On August 19, 2015 Boehringer Ingelheim reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for an update to the European label for Giotrif (afatinib*), strengthening and broadening the efficacy profile based on additional Phase III data (Press release, Boehringer Ingelheim, AUG 18, 2015, View Source [SID:1234507295]).

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The CHMP recommendation includes data from the LUX-Lung 3 and 6 trials which showed patients whose tumours have the most common EGFR mutation (deletion in exon 19; del19) lived more than one year longer when treated with first-line Giotrif compared to standard chemotherapy (overall survival; OS = secondary endpoint, progression-free survival; PFS = primary endpoint).1

Dr. Mehdi Shahidi, Medical Head, Solid Tumour Oncology, Boehringer Ingelheim commented, "This update to the European label reinforces the importance of Giotrif as a targeted treatment for patients with EGFR mutation-positive NSCLC, especially for those whose tumours harbor the most common mutation, del19. Giotrif is the first and only targeted agent to date to have shown an overall survival benefit for these patients in the first-line setting."

Following CHMP positive opinion, the European prescribing information will now be updated to include additional data from LUX-Lung 3 and LUX-Lung 6. Both studies met the primary endpoint of PFS for patients whose tumours have common EGFR mutations receiving first-line Giotrif.2,3 In addition to new OS data, updated PFS data from the two trials will also be reflected in the updated European label, as will the significant improvements in lung cancer-related symptoms (cough, shortness of breath, pain) and quality of life observed with Giotrif compared to chemotherapy.1

Adverse events for Giotrif in the LUX-Lung 3 and 6 trials were as expected with EGFR inhibition and were predictable, manageable and reversible.1,2,3 Diarrhoea and rash/acne were the most frequently reported side effects with Giotrif therapy.1,2,3

NSCLC is the most common form of lung cancer comprising over 85% of lung cancer cases.4,5 EGFR mutation-positive NSCLC is a subtype of lung cancer. EGFR mutations are found in 10-15% of Caucasian and 40% of Asian patients with NSCLC.6 There are different types of EGFR mutations; the most common, which account for 90% of all EGFR mutations being del19 (approx. 50%) and L858R (approx. 40%).2,3 Afatinib, an oral, once daily ErbB family blocker, is currently approved in more than 60 countries for the first-line treatment of specific types of EGFR mutation-positive NSCLC (under brand names: Giotrif / Gilotrif).

On August 18, 2015 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported the U.S. Food and Drug Administration (FDA) has accepted for review a supplemental Biologics License Application (sBLA) for KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy (Press release, Merck & Co, AUG 18, 2015, View Source [SID:1234507293]).

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Merck is seeking approval for KEYTRUDA, at the currently approved dose of 2 mg/kg every three weeks, for the first-line treatment of unresectable or metastatic melanoma patients. The FDA granted Priority Review with a PDUFA, or target action, date of December 19, 2015. Additionally, the FDA has extended the action date for a separate sBLA for KEYTRUDA for the treatment of patients with ipilimumab-refractory advanced melanoma. The new action date is now December 24, 2015.

"Through our clinical program for KEYTRUDA we have accumulated substantial data on the role of our anti-PD-1 therapy in advanced melanoma. We look forward to the FDA’s review of each of these applications, and to delivering on our goal of helping patients with advanced melanoma to achieve long-term disease control and survival," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories.

KEYTRUDA is currently indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks 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 sBLA submission for first-line use in advanced melanoma was based in part on data from KEYNOTE-006, a Phase 3 study which evaluated KEYTRUDA in 834 patients with unresectable or metastatic melanoma with progression of disease. Findings from this study were presented at the 2015 American Associated for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting and published in the New England Journal of Medicinei.

Update on sBLA in Ipilimumab-Refractory Advanced Melanoma

The sBLA for ipilimumab-refractory advanced melanoma included data from KEYNOTE-002. KEYNOTE-002 is the Phase 2 study which demonstrated KEYTRUDA was superior to chemotherapy in helping more patients with ipilimumab-refractory advanced melanoma achieve progression-free survival (PFS). In an effort to provide the FDA with the most robust data for KEYTRUDA in this population, Merck submitted an additional analysis from KEYNOTE-002. The submission constitutes a major amendment which will require additional time for review.

About KEYTRUDA (pembrolizumab)

KEYTRUDA (pembrolizumab) 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.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 100 clinical trials – across more than 30 tumor types and enrolling more than 16,000 patients – both as a monotherapy and in combination with other therapies.

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. 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 (pembrolizumab). 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 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 receiving KEYTRUDA, 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 (pembrolizumab) 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 (pembrolizumab): 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.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 9% of 411 patients across all doses studied. Adverse reactions, reported in at least two patients, that led to discontinuations of KEYTRUDA were: pneumonitis, renal failure, and pain. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ≥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 (pembrolizumab). 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.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,000 new cases were diagnosed worldwide in 2012. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2015, an estimated 73,870 people are expected to be diagnosed and an estimated 9,940 people are expected to die of the disease in the U.S. alone. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 percent.

On August 18, 2015 Deciphera Pharmaceuticals, a clinical-stage biotechnology company focused on developing advanced kinase inhibitor treatments targeting the tumor cell and the tumor microenvironment, reported the publication of study results describing the preclinical profile of its Phase 1 anti-cancer product candidate, altiratinib, a balanced, spectrum-selective inhibitor of MET, TIE2, and VEGFR2 kinases (Press release, Deciphera Pharmaceuticals, AUG 18, 2015, View Source [SID:1234507291]).

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The article, which will appear in the September 2015 issue of Molecular Cancer Therapeutics, was pre-published on-line on August 18, 2015. Altiratinib is currently in Phase 1 clinical evaluation in cancer patients (NCT02228811).

In the article the authors describe how altiratinib’s balanced inhibition of the three key kinases, MET, TIE2, and VEGFR2 was achieved using Deciphera’s proprietary switch control kinase inhibitor platform. Moreover, altiratinib was shown to inhibit not only wild type MET, but also oncogenic mutant forms of MET not readily inhibited by other MET inhibitors in development. The ability to inhibit MET mutants during the course of treatment is a key component to altiratinib’s product profile, which Deciphera believes will provide more durable therapy for cancer patients compared to existing agents. MET mutations are driver mutations in certain cancers and can also arise as a resistance mechanism in patients with pre-existing MET amplifications, highlighting the need for durable inhibition of various forms of genomically altered MET.

The report further discloses altiratinib’s ability to block drug resistance mechanisms mediated by the tumor microenvironment. Through its balanced inhibitory potency, altiratinib was shown to inhibit three major evasive cancer (re)vascularization and resistance pathways with comparable single-digit nanomolar inhibitory potency, including HGF, ANG, and VEGF and to block tumor invasion and metastasis. Notably, in a glioblastoma tumor model known to exhibit these tumor microenvironment disease progression mechanisms, altiratinib was shown to double the overall survival of mice compared to vehicle control treated mice and, in combination with bevacizumab, to double survival compared to single-agent bevacizumab-treated mice.

"Altiratinib has a unique profile with the potential to provide cancer patients with a more durable therapy than currently approved and investigational kinase inhibitors in this space," said Daniel L. Flynn, Ph.D., Chief Scientific Officer and Founder of Deciphera Pharmaceuticals. "Already clinical oncologists are seeing the rise in secondary MET mutations, which confer resistance to current MET inhibitors. Altiratinib’s mechanism of action targets not only the wild type form of MET kinase, but also these various secondary mutations."

On August 18, 2015 OncoSec Medical Incorporated ("OncoSec") (NASDAQ: ONCS), a company developing DNA-based intratumoral cancer immunotherapies, reported enrollment of the first patient into the Phase II Investigator Sponsored Trial led by the University of California, San Francisco (UCSF) to assess the anti-tumor activity, safety, and tolerability of the combination of OncoSec’s investigational therapy, ImmunoPulse IL-12, and Merck’s approved anti-PD-1 agent, KEYTRUDA (pembrolizumab), in patients with unresectable metastatic melanoma (Press release, OncoSec Medical, AUG 18, 2015, View Source [SID:1234507287]).

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The primary endpoint is the best Overall Response Rate (bORR) of the combination regimen in patients whose tumors are characterized by low numbers of tumor-infiltrating lymphocytes (TILs).

"There is increasing evidence that tumors need to be inflamed and have TILs in order for anti-PD-1 therapies to be most effective," said Mai H. Le, MD, Chief Medical Officer of OncoSec. "Both preclinical and clinical evidence suggest that ImmunoPulse IL-12 can promote tumor immunogenicity. We anticipate that ImmunoPulse IL-12 will increase the proportion of patients who will respond to immune checkpoint inhibitors like KEYTRUDA and that the combination will have synergistic anti-tumor activity."

"This is the first study in the field of immuno-oncology to evaluate the combination of DNA-based interleukin-12 with electroporation and an anti-PD-1/PD-L1 inhibitor," said Punit Dhillon, CEO and President of OncoSec. "We believe the combination of OncoSec’s intratumoral cancer immunotherapy and checkpoint inhibitors has the potential to be a powerful approach in the fight against cancer."

This multi-center, open label, single-arm trial will enroll approximately 42 patients with unresectable, "low-TIL" metastatic melanoma. Alain Algazi, MD, a skin cancer specialist in the Melanoma Center at the UCSF Helen Diller Family Comprehensive Cancer Center, is the study’s sponsor and principal investigator. The key endpoints of the study include: best Overall Response Rate by RECIST v1.1 and immune related-Response Criteria (irRC); safety and tolerability; duration of response; 24-week landmark progression-free survival; median progression-free survival; and overall survival.

The treatment schedule for the trial follows the standard schedule for pembrolizumab. Pembrolizumab will be administered systematically once every three weeks and ImmunoPulse IL-12 will be administered on three separate days every six weeks. ImmunoPulse IL-12 employs intratumoral delivery of DNA-based IL-12 followed by electroporation. Merck will supply pembrolizumab, and OncoSec will provide ImmunoPulse IL-12.

To learn more about the trial, visit www.oncosec.com. Additional details can also be found at www.clinicaltrials.gov.

About Melanoma
Melanoma is one of the most dangerous forms of skin cancer and accounts for the vast majority of skin cancer deaths.1 When melanoma is caught early enough, surgical excision can be curative in the majority of Stage I and II melanomas. The overall 5-year survival rate for patients with localized melanoma is 98 percent in the United States.1 At later stages, malignant melanoma remains a deadly and frequently difficult to treat cancer. The overall 5-year survival rate for patients falls to 63 percent when the disease reaches the lymph nodes and 16 percent when the disease metastasizes to distant organs.1

Melanoma that has spread to distant sites may be treated with surgery, immunotherapy, chemotherapy and/or radiation therapy.1 Numerous chemotherapy regimens have been tested in melanoma with only modest success and limited overall survival benefit.2 Two approaches – checkpoint inhibitors and targeted kinase inhibitors – have demonstrated improvement in overall survival of patients compared to chemotherapy. 2

While immunotherapy can be extremely effective, the currently approved regimens do not benefit the majority of patients. However, early data of combination approaches with immunotherapies are promising.2 Researchers also continue to focus efforts on targeting pathways of T cell activation.3 The presence of CD8+ T cells seems to correlate with improved prognosis and long-term survival in solid malignancies, such as melanoma,4,5 thus many emerging experimental immunotherapies seek to enhance the tumor’s immunogenicity and increase the anti-tumor CD8+ T cell response.