On December 18, 2015 Merck & Co reported that the U.S. Food and Drug Administration (FDA) has approved an expanded indication for KEYTRUDA (pembrolizumab), the company’s anti-PD-1 (programmed death receptor-1) therapy, to include the first-line treatment of patients with unresectable or metastatic melanoma (Press release, Merck & Co, DEC 18, 2015, View Source [SID:1234508608]).

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This approval marks the second FDA-approved indication in advanced melanoma for KEYTRUDA, which is now the first anti-PD-1 therapy approved for previously untreated advanced melanoma patients regardless of BRAF status. The FDA-approved dose of KEYTRUDA is 2 mg/kg every three weeks.

In a Phase 3 trial, KEYNOTE-006, patients with unresectable or metastatic melanoma who were treated with KEYTRUDA experienced superior overall survival (OS) compared to those treated with ipilimumab. In this study supporting the first-line approval, patients given KEYTRUDA 10 mg/kg every two weeks demonstrated a 37 percent reduction in the risk of death and those given KEYTRUDA 10 mg/kg every three weeks demonstrated a 31 percent reduction in the risk of death, both compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively).

Immune-mediated adverse reactions occurred with KEYTRUDA including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or discontinued and corticosteroids administered. For more information regarding immune-mediated adverse reactions, see "Selected Important Safety Information" below.

"As recently as five years ago, there were few treatment options for patients suffering from advanced melanoma," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "Today’s news is another exciting milestone for KEYTRUDA and for patients with this disease. Data supporting the approval emerged from a large and diverse patient population, including patients with very advanced disease and patients whose tumors carried BRAF mutations, thus demonstrating both the breadth of our clinical development program for KEYTRUDA, and the potential of KEYTRUDA to extend the lives of those afflicted with this grievous malignancy."

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

"This growing body of evidence in patients with advanced melanoma supports the expanded indication for KEYTRUDA," said Dr. Omid Hamid, Director of the Melanoma Center at The Angeles Clinic and Research Institute, and a principal investigator for the KEYTRUDA melanoma clinical program. "This approval highlights the importance of KEYTRUDA for advanced melanoma, where we are in need of additional treatment options."

Data Supporting First-Line Indication in Advanced Melanoma and KEYTRUDA Full Approval

The approval was based on data from a multicenter, controlled, Phase 3 study, KEYNOTE-006, which evaluated KEYTRUDA compared to ipilimumab in 834 patients with unresectable or metastatic melanoma with progression of disease; no prior therapy with ipilimumab; and prior therapy with at most one other systemic treatment. Patients were randomized (1:1:1) to receive KEYTRUDA at a dose of 10 mg/kg every two (n=279) or three weeks (n=277) until disease progression or unacceptable toxicity, or ipilimumab, the standard of care at the time of the study, at a dose of 3 mg/kg every three weeks for four doses unless discontinued earlier for disease progression or unacceptable toxicity (n=278). The primary efficacy outcome measures were OS and progression-free survival (PFS) (as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. KEYTRUDA 10 mg/kg every two or three weeks showed superior OS compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively). Median PFS was 5.5 months (95% CI: 3.4, 6.9), 4.1 months (95% CI: 2.9, 6.9), and 2.8 months (95% CI: 2.8, 2.9) with KEYTRUDA 10 mg/kg every two weeks, KEYTRUDA 10 mg/kg every three weeks and ipilimumab, respectively. For PFS, both schedules for KEYTRUDA 10 mg/kg every two or three weeks resulted in superior outcomes compared to ipilimumab (hazard ratio: 0.58 [95% CI: 0.46, 0.72; p<0.001] and hazard ratio: 0.58 [95% CI: 0.47, 0.72; p<0.001], respectively). KEYTRUDA every two or three weeks demonstrated a 42 percent reduction in the risk of disease progression or death as compared to ipilimumab. The ORR was 34 percent (95% CI: 28, 40) with KEYTRUDA 10 mg/kg every two weeks and 33 percent (95% CI: 27, 39) with KEYTRUDA (pembrolizumab) 10 mg/kg every three weeks, as compared with 12 percent (95% CI: 8, 16) with ipilimumab. KEYTRUDA 10 mg/kg every two weeks and three weeks achieved partial response rates of 29 percent and 27 percent, respectively, and complete response rates of 5 percent and 6 percent, respectively; there was a 10 percent partial response rate and 1 percent complete response rate for ipilimumab. Among the 94 patients randomized to KEYTRUDA 10 mg/kg every two weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Among the 91 patients randomized to KEYTRUDA 10 mg/kg every three weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months.

Eighty percent of patients had PD-L1 positive melanoma, 18 percent had PD-L1 negative melanoma, and 2 percent had unknown PD-L1 status (positive: greater than or equal to 1 percent of tumor cells using an Investigational Use Only assay). BRAF mutations were reported in 36 percent of patients, of which 46 percent were previously treated with a BRAF-inhibitor. Patients with BRAF V600E mutated melanoma were not required to have received prior BRAF inhibitor therapy.

The most commonly reported adverse reactions were fatigue (28% with KEYTRUDA vs. 28% with ipilimumab), diarrhea (26% with KEYTRUDA), rash (24% with KEYTRUDA vs. 23% with ipilimumab), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2,117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

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

FDA Approves Labeling Update in Advanced Melanoma: Supporting Data from KEYNOTE-002

Additionally, the FDA approved an update to the product labeling for KEYTRUDA for the treatment of patients with ipilimumab-refractory advanced melanoma. This update is based on results from the randomized Phase 2 trial, KEYNOTE-002, which demonstrated KEYTRUDA was superior to investigator’s choice chemotherapy.

KEYNOTE-002 is a multicenter, randomized controlled study of KEYTRUDA (pembrolizumab) 2 mg/kg every three weeks or 10 mg/kg every three weeks compared to investigator‘s choice chemotherapy (dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin) in 540 patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. Patients on chemotherapy who experienced progression of disease were offered KEYTRUDA. Median PFS was 2.9 months (95% CI: 2.8, 3.8), 2.9 months (95% CI: 2.8, 4.7), and 2.7 months (95% CI: 2.5, 2.8) with KEYTRUDA 2 mg/kg every three weeks (n=180), KEYTRUDA 10 mg/kg every three weeks (n=181) and chemotherapy (n=179), respectively. Doses of KEYTRUDA 2 mg/kg or 10 mg/kg every three weeks were superior compared to chemotherapy for the PFS primary endpoint (hazard ratio: 0.57 [95% CI: 0.45, 0.73; p<0.001] and hazard ratio: 0.50 [95% CI: 0.39, 0.64; p<0.001], respectively). KEYTRUDA 2 mg/kg every three weeks demonstrated a 43 percent reduction in the risk of disease progression or death compared to chemotherapy. There was no statistically significant difference between KEYTRUDA and chemotherapy in the interim OS analysis. The ORR was 21 percent (95% CI: 15, 28) with KEYTRUDA 2 mg/kg every three weeks and 25 percent (95% CI: 19, 32) with KEYTRUDA 10 mg/kg every three weeks, as compared with 4 percent (95% CI: 2, 9) with chemotherapy. KEYTRUDA 2 mg/kg and 10 mg/kg every three weeks achieved partial response rates of 19 percent and 23 percent, respectively, and complete response rates of 2 percent and 3 percent, respectively; there was a 4 percent partial response rate and no complete responses for chemotherapy. Among the 38 patients randomized to KEYTRUDA 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to KEYTRUDA 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months.

The most commonly reported adverse reactions were fatigue (43% with KEYTRUDA), pruritus (28% with KEYTRUDA vs. 8% with chemotherapy), rash (24% with KEYTRUDA vs. 8% with chemotherapy), constipation (22% with KEYTRUDA vs. 20% with chemotherapy), nausea (22% with KEYTRUDA), diarrhea (20% with KEYTRUDA vs. 20% with chemotherapy), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

KEYTRUDA was initially approved in 2014 under the FDA’s accelerated approval process for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. At the time of the initial approval, an improvement in survival or disease-related symptoms was not established. In accordance with the accelerated approval process, full approval was contingent upon verification and description of clinical benefit, which has now been demonstrated in KEYNOTE-002 and KEYNOTE-006.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

Immune-mediated pneumonitis, including fatal cases, occurred in patients receiving KEYTRUDA. Pneumonitis occurred in 32 (2%) of 1,567 patients with melanoma, including Grade 1 (0.8%), 2 (0.8%), and 3 (0.4%) pneumonitis. Pneumonitis occurred in 19 (3.5%) of 550 patients with non-small cell lung cancer (NSCLC), including Grade 2 (1.1%), 3 (1.3%), 4 (0.4%), or 5 (0.2%) pneumonitis. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-mediated colitis occurred in 31 (2%) of 1,567 patients with melanoma, including Grade 2 (0.5%), 3 (1.1%), and 4 (0.1%) colitis. Immune-mediated colitis occurred in 4 (0.7%) of 550 patients with NSCLC, including Grade 2 (0.2%) or 3 (0.4%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-mediated hepatitis occurred in 16 (1%) of 1,567 patients with melanoma, including Grade 2 (0.1%), 3 (0.7%), and 4 (0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 13 (0.8%) of 1,567 patients with melanoma, including Grade 2 (0.3%), 3 (0.3%), and 4 (0.1%) hypophysitis. Hypophysitis occurred in 1 (0.2%) of 550 patients with NSCLC, which was Grade 3 in severity. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

Hyperthyroidism occurred in 51 (3.3%) of 1,567 patients with melanoma, including Grade 2 (0.6%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 127 (8.1%) of 1,567 patients with melanoma, including Grade 3 (0.1%) hypothyroidism. Hyperthyroidism occurred in 10 (1.8%) of 550 patients with NSCLC, including Grade 2 (0.7%) or 3 (0.3%) hyperthyroidism. Hypothyroidism occurred in 38 (6.9%) of 550 patients with NSCLC, including Grade 2 (5.5%) or 3 (0.2%) hypothyroidism. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA (pembrolizumab) for Grade 3 or 4 hyperthyroidism.

Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 3 (0.1%) of 2,117 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer anti-hyperglycemics in patients with severe hyperglycemia.

Immune-mediated nephritis occurred in 7 (0.4%) of 1,567 patients with melanoma, including Grade 2 (0.2%), 3 (0.2%) and Grade 4 (0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

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

The following clinically significant, immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 1567 patients with melanoma: arthritis (1.6%), exfoliative dermatitis, bullous pemphigoid, uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of 550 patients with NSCLC: rash, vasculitis, hemolytic anemia, serum sickness, and myasthenia gravis.

Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2,117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

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

In Trial 6, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). Adverse reactions leading to interruption of KEYTRUDA occurred in 21% of patients; the most common (≥1%) was diarrhea (2.5%). The most common adverse reactions were fatigue (28% with KEYTRUDA vs. 28% with ipilimumab), diarrhea (26% with KEYTRUDA), rash (24% with KEYTRUDA vs. 23% with ipilimumab), and nausea (21% with KEYTRUDA). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

In Trial 2, KEYTRUDA was discontinued due to adverse reactions in 12% of 357 patients with advanced melanoma; the most common (≥1%) were general physical health deterioration (1%), asthenia (1%), dyspnea (1%), pneumonitis (1%), and generalized edema (1%). Adverse reactions leading to interruption of KEYTRUDA occurred in 14% of patients; the most common (≥1%) were dyspnea (1%), diarrhea (1%), and maculo-papular rash (1%). The most common adverse reactions were fatigue (43% with KEYTRUDA), pruritus (28% with KEYTRUDA vs. 8% with chemotherapy), rash (24% with KEYTRUDA vs. 8% with chemotherapy), constipation (22% with KEYTRUDA vs. 20% with chemotherapy), nausea (22% with KEYTRUDA), diarrhea (20% with KEYTRUDA vs. 20% with chemotherapy), and decreased appetite (20% with KEYTRUDA). Corresponding incidence rates are listed for chemotherapy only for those adverse reactions that occurred at the same or lower rate than with KEYTRUDA.

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

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

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

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

On December 18, 2015 AstraZeneca reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending the marketing authorisation of TAGRISSO (AZD9291, osimertinib) 80mg once-daily tablets for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, DEC 18, 2015, View Source;receives-positive-chmp-opinion-18122015.html [SID:1234508606]).

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This indication includes NSCLC patients whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and patients with a T790M mutation who have not been treated with an EGFR-TKI.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The CHMP’s recommendation for osimertinib to receive marketing approval is a positive step for patients in Europe. This follows the recent US accelerated approval of osimertinib and its adoption in the UK under the Early Access to Medicines Scheme to meet urgent unmet need. Building on the breakthrough clinical evidence, we’re investigating osimertinib’s full potential as a monotherapy and in novel combinations with other precision medicines and immunotherapies from our comprehensive oncology pipeline."

AURA study clinical investigator Professor Jean-Charles Soria, Head of Drug Development Department, Gustave Roussy Cancer Center, Paris, France added; "In Europe, lung cancer kills over 260,000 people every year, so there is an urgent need for new treatments. As a treating physician, it is very gratifying to see the progression of osimertinib towards use in clinical practice for patients living with EGFRm T790M non-small cell lung cancer."

Osimertinib is an EGFR-TKI designed to inhibit both the activating, sensitising mutation (EGFRm), and T790M, a genetic mutation responsible for EGFR-TKI treatment resistance. Nearly two-thirds of patients with EGFRm NSCLC whose disease progresses after EGFR-TKI treatment develop the T790M resistance mutation, for which treatment options are limited.

The CHMP recommendation for osimertinib is based on data from two Phase II studies (AURA extension and AURA2) and the AURA Phase I expansion study, which demonstrated efficacy in 474 EGFRm T790M NSCLC patients who had progressed on or after an EGFR-TKI. In the combined Phase II studies, the objective response rate (ORR, a measurement of tumor shrinkage) was 66%, and in the Phase I study it was 62%. Progression-free survival (PFS) was 9.7 months in the combined Phase II studies and 11 months in the Phase I trial. Median duration of response (DOR) in the Phase I study was 9.7 months and in the combined Phase II studies, median duration of response was not reached.

The most common adverse events based on data from the two AURA Phase II studies were generally mild to moderate and included diarrhoea (42% all grades; 1.0% Grade 3/4), rash (41% all grades; 0.5% Grade 3/4), dry skin (31% all grades; 0% Grade 3/4), and nail toxicity (25% all grades; 0% Grade 3/4). Warnings and precautions include interstitial lung disease, QT interval prolongation and embryofoetal toxicity.

The positive CHMP recommendation has been received through the EMA’s Accelerated Assessment and follows the recent US Accelerated Approval of osimertinib by the Food and Drug Administration (FDA). In Japan, osimertinib was granted Priority Review by the Pharmaceuticals and Medical Devices Agency (PMDA). Interactions with regulatory authorities in the rest of the world are ongoing.

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined. Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe and 30-40 percent of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with the approved EGFR-TKIs, gefitinib, erlotinib or afatinib, this resistance is caused by the secondary mutation, T790M.

About osimertinib

Osimertinib 80mg once-daily tablet is the first potential medicine indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC. Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.

Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M-positive, locally advanced, or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, and in combination with other compounds.December 2015

AstraZeneca reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion, recommending the marketing authorisation of TAGRISSO (AZD9291, osimertinib) 80mg once-daily tablets for the treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC).

This indication includes NSCLC patients whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and patients with a T790M mutation who have not been treated with an EGFR-TKI.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "The CHMP’s recommendation for osimertinib to receive marketing approval is a positive step for patients in Europe. This follows the recent US accelerated approval of osimertinib and its adoption in the UK under the Early Access to Medicines Scheme to meet urgent unmet need. Building on the breakthrough clinical evidence, we’re investigating osimertinib’s full potential as a monotherapy and in novel combinations with other precision medicines and immunotherapies from our comprehensive oncology pipeline."

AURA study clinical investigator Professor Jean-Charles Soria, Head of Drug Development Department, Gustave Roussy Cancer Center, Paris, France added; "In Europe, lung cancer kills over 260,000 people every year, so there is an urgent need for new treatments. As a treating physician, it is very gratifying to see the progression of osimertinib towards use in clinical practice for patients living with EGFRm T790M non-small cell lung cancer."

Osimertinib is an EGFR-TKI designed to inhibit both the activating, sensitising mutation (EGFRm), and T790M, a genetic mutation responsible for EGFR-TKI treatment resistance. Nearly two-thirds of patients with EGFRm NSCLC whose disease progresses after EGFR-TKI treatment develop the T790M resistance mutation, for which treatment options are limited.

The CHMP recommendation for osimertinib is based on data from two Phase II studies (AURA extension and AURA2) and the AURA Phase I expansion study, which demonstrated efficacy in 474 EGFRm T790M NSCLC patients who had progressed on or after an EGFR-TKI. In the combined Phase II studies, the objective response rate (ORR, a measurement of tumor shrinkage) was 66%, and in the Phase I study it was 62%. Progression-free survival (PFS) was 9.7 months in the combined Phase II studies and 11 months in the Phase I trial. Median duration of response (DOR) in the Phase I study was 9.7 months and in the combined Phase II studies, median duration of response was not reached.

The most common adverse events based on data from the two AURA Phase II studies were generally mild to moderate and included diarrhoea (42% all grades; 1.0% Grade 3/4), rash (41% all grades; 0.5% Grade 3/4), dry skin (31% all grades; 0% Grade 3/4), and nail toxicity (25% all grades; 0% Grade 3/4). Warnings and precautions include interstitial lung disease, QT interval prolongation and embryofoetal toxicity.

The positive CHMP recommendation has been received through the EMA’s Accelerated Assessment and follows the recent US Accelerated Approval of osimertinib by the Food and Drug Administration (FDA). In Japan, osimertinib was granted Priority Review by the Pharmaceuticals and Medical Devices Agency (PMDA). Interactions with regulatory authorities in the rest of the world are ongoing.

NOTES TO EDITORS

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-third of all cancer deaths, and more than breast, prostate and colorectal cancers combined. Patients who have the EGFRm form of NSCLC, which occurs in 10-15 percent of NSCLC patients in Europe and 30-40 percent of NSCLC patients in Asia, are particularly sensitive to treatment with currently available EGFR-TKIs, which block the cell signalling pathways that drive the growth of tumour cells. However, tumours almost always develop resistance to treatment, leading to disease progression. In approximately two-thirds of patients treated with the approved EGFR-TKIs, gefitinib, erlotinib or afatinib, this resistance is caused by the secondary mutation, T790M.

About osimertinib

Osimertinib 80mg once-daily tablet is the first potential medicine indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC. Non-clinical in vitro studies have demonstrated that osimertinib has high potency and inhibitory activity against mutant EGFR phosphorylation across the range of clinically relevant EGFRm and T790M mutant NSCLC cell lines, with significantly less activity against EGFR in wild-type cell lines.

Osimertinib is being compared with platinum-based doublet chemotherapy in the confirmatory AURA3 Phase III study in patients with EGFR T790M-positive, locally advanced, or metastatic NSCLC who have progressed after EGFR-TKI therapy. It is also being investigated in the adjuvant and metastatic first-line settings, including in patients with brain metastases, and in combination with other compounds.

On December 18, 2015 Agios Pharmaceuticals, Inc. (NASDAQ:AGIO), a leader in the fields of cancer metabolism and rare genetic metabolic disorders, reported the initiation of a Phase 1b, multicenter, international, open-label study of AG-221 or AG-120 in combination with induction and consolidation therapy in patients with newly diagnosed acute myeloid leukemia (AML) with an isocitrate dehydrogenase (IDH) mutation who are eligible for intensive chemotherapy. AG-221 and AG-120 are first-in-class, oral, selective, potent inhibitors of mutant IDH2 and IDH1, respectively, and are being developed in collaboration with Celgene (Press release, Agios Pharmaceuticals, DEC 18, 2015, View Source [SID:1234508605]).

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"The five-year survival rate for AML is just 20 to 25 percent, and treatment options for newly diagnosed AML patients have not changed in decades," said Courtney DiNardo, M.D., lead investigator and assistant professor, department of leukemia at the University of Texas MD Anderson Cancer Center. "By combining a targeted therapy such as AG-221 or AG-120 with standard-of-care intensive chemotherapy in the newly diagnosed setting, we have the potential to provide significant clinical benefit early in the course of treatment."

"Having established favorable safety profiles and durable single agent response rates for AG-221 and AG-120 in advanced AML, we believe there is a compelling case to evaluate our IDH mutant inhibitors in the frontline setting with standard of care," said Chris Bowden, M.D., chief medical officer of Agios. "Our goal is to advance AG-221 and AG-120 as rapidly as possible in a broad population in order to bring better treatment options to patients in need. This study is the first wave of our frontline strategy, with a second trial, being conducted by Celgene, combining our IDH mutant inhibitors with VIDAZA in patients not eligible for intensive chemotherapy planned for the first quarter of 2016."

About the Phase 1b Frontline Combination Trial of AG-221 or AG-120 in Newly Diagnosed AML Patients Eligible for Intensive Chemotherapy

The Phase 1b, multicenter, international, open-label clinical trial will evaluate the safety and clinical activity of AG-221 or AG-120 in combination with induction and consolidation therapy in patients with newly diagnosed AML with an IDH2 and/or IDH1 mutation who are eligible for intensive chemotherapy. The study will evaluate continuous dosing for up to one year with AG-221 administered at an initial oral dose of 100 mg once daily in patients with an IDH2 mutation or AG-120 administered at an initial oral dose of 500 mg once daily in patients with an IDH1 mutation. AG-221 or AG-120 will be administered with two types of AML induction therapies (cytarabine with either daunorubicin or idarubicin) and two types of AML consolidation therapies (mitoxantrone with etoposide [ME] or cytarabine).

The primary endpoint of the trial is to determine safety and tolerability, and the secondary endpoints include: characterization of pharmacokinetics, establishment of the recommended Phase 2 dose, and evaluation of 2-HG levels and clinical activity of the combination with standard induction. This study is open for enrollment and will include approximately twenty centers that will enroll up to 90 patients.

All patients will receive induction therapy in combination with AG-120 or AG-221. Patients who achieve a complete remission (CR), CR with incomplete platelet recovery (CRp) or CR with incomplete hematologic recovery (CRi) at the end of induction therapy will go on to receive consolidation therapy. Following consolidation therapy, patients may continue on maintenance therapy and receive daily treatment with AG-120 or AG-221 for up to one year, until relapse, development of an unacceptable toxicity or hematopoietic stem cell transplant (HSCT).

On December 18, 2015 AstraZeneca reported an update on preliminary findings from the ATLANTIC trial of durvalumab as 3rd-line or later stage therapy in patients with locally advanced or metastatic programmed death ligand-1 (PD-L1) positive non-small cell lung cancer (NSCLC) that lacks epidermal growth factor receptor (EGFR) or ALK alterations (Press release, AstraZeneca, DEC 18, 2015, View Source [SID:1234508599]).

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An initial analysis supports durvalumab’s clinical activity, with durable responses and an established safety profile in these difficult-to-treat patients.

ATLANTIC investigated the efficacy and tolerability of durvalumab in patients who received at least two prior systemic treatment regimens including platinum-based chemotherapy, and who have limited options for further therapy. A full evaluation of the data is ongoing and the results will be presented at a scientific congress in 2016.

Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: "As we have seen in other studies, durvalumab has demonstrated expected clinical activity and durable response in these heavily pre-treated patients. As previously communicated, the treatment and regulatory landscape in lung cancer is evolving. We now believe it is unlikely that ATLANTIC can be used for regulatory submission as a monotherapy, but we will make that determination following a full analysis of the data. Durvalumab is a cornerstone of our immuno-oncology portfolio with a fast advancing development programme focused primarily on novel combinations."

A comprehensive durvalumab registration programme is underway across multiple tumour types, stages of disease, and lines of therapy both as monotherapy and in combination. This forms part of AstraZeneca’s late-stage immuno-oncology programme and includes more than 9,000 patients in 16 clinical trials in lung, bladder, head & neck, and other cancers, summarised below.

NOTES TO EDITORS

About durvalumab (MEDI4736)

Durvalumab is an investigational human monoclonal antibody directed against PD-L1. Signals from PD-L1 help tumours avoid detection by the immune system. Durvalumab blocks these signals, countering the tumour’s immune-evading tactics. Durvalumab is being developed, alongside other immunotherapies, to empower the patient’s immune system and attack the cancer. Durvalumab is being investigated in an extensive clinical trial programme, as monotherapy or in combination with tremelimumab, in NSCLC, head and neck, gastric, pancreatic, bladder and blood cancers.

About the ATLANTIC trial

ATLANTIC is a Phase II, non-comparative, open-label, multi-centre, international trial of durvalumab in patients with locally advanced or metastatic NSCLC (Stage IIIB-IV) who have received at least two prior systemic treatment regimens including one platinum-based chemotherapy regimen.