On April 20, 2015 TetraLogic Pharmaceuticals and Merck reported they have entered into an oncology clinical study collaboration (Press release, Merck & Co, APR 20, 2015, http://www.mercknewsroom.com/news-release/oncology-newsroom/tetralogic-and-merck-collaborate-evaluation-birinapant-combination-ke [SID:1234503073]). The companies will collaborate on a Phase 1 study to evaluate the safety and efficacy of birinapant, TetraLogic’s SMAC-mimetic, in combination with KEYTRUDA (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with relapsed or refractory solid tumors. The study is expected to begin in late 2015.

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KEYTRUDA and birinapant target different elements of cancer’s block against the immune system. TetraLogic’s birinapant (TL32711) is a potent, bivalent SMAC-mimetic that binds with differential affinity to multiple members of the IAP family in order to re-establish the immune system’s ability to kill abnormal cells via an extracellular TNF signal. Merck’s KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 (programmed death receptor-1) and its ligands, PD-L1 and PD-L2. The proposed collaboration is based on preclinical data that suggest SMAC-mimetics have the potential to enhance existing immuno-oncology agents, such as KEYTRUDA.

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"We are very excited to work with Merck to evaluate birinapant in combination with KEYTRUDA," said J. Kevin Buchi, President and Chief Executive Officer of TetraLogic. "Both molecules are designed to help the body’s immune system better attack cancer cells, and we think the combination could be very promising."

"We are establishing a broad base of clinical evidence with our anti-PD-1 therapy, KEYTRUDA, as monotherapy across different types of cancer," said Dr. Eric Rubin, vice president and therapeutic area head, oncology early-stage development, Merck Research Laboratories. "We believe there is great potential to advance our clinical program and the field of immuno-oncology research through strategic collaborations and synergistic combinations, such as with KEYTRUDA and birinapant."

Under the terms of the agreement, TetraLogic and Merck, through subsidiaries, will collaborate on an initial Phase 1 dose-escalation study of birinapant in combination with KEYTRUDA in patients with relapsed or refractory solid tumors. TetraLogic will sponsor and fund the study and Merck will provide KEYTRUDA. The companies have formed a Joint Development Committee to collaboratively oversee the conduct of the study. Results from the study will be used to determine the path for further clinical development of the combination.

About Birinapant

Cancer and chronically infected cells are able to evade a critical mechanism by which the immune system normally kills abnormal or genetically modified cells. They do this by upregulating the Inhibitors of Apoptosis (IAP) Proteins. Birinapant (TL32711) is a potent, bivalent SMAC-mimetic that binds with differential affinity to multiple members of the IAP family in order to re-establish the immune system’s ability to kill abnormal cells via an extracellular TNF signal. Birinapant has been studied in over 350 patients, and is currently in Phase 1 and Phase 2 trials for Myelodysplastic Syndrome (MDS), Ovarian Cancer and Hepatitis B.

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.

KEYTRUDA is 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.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 85 clinical trials – across more than 30 tumor types and over 14,000 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 with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), 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. 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. 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.

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 for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

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.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, 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.

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 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. 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. 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 April 17, 2015 Bristol-Myers Squibb reported that an open-label, randomized Phase III study evaluating Opdivo (nivolumab) versus docetaxel in previously treated patients with advanced non-squamous non-small cell lung cancer (NSCLC) was stopped early because an assessment conducted by the independent Data Monitoring Committee (DMC) concluded that the study met its endpoint, demonstrating superior overall survival in patients receiving Opdivo compared to the control arm (Press release, Bristol-Myers Squibb, APR 17, 2015, View Source [SID:1234503038]). The company looks forward to sharing these data with health authorities soon.

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"The results of CheckMate -057 mark the second time Opdivo has demonstrated a survival advantage in lung cancer," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Through our Opdivo clinical development program, we seek to bring the potential for long-term survival to a broad range of patients, across lines of therapy and stages of disease."

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CheckMate -057 investigators are being informed of the decision to stop the comparative portion of the trial. Bristol-Myers Squibb is working to ensure that eligible patients will be informed of the opportunity to continue or start treatment with Opdivo in an open-label extension as part of the company’s commitment to providing patient access to Opdivo, and characterizing long-term survival. The company will complete a full evaluation of the final CheckMate -057 data and work with investigators on the future presentation and publication of the results.

About CheckMate -057

CheckMate -057 is a Phase III, open-label, randomized study of Opdivo versus docetaxel in previously treated patients with advanced or metastatic non-squamous NSCLC. The trial randomized 582 patients to receive either nivolumab 3 mg/kg intravenously every two weeks or docetaxel 75 mg/m2 intravenously every three weeks. The primary endpoint is overall survival. Secondary endpoints include objective response rate and progression free survival.

About Lung Cancer

Lung cancer is the leading cause of cancer deaths globally, resulting in more than 1.5 million deaths each year according the World Health Organization. NSCLC is one of the most common types of the disease and accounts for approximately 85 percent of cases. Survival rates vary depending on the stage and type of the cancer when it is diagnosed. Globally, the five-year survival rate for Stage I NSCLC is between 47 and 50 percent; for Stage IV NSCLC, the five-year survival rate drops to two percent.

Immuno-Oncology at Bristol-Myers Squibb

Surgery, radiation, cytotoxic or targeted therapies have represented the mainstay of cancer treatment over the last several decades, but long-term survival and a positive quality of life have remained elusive for many patients with advanced disease.

To address this unmet medical need, Bristol-Myers Squibb is leading research in an innovative field of cancer research and treatment known as immuno-oncology, which involves agents whose primary mechanism is to work directly with the body’s immune system to fight cancer. The company is exploring a variety of compounds and immunotherapeutic approaches for patients with different types of cancer, including researching the potential of combining immuno-oncology agents that target different and complementary pathways in the treatment of cancer.

Bristol-Myers Squibb is committed to advancing the science of immuno-oncology, with the goal of changing survival expectations and the way patients live with cancer.

About Opdivo

Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that has received approval from the U.S. Food and Drug Administration as a monotherapy in two cancer indications. On March 5, 2015, Opdivo received FDA approval for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

In the U.S., Opdivo is also indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy (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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Opdivo became the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world on July 4, 2014 when Ono Pharmaceutical Co. announced that it received manufacturing and marketing approval in Japan for the treatment of patients with unresectable melanoma. Bristol-Myers Squibb has a broad, global development program to study Opdivo in multiple tumor types consisting of more than 50 trials – as monotherapy or in combination with other therapies – in which more than 7,000 patients have been enrolled worldwide.

IMPORTANT SAFETY INFORMATION

Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immune-mediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis

In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immune-mediated hepatitis.

Immune-Mediated Nephritis and Renal Dysfunction

In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyeliniation, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone- replacement therapy.

Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO is present in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see U.S. Full Prescribing Information for OPDIVO available at www.bms.com.

On April 17, 2015 AstraZeneca reported that the US Food and Drug Administration has granted Orphan Drug Designation for the MEK inhibitor selumetinib, for the treatment of uveal melanoma (Press release, AstraZeneca, APR 17, 2015, View Source;selumetinib-granted-orphan-drug-designation-by-us-fda [SID:1234503032]).

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Uveal melanoma is a rare disease in which cancer cells form in the tissues of the eye. It is the most common primary intraocular malignancy in adults and comprises 5% of all melanomas1,2.

"Uveal melanoma is a rare and devastating disease for which there are currently no effective treatment options once it spreads beyond the tissues of the eye. Selumetinib could potentially become the first effective treatment for these patients. The Orphan Drug Designation is an important regulatory advancement as we further our development plans for selumetinib in uveal melanoma," said Antoine Yver, Head of Oncology, Global Medicines Development at AstraZeneca.

The Orphan Drug Designation programme provides orphan status to drugs and biologics, which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US3.

Selumetinib, originally licensed from Array BioPharma Inc., inhibits the MEK pathway in cancer cells to prevent the tumour from growing. Data from a phase III study evaluating selumetinib in combination with chemotherapy in patients with first-line metastatic uveal melanoma is expected to be available later this year. In addition to uveal melanoma, selumetinib is being investigated in Phase III studies in KRAS mutation positive lung cancer and thyroid cancer and in Phase II in children with neurofibromatosis Type 1.

Initial data from a combination study of selumetinib with other AstraZeneca pipeline molecules including AZD9291 (T790M-directed EGFR inhibitor) and MEDI4736 (anti-PD-L1) in non-small cell lung cancer will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting 2015.

On April 17, 2015 AstraZeneca reported latest data from the ongoing AURA Phase I/II study of AZD9291 in patients with advanced epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC), who also have the T790M resistance mutation (Press release, AstraZeneca, APR 17, 2015, View Source;astrazeneca-announces-update-azd9291 [SID:1234503031]). The data demonstrated a median progression free survival (PFS) of 13.5 months (95% confidence interval (CI) 8.3 months to not calculable (NC))1. These PFS findings relate to independently reviewed data from 63 patients with T790M tumours treated with AZD9291 at a dose of 80mg per day, and are based on only 38% of patients having tumour progression.

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The updated data also show an overall response rate with AZD9291 80mg of 54% (95% CI 41% to 67%) and a median duration of response of 12.4 months (95% CI 8.3 months to NC).

Presenting the latest analysis at the European Lung Cancer Conference (ELCC) 2015 in Geneva, Switzerland, AURA principal investigator Dr Pasi A. Jänne MD, PhD, Director, Lowe Center for Thoracic Oncology Dana-Farber Cancer Institute and Professor of Medicine Harvard Medical School, emphasised the sustained activity of AZD9291 as indicated by the key parameters of patient response: "There are few treatment options currently available for patients with advanced EGFRm non-small cell lung cancer who experience disease progression due to a second mutation known as T790M. Management is usually limited to chemotherapy or re-challenge with EGFR tyrosine kinase inhibitors. As AURA continues to mature, and the trend in progression free survival and durable clinical response is maintained, this may support the potential for AZD9291 as a future treatment option for advanced EGFRm NSCLC."

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AZD9291 is a once daily, selective, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to target both the activating sensitising mutation, EGFRm, and T790M, the genetic mutation responsible for EGFR TKI treatment resistance in up to approximately two-thirds of cases of EGFRm advanced NSCLC. There are currently no treatments specifically approved for patients with EGFRm T790M advanced NSCLC.

Antoine Yver, Head of Oncology, Global Medicines Development, AstraZeneca, said: "We are committed to developing novel medicines that address the significant unmet need in lung cancer by focusing on the genetic drivers underlying the disease. We are on track for a regulatory submission of AZD9291 in the US in the second quarter of this year. Our extensive clinical research programme is also investigating the potential of AZD9291 in earlier disease and in combination with other pipeline assets including immuno-oncology molecules. With this comprehensive approach, our goal is to develop a broad range of potential treatment options for patients with EGFR mutation positive non-small cell lung cancer."

The ongoing AURA Phase I/II study is investigating AZD9291 in patients with advanced NSCLC and disease progression following treatment with an EGFR TKI. As of 2 December 2014, 283 patients with EGFRm advanced NSCLC and acquired resistance to EGFR TKIs were enrolled – 31 patients in dose escalation and 252 patients in expansion cohorts. Of these patients, 163 had T790M tumours confirmed by central testing1. The updated results presented at ELCC build on previously reported data presented at the European Society for Medical Oncology 20142.

In patients treated with AZD9291 80mg, the most common all-cause adverse events (AEs) of any grade were rash, 38% (0% Grade ≥3) and diarrhea, 36% (1% Grade ≥3). Investigator-determined treatment-related Grade ≥3 AEs occurred in 14% of patients.

As of 19 March 2015, of more than 1000 patients across all studies dosed with AZD9291, interstitial lung disease (ILD) grouped term events were reported in approximately 2.7% of patients (27 events): 12 common terminology criteria for adverse events (CTCAE) grade 1–2; 13 grade ≥3; 2 currently ungraded. Of these, a total of 3 patients were reported to have died due to ILD (Grade 5).

AstraZeneca is currently also investigating AZD9291 as first line therapy for EGFRm NSCLC patients, and in combination with MEDI4736 (anti-PDL1 immunotherapy), selumetinib (MEK inhibitor) and AZD6094 (MET inhibitor) in NSCLC. Initial data will be presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting 2015.

NOTES TO EDITORS

1 Jänne PA, et al. A Phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC – updated progression-free survival and duration of response data. Presented at the European Lung Cancer Conference (ELCC) Annual Meeting, Geneva; 15-18 April 2015.

2 Yang, J, et al. Updated safety and efficacy from a Phase 1 study of AZD9291 in patients (pts) with EGFR-TKI-resistant non-small cell lung cancer (NSCLC). Presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Meeting, Madrid; 26-30 September 2014. Abstract available at: View Source Accessed March 2015.

About AZD9291

AZD9291 is an investigational, highly selective, irreversible inhibitor of both activating sensitising EGFRm and the resistance mutation, T790M, while sparing the activity of wild type EGFR.2 AZD9291 is also designed to achieve minimal or no activity against two biological receptors, known as the insulin receptor and insulin-like growth factor receptor (IFGR), in order to avoid the potential for hyperglycaemia. Hyperglycaemia (high blood sugar) can lead to patients requiring treatment with additional medications.

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, tumour cells almost always develop resistance to treatment, leading to disease progression. In up to approximately two-thirds of patients with EGFRm advanced NSCLC, this resistance is caused by a secondary mutation known as T790M. There are currently no treatments specifically approved specifically for EGFRm T790M advanced NSCLC.

AZD9291 has been granted Breakthrough Therapy designation, Orphan Drug and Fast Track status by the US Food and Drug Administration (FDA).