ErbB Family Blockade. The Phase III LUX-Lung 8 trial compared afatinib to erlotinib in patients with advanced SCC of the lung progressing after treatment with first-line platinum-based chemotherapy. Data from the trial showed that treatment with afatinib resulted in superior PFS, reducing the risk of cancer progression by 19%, and superior OS, reducing the risk of death by 19% compared to erlotinib in this patient population.1,2 The PFS and OS advantages observed with afatinib compared to erlotinib were independent of the EGFR mutation status of the tumours analysed from this trial.2

Further data presented at ECC confirm the efficacy of afatinib observed in the LUX-Lung 8 trial was associated with improvements in patient reported outcomes.3 More patients had improved overall health-related quality-of-life (36% vs 28%, p=0•041), cough (43% vs 35%, p=0•029) and dyspnoea (51% vs 44%, p=0•061) with afatinib than with erlotinib.3 The rate of severe adverse events in the LUX-Lung 8 trial was similar between the two treatment arms with differences observed in the incidence of certain side effects.1 A higher incidence of severe diarrhoea and stomatitis (mouth sores) was observed with afatinib compared to erlotinib (grade 3 diarrhoea: 10% vs 2%; grade 3 stomatitis: 4% vs 0%), while a higher incidence of severe rash/acne was reported with erlotinib compared to afatinib (grade 3 rash/acne: 10% vs 6%).1 Diarrhoea occurring in patients treated with afatinib was manageable.3

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented: "We are pleased to present these data at ECC 2015 which confirm that the advantages of afatinib, compared to erlotinib, are not limited to patients with squamous cell lung cancer whose tumours expressed EGFR mutations, which are rare in this disease. The LUX-Lung 8 trial shows that treatment with afatinib versus erlotinib not only leads to improved survival outcomes but also offered patients an improved quality of life. Afatinib is under review by both the FDA and EMA for the treatment of SCC of the lung and we look forward to working with regulatory authorities in the hope of making this much needed new treatment option available to patients."

Afatinib is currently approved in more than 60 countries for the first-line treatment of specific types of EGFR mutation-positive non-small cell lung cancer (NSCLC) (under brand names: GIOTRIF / GILOTRIF). Both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently accepted filing applications for afatinib for the treatment of patients with advanced SCC of the lung progressing after treatment with first-line chemotherapy, based on the positive PFS and OS data from the LUX-Lung 8 trial. Afatinib has also been granted orphan drug designation by the FDA – a status given to a product intended for the treatment of a rare disease or condition.

On September 28, 2015 Boehringer Ingelheim reported at the European Cancer Congress (ECC) in Vienna, Austria, further data to support the efficacy of VARGATEF (nintedanib*) in combination with docetaxel for the treatment of advanced non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Press release, Boehringer Ingelheim, SEP 26, 2015, View Source [SID:1234507557]). Further analysis of the data from the pivotal LUME-Lung 1 trial showed that after first-line chemotherapy adenocarcinoma patients receiving VARGATEF plus docetaxel had a significantly reduced rate of tumour growth over time, compared to patients receiving docetaxel alone.1 At the time of treatment initiation, the average tumour size of the 658 adenocarcinoma patients who took part in the trial was 82.5mm (diameter). After six months of treatment, the adenocarcinoma patients receiving VARGATEF plus docetaxel experienced about 10% less tumour growth over time (9.7mm), compared to those receiving placebo plus docetaxel (tumour size at 6 months: 98.4mm placebo plus docetaxel vs 88.7mm nintedanib plus docetaxel).1

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Advanced adenocarcinoma patients with the poorest prognosis received an even more pronounced benefit from VARGATEF plus docetaxel, compared to docetaxel alone, after first-line chemotherapy:

Adenocarcinoma patients whose disease progressed within nine months of starting first-line chemotherapy (T<9) received a 16.8mm reduction in tumour size over time after six months (tumour size at baseline 88.3mm; tumour size at 6 months: 114.6mm placebo plus docetaxel vs 97.8mm nintedanib plus docetaxel; difference in growth over time of 13%)
Adenocarcinoma patients who had continuously progressed during first-line therapy (PD-FLT) experienced a 19.7mm reduction in tumour size over time after six months (tumour size at baseline 98.1mm; tumour size at 6 months: 124.7mm placebo plus docetaxel vs 105mm nintedanib plus docetaxel; a difference in growth over time of 15%)

Professor Martin Reck, lead investigator of the LUME-Lung 1 trial said, "The reduction in tumour burden seen in adenocarcinoma patients receiving nintedanib plus docetaxel is very encouraging and it is particularly positive to see the additional benefit for those patients who progress quickly when receiving first-line therapy as they often have the poorest prognosis. Tumour burden is commonly associated with clinical outcomes and as such is a relevant and valuable measurement. These latest data add to our wealth of knowledge and reiterate the efficacy of nintedanib which has previously been shown to extend overall survival to over one year for this difficult to treat cancer."

The Phase III LUME-Lung 1 trial randomised 1,314 patients with stage IIIB/IV recurrent NSCLC to receive either VARGATEF plus docetaxel or placebo plus docetaxel (1:1).2 Tumour growth was evaluated in a planned post-hoc analysis using all available tumour measurements. Mixed-effects models were employed to measure the relationship between time from treatment initiation and tumour size (measured as the sum of longest diameter of target lesions [SLD]).1

Dr Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "The announcement of the latest data from the LUME-Lung 1 trial further illustrates how VARGATEF in combination with docetaxel can potentially improve the lives of lung cancer sufferers following its EU approval in 2014. We have a long-term commitment to discovering novel and innovative treatments to better the lives of patients with different types of cancer and look forward to bringing further advances in the future."

VARGATEF in combination with docetaxel was approved in the EU in 2014 for use by adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. The LUME-Lung 1 study demonstrated the efficacy and safety of the treatment:2

VARGATEF plus docetaxel significantly prolonged progression-free survival compared to docetaxel alone for patients with adenocarcinoma (PFS: primary endpoint; 4.0 vs 2.8 months)
VARGATEF plus docetaxel significantly extended overall survival to beyond one year for patients with adenocarcinoma, compared to docetaxel alone (OS: key secondary endpoint; 12.6 vs 10.3 months)
VARGATEF plus docetaxel enabled one in four patients with adenocarcinoma to live for at least two years after first-line chemotherapy

VARGATEF in combination with docetaxel demonstrated a familiar and generally manageable side-effect profile without further compromising patients’ overall, health-related, quality of life compared to docetaxel alone. The most common adverse events for patients taking docetaxel vs VARGATEF plus docetaxel included: nausea 18% vs 24%; vomiting 9% vs 17%; diarrhoea 22% vs 42% and elevated liver enzymes 8% vs 29%.

Adenocarcinoma is the most common type of lung cancer and the majority of patients are diagnosed in an advanced stage.3 Most patients will experience disease progression during or after first-line chemotherapy and there is a significant need for new, effective second-line treatments.2,3

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).

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"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.

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]).

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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 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].

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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.