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Pfizer Presents Overall Survival Data of XALKORI in Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer

On September 11, 2017 Pfizer Inc. (NYSE:PFE) reported final overall survival (OS) data from the PROFILE 1014 trial examining XALKORI (crizotinib) in previously untreated patients with ALK-positive advanced non-small cell lung cancer(NSCLC) (Press release, Pfizer, SEP 11, 2017, View Source [SID1234520471]). After a median follow-up of 46 months, the median OS for patients randomized to XALKORI was not reached (95% CI: 45.8 months, not reached) and was 47.5 months for patients randomized to chemotherapy (95% CI: 32.2 months, not reached). Results indicated a numerical improvement in OS for patients treated with first-line XALKORI compared with chemotherapy, though this difference did not quite achieve statistical significance (HR=0.760 [95% CI: 0.548, 1.053]; p=0.0978). These data [Abstract #LBA50] were presented today at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, Spain.

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The majority (84%) of patients initially randomized to chemotherapy received XALKORI after they progressed and this likely affected the overall survival results. A pre-specified, exploratory statistical analysis, adjusting for the effects of crossover, determined that median OS would have been longer for patients randomized to XALKORI than for patients randomized to chemotherapy, if patients had not been allowed to cross over [HR: 0.346 (95% CI: 0.081, 0.718)].

"PROFILE 1014 has provided important new data for patients with non-small cell lung cancer," said Professor Tony Mok, Chair of Department of Clinical Oncology, The Chinese University of Hong Kong. "This is the first set of prospective data from a randomized Phase 3 study to report long-term survival outcomes for patients with ALK-positive non-small cell lung cancer. The longest survival outcomes were in patients who received two or more tyrosine kinase inhibitors, which provides insight into optimal treatment sequencing."

Overall survival was a secondary endpoint of PROFILE 1014 and the threshold for statistical significance was p≤0.0247.1 PROFILE 1014 was a global, randomized, open-label, two-arm Phase 3 study that evaluated the efficacy and safety of XALKORI in patients with previously untreated ALK-positive advanced NSCLC. Progression-free survival (PFS) was the primary endpoint, and these results were previously published in The New England Journal of Medicine (NEJM). There was a statistically significant improvement in PFS in the patients treated with XALKORI than with chemotherapy (p<0.001). A total of 343 patients were randomized into the trial, with approximately half of the patients in the XALKORI arm and the other half of the patients in the platinum doublet chemotherapy arm.

"XALKORI was the first biomarker-driven therapy for ALK-positive NSCLC and as such, dramatically changed the treatment paradigm for these patients. It remains the only ALK inhibitor with mature survival data from a randomized Phase 3 trial. We are extremely proud of the impact XALKORI continues to make on patients’ lives," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development.

The most commonly reported adverse events with XALKORI were vision disorder (71%), diarrhea (61%), nausea (56%) and edema (49%), and with chemotherapy, nausea (59%), fatigue (38%), vomiting (36%) and decreased appetite (34%). Most adverse events in both treatment groups were grade 1 or 2 in severity. Grade 3 or 4 elevations of aminotransferase levels occurred in 14% of patients in the XALKORI group and 2% of patients in the chemotherapy group, and these elevations were managed primarily with dose interruptions or dose reductions. Grade 3 or 4 neutropenia occurred in 11% and 15% of patients in the XALKORI and chemotherapy groups, respectively, with no cases of febrile neutropenia reported with XALKORI and two cases with chemotherapy.

About Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death worldwide.2 NSCLC accounts for about 85 percent of lung cancer cases and remains difficult-to-treat, particularly in the metastatic setting.3 Approximately 75 percent of NSCLC patients are diagnosed late with metastatic, or advanced, disease where the five-year survival rate is only 5 percent.3,4,5

About XALKORI (crizotinib)

XALKORI is a tyrosine kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. XALKORI has received approval for patients with ALK-positive NSCLC in more than 90 countries6including Australia, Canada, China, Japan, South Korea and the European Union.

XALKORI Important Safety Information

Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome occurred in 0.1% of patients treated with XALKORI across clinical trials (n=1719). Transaminase elevations generally occurred within the first 2 months. Monitor liver function tests, including ALT, AST, and total bilirubin, every 2 weeks during the first 2 months of treatment, then once a month, and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Permanently discontinue for ALT/AST elevation >3 times ULN with concurrent total bilirubin elevation >1.5 times ULN (in the absence of cholestasis or hemolysis); otherwise, temporarily suspend and dose-reduce XALKORI as indicated.

Interstitial Lung Disease (Pneumonitis): Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis can occur. Across clinical trials (n=1719), 2.9% of XALKORI-treated patients had any grade ILD, 1.0% had Grade 3/4, and 0.5% had fatal ILD. ILD generally occurred within 3 months after initiation of treatment. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Exclude other potential causes and permanently discontinue XALKORI in patients with drug-related ILD/pneumonitis.

QT Interval Prolongation: QTc prolongation can occur. Across clinical trials (n=1616), 2.1% of patients had QTcF (corrected QT by the Fridericia method) 500 ms and 5.0% had an increase from baseline QTcF 60 ms by automated machine-read evaluation of ECGs. Avoid use in patients with congenital long QT syndrome. Monitor ECGs and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that prolong the QT interval. Permanently discontinue XALKORI in patients who develop QTc >500 ms or 60 ms change from baseline with Torsade de pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia. Withhold XALKORI in patients who develop QTc >500 ms on at least 2 separate ECGs until recovery to a QTc -480 ms, then resume at a reduced dose.

Bradycardia: Symptomatic bradycardia can occur. Across clinical trials, bradycardia occurred in 12.7% of patients treated with XALKORI (n=1719). Avoid use in combination with other agents known to cause bradycardia. Monitor heart rate and blood pressure regularly. In cases of symptomatic bradycardia that is not life-threatening, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm, re-evaluate the use of concomitant medications, and adjust the dose of XALKORI. Permanently discontinue for life-threatening bradycardia due to XALKORI; however, if associated with concomitant medications known to cause bradycardia or hypotension, hold XALKORI until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm. If concomitant medications can be adjusted or discontinued, restart XALKORI at 250 mg once daily with frequent monitoring.

Severe Visual Loss: Across clinical trials, the incidence of Grade 4 visual field defect with vision loss was 0.2% (n=1719). Discontinue XALKORI in patients with new onset of severe visual loss (best corrected vision less than 20/200 in one or both eyes). Perform an ophthalmological evaluation. There is insufficient information to characterize the risks of resumption of XALKORI in patients with a severe visual loss; a decision to resume should consider the potential benefits to the patient.

Vision Disorders: Most commonly visual impairment, photopsia, blurred vision or vitreous floaters, occurred in 63.1% of 1719 patients. The majority (95%) of these patients had Grade 1 visual adverse reactions. 0.8% of patients had Grade 3 and 0.2% had Grade 4 visual impairment. The majority of patients on the XALKORI arms in Studies 1 and 2 (>50%) reported visual disturbances which occurred at a frequency of 4-7 days each week, lasted up to 1 minute, and had mild or no impact on daily activities.

Embryo-Fetal Toxicity: XALKORI can cause fetal harm when administered to a pregnant woman. Advise of the potential risk to the fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment and for at least 45 days (females) or 90 days (males) respectively, following the final dose of XALKORI.

ROS1-positive Metastatic NSCLC: Safety was evaluated in 50 patients with ROS1-positive metastatic NSCLC from a single-arm study, and was generally consistent with the safety profile of XALKORI evaluated in patients with ALK-positive metastatic NSCLC. Vision disorders occurred in 92% of patients in the ROS1 study; 90% of patients had Grade 1 vision disorders and 2% had Grade 2.

Adverse Reactions: Safety was evaluated in a phase 3 study in previously untreated patients with ALK-positive metastatic NSCLC randomized to XALKORI (n=171) or chemotherapy (n=169). Serious adverse events were reported in 34% of patients treated with XALKORI, the most frequent were dyspnea (4.1%) and pulmonary embolism (2.9%). Fatal adverse events in XALKORI-treated patients occurred in 2.3% of patients, consisting of septic shock, acute respiratory failure, and diabetic ketoacidosis. Common adverse reactions (all grades) occurring in ≥25% and more commonly (≥5%) in patients treated with XALKORI vs chemotherapy were vision disorder (71% vs 10%), diarrhea (61% vs 13%), edema (49% vs 12%), vomiting (46% vs 36%), constipation (43% vs 30%), upper respiratory infection (32% vs 12%), dysgeusia (26% vs 5%), and abdominal pain (26% vs 12%). Grade 3/4 reactions occurring at a ≥2% higher incidence with XALKORI vs chemotherapy were QT prolongation (2% vs 0%), esophagitis (2% vs 0%), and constipation (2% vs 0%). In patients treated with XALKORI vs chemotherapy, the following occurred: elevation of ALT (any grade [79% vs 33%] or Grade 3/4 [15% vs 2%]); elevation of AST (any grade [66% vs 28%] or Grade 3/4 [8% vs 1%]); neutropenia (any grade [52% vs 59%] or Grade 3/4 [11% vs 16%]); lymphopenia (any grade [48% vs 53%] or Grade 3/4 [7% vs 13%]); hypophosphatemia (any grade [32% vs 21%] or Grade 3/4 [10% vs 6%]). In patients treated with XALKORI vs chemotherapy, renal cysts occurred (5% vs 1%). Nausea (56%), decreased appetite (30%), fatigue (29%), and neuropathy (21%) also occurred in patients taking XALKORI.

Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Avoid concomitant use of CYP3A substrates with narrow therapeutic range in patients taking XALKORI. If concomitant use of CYP3A substrates with narrow therapeutic range is required in patients taking XALKORI, dose reductions of the CYP3A substrates may be required due to adverse reactions.

Lactation: Because of the potential for adverse reactions in breastfed infants, advise females not to breastfeed during treatment with XALKORI and for 45 days after the final dose.

Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.

Renal Impairment: Decreases in estimated glomerular filtration rate occurred in patients treated with XALKORI. Administer XALKORI at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr <30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.

For more information and full prescribing information, please visit www.XALKORI.com.

Novartis Phase III study demonstrates adjuvant Tafinlar® + Mekinist® reduced the risk of disease recurrence by 53% in patients with resected BRAF V600 mutation-positive melanoma

On September 11, 2017 Novartis reported results from a Phase III study of 870 patients with stage III BRAF V600E/K mutation-positive melanoma after complete surgical resection treated with the combination of Tafinlar (dabrafenib) + Mekinist (trametinib) [1] (Press release, Novartis, SEP 11, 2017, View Source [SID1234520470]). Findings from the COMBI-AD study, which met its primary endpoint, found a statistically significant 53% reduction in the risk of death or recurrence in patients treated with the BRAF and MEK inhibitor combination therapy versus placebo (HR [hazard ratio]: 0.47 [95% CI (confidence interval): 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001), with no new safety signals reported [1]. Results of the study will be presented during the Presidential Symposium today at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) in Madrid (Abstract #LBA6), and were simultaneously published in the New England Journal of Medicine[1],[2].

“The efficacy and tolerability of Tafinlar in combination with Mekinist seen in this study represent an important step forward in the treatment of stage III BRAF V600E/K mutation-positive melanoma,” said lead investigator Axel Hauschild, MD, PhD, Professor of Dermatology, University Hospital Schleswig-Holstein, in Kiel, Germany. “These unprecedented results confirm a targeted therapy combination has the potential to transform the standard of care in the melanoma adjuvant setting.”

“While surgery is a curative option for most patients with localized melanoma, there is a need for improved standard of care therapies for patients – especially for stage III disease, which carries a higher risk of relapse and death following resection,” said Vas Narasimhan, Global Head Drug Development and Chief Medical Officer, Novartis. “The COMBI-AD data results address a significant unmet need in patients with stage III melanoma. We look forward to discussing the results with regulatory authorities worldwide.”

The COMBI-AD study evaluated Tafinlar + Mekinist among patients with stage III, BRAF V600E/K-mutant melanoma without prior anticancer therapy, randomized within 12 weeks of complete surgical resection. Patients received the Tafinlar (150 mg BID) and Mekinist (2 mg QD) combination (n = 438) or matching placebos (n = 432)[1]. After a median follow-up of 2.8 years, the primary endpoint was met in that combination therapy significantly reduced the risk of disease recurrence or death by 53% vs. placebo (HR: 0.47 [95% CI: 0.39-0.58]; median not reached vs. 16.6 months, respectively; p<0.001) [1]. The relapse-free survival benefit among the combination arm was observed across all patient subgroups, including stage III A, B and C. The estimated one-year, two-year, and three-year RFS were consistently higher than placebo (one year: 88% vs. 56%; two year: 67% vs. 44%; three year: 58% vs. 39%) [1]. The combination treatment group also saw an improvement in a key secondary endpoint of OS (HR: 0.57 [95% CI: 0.42-0.79] p=0.0006, which did not cross the predefined interim analysis boundary of p=0.000019 to claim statistical significance). Other secondary endpoints where the combination demonstrated a clinically meaningful benefit include DMFS (HR: 0.51 [95% CI: 0.40-0.65]), and FFR (HR: 0.47 [95% CI: 0.39-0.57]) [1]. Adverse events (AEs) were consistent with other Tafinlar + Mekinist studies, and no new safety signals were reported [1]. Of patients treated with the combination, 97% experienced an AE; 41% had grade 3/4 AEs and 26% had AEs leading to treatment discontinuation (vs. 88%, 14% and 3%, respectively, with placebo) [1]. In a separate study, Novartis presented Phase II results from BRF113928, showing efficacy for patients with BRAF V600E-mutant metastatic non-small cell lung cancer (NSCLC) without prior systemic therapy for metastatic disease when treated with the combination of Tafinlar + Mekinist (Abstract #LBA51) [3]. Among the 36 treatment-naïve patients receiving 150 mg of Tafinlar twice daily and 2 mg of Mekinist once daily, the overall response rate (ORR) was 64% (95% CI: 46%-79%). After a median follow-up of 15.9 months, median duration of response (DoR) was 10.4 months (95% CI: 8.3-17.9 months), and median progression-free survival (PFS) was 10.9 months (95% CI: 7.0-16.6 months) [3]. Median OS was 24.6 months (95% CI: 12.3 months-not estimable), two-year OS rate was 51% (95% CI: 33-67%)[3]. These study results were simultaneously published in The Lancet Oncology [4]. Findings from the study demonstrated clinically meaningful antitumor activity in patients who had not received prior systemic therapy and in patients who had received at least one platinum-based chemotherapy for their metastatic NSCLC, supporting recent approvals by the European Commission (EC) and US Food and Drug Administration (FDA). The most common AEs (incidence >20%) were pyrexia, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, edema, rash, chills, hemorrhage, cough and dyspnea.

Additional poster and oral presentations related to the investigational use of Tafinlar and Mekinist in melanoma were also presented at the meeting, including:

Phase II Study of Neoadjuvant Dabrafenib + Trametinib (D+T) for Resectable Stage IIIB/C BRAF V600-Mutant Melanoma [Abstract #1220PD]
Five-year Efficacy and Safety Update From METRIC: Trametinib vs. Chemotherapy in Patients with BRAF V600E/K-Mutant Advanced or Metastatic Melanoma [Abstract #1226PD]
A Phase III Randomized, Double-Blind, Placebo-Controlled Study Comparing the Combination of PDR001 + Dabrafenib + Trametinib vs. Placebo + Dabrafenib + Trametinib in Treatment-Naïve Patients with Unresectable or Metastatic BRAF V600-Mutant Melanoma (COMBI-i) [Abstract #1259TiP]
KEYNOTE-022 Update: Phase I Study of First-Line Pembrolizumab (pembro) Plus Dabrafenib (D) and Trametinib (T) for BRAF-Mutant Advanced Melanoma [Abstract # 1216O]
A Phase II, Randomized, Open Label Study of Neoadjuvant Pembrolizumab with/without Dabrafenib and Trametinib (D+T) in BRAF V600-Mutant Resectable Stage IIIB/C/D Melanoma (NeoTrio Trial) [Abstract #1256TiP]
Dabrafenib and Trametinib Combination in Real Life Patients Including Brain Metastases: French Experience within MelBase [Abstract #1255P]
About COMBI-AD
The COMBI-AD study is a randomized, double-blind, placebo-controlled, Phase III study and included a total of 870 patients with stage III, BRAF V600E/K-mutant melanoma who had undergone prior complete surgical resection. Patients were treated for 12 months and stratified based on BRAF mutation (V600E vs. V600K) and stage (IIIA vs. IIIB vs. IIIC).

The primary endpoint was RFS. Secondary endpoints included OS, DMFS, FFR, and safety.

About Melanoma
There are about 200,000 new cases of melanoma diagnosed worldwide each year, approximately half of which have BRAF mutations. Gene tests can determine whether a tumor has a BRAF mutation [5],[6]. Patients who receive surgical treatment for melanoma may have a high risk of recurrence because melanoma cells can remain in the body after surgery[7]. Adjuvant therapy may be recommended for patients with high-risk melanoma to help reduce the risk of melanoma returning [7].

About Tafinlar + Mekinist Combination
Combination use of Tafinlar + Mekinist in patients with unresectable or metastatic melanoma who have a BRAF V600 mutation is approved in the US, EU, Australia, Canada and other countries.

The combination of Tafinlar + Mekinist is also approved for the treatment of metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation in the US and advanced NSCLC with a BRAF V600 mutation in the EU.

Tafinlar and Mekinist target different kinases within the serine/threonine kinase family – BRAF and MEK1/2, respectively – in the RAS/RAF/MEK/ERK pathway, which is implicated in NSCLC and melanoma, among other cancers. When Tafinlar is used with Mekinist, the combination has been shown to slow tumor growth more than either drug alone. The combination of Tafinlar + Mekinist is currently being investigated in an ongoing clinical trial program across a range of tumor types conducted in study centers worldwide.

The safety and efficacy profile of the Tafinlar + Mekinist combination has not yet been established outside of the approved indications.

Tafinlar and Mekinist are also indicated in more than 60 countries worldwide, including the US and EU, as single agents to treat patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Tafinlar + Mekinist Combination Important Safety Information
Tafinlar + Mekinist combination may cause serious side effects.

Tafinlar in combination with Mekinist should only be used to treat patients with a change (mutation) in the BRAF gene; therefore, doctors should test their patients before treatment, as patients without a BRAF mutation and with a RAS mutation can be at risk of increased cell proliferation in the presence of a BRAF inhibitor.

Doctors should also consider other treatment options for their patients if they had been previously treated with a BRAF inhibitor as single agent, as the limited data available have shown that the efficacy of Tafinlar + Mekinist is lower in these patients.

When Tafinlar is used in combination with Mekinist, or when Tafinlar is administered as monotherapy, it can cause new cancers (both skin cancer and non-skin cancer). Patients should be advised to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or signs and symptoms of other malignancies.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause severe bleeding, and in some cases can lead to death. Patients should be advised to call their healthcare provider and get medical help right away if they have headaches, dizziness, or feel weak, cough up blood or blood clots, vomit blood or their vomit looks like “coffee grounds,” have red or black stools that look like tar, or any unusual signs of bleeding.

Tafinlar in combination with Mekinist, or either drug alone, can cause severe eye problems that can lead to blindness. Patients should be advised to call their healthcare provider right away if they get these symptoms of eye problems: blurred vision, loss of vision, or other vision changes, seeing color dots, halo (seeing blurred outline around objects), eye pain, swelling, or redness.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause fever which may be serious. When taking Tafinlar in combination with Mekinist, fever may happen more often or may be more severe. In some cases, chills or shaking chills, too much fluid loss (dehydration), low blood pressure, dizziness, or kidney problems may happen with the fever. Patients should be advised to call their healthcare provider right away if they get a fever above 38.5oC (101.3oF) while taking Tafinlar.

Tafinlar in combination with Mekinist, or Mekinist alone, can affect how well the heart pumps blood. A patient’s heart function should be checked before and during treatment. Patients should be advised to call their healthcare provider right away if they have any of the following signs and symptoms of a heart problem: feeling like their heart is pounding or racing, shortness of breath, swelling of their ankles and feet, or feeling lightheaded.

Tafinlar in combination with Mekinist, or Tafinlar alone, can cause abnormal kidney function or inflammation of the kidney. Abnormal kidney function may happen more often for patients with fever or too much fluid loss. Patients should be advised to call their healthcare provider right away if they have a fever above 38.5oC (101.3oF), decreased urine, fatigue, loss of appetite or discomfort in lower abdomen or back. Tafinlar has not been studied in patients with renal insufficiency (defined as creatinine > 1.5 x ULN) therefore caution should be used in this setting.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause abnormal liver function. A patient may feel tired, lose appetite, yellow skin, dark urine colour, or discomfort in abdomen. The liver function abnormality needs to be assessed by laboratory test of the blood. Patients should consult their healthcare provider if they have such experience. Administration of Tafinlar or Mekinist should be done with caution in patients with moderate to severe hepatic impairment.

Elevations in blood pressure have been reported in association with Mekinist in combination with Tafinlar, or with Mekinist alone, in patients with or without pre-existing hypertension. Patients should be advised to monitor blood pressure during treatment with Mekinist and control potential hypertension by standard therapy, as appropriate.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause inflammation of the lung tissue. Patients should notify their doctor if they experience any new or worsening symptoms of lung or breathing problems, including shortness of breath or cough.

Rash is a common side effect of Tafinlar in combination with Mekinist, or with Mekinist alone. Tafinlar in combination with Mekinist, or Mekinist alone, can also cause other skin reactions which can be severe, and may need to be treated in a hospital. Patients should be advised to call their healthcare provider if they get any of the following symptoms: skin rash that bothers them or does not go away, acne, redness, swelling, peeling, or tenderness of hands or feet, skin redness.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause muscle breakdown, a condition called Rhabdomyolysis. Patients experiencing muscle pain, tenderness, weakness or a swelling of their muscles should contact their healthcare provide immediately.

Tafinlar in combination with Mekinist, or Tafinlar alone, can uncommonly cause an inflammation of the pancreas (pancreatitis). Patients should be promptly investigated if they experience unexplained abdominal pain and closely monitored if they re-start Tafinlar after a prior episode of pancreatitis.

Tafinlar in combination with Mekinist, or Mekinist alone, can cause blood clots in the arms or legs, which can travel to the lungs and can lead to death. Patients should be advised to get medical help right away if they have the following symptoms: chest pain, sudden shortness of breath or trouble breathing, pain in their legs with or without swelling, swelling in their arms or legs, or a cool or pale arm or leg.

Mekinist in combination with Tafinlar, or Mekinist alone, may increase the risk of developing holes in the stomach or intestine (gastrointestinal perforation). Treatment with Mekinist alone or in combination with Tafinlar should be used with caution in patients with risk factors for gastrointestinal perforation, including concomitant use of medications with a recognized risk of gastrointestinal perforation.

Tafinlar and Mekinist both can cause harm to an unborn baby when taken by a pregnant woman. Tafinlar can also render hormonal contraceptives ineffective.

The most common side effects of Tafinlar + Mekinist combination include fever, nausea, diarrhea, fatigue, chills, headache, vomiting, joint pain, high blood pressure, rash and cough. The incidence and severity of fever is increased when Mekinist is used in combination with Tafinlar.

Patients should tell their doctor of any side effect that bothers them or does not go away. These are not all of the possible side effects of Tafinlar + Mekinist combination. For more information, patients should ask their doctor or pharmacist.

Patients should take Tafinlar + Mekinist combination exactly as their health care provider tells them. Patients should not change their dose or stop taking Tafinlar + Mekinist combination unless their health care provider advises them to. Mekinist should be taken only once daily (either in the morning or evening, at the same time as Tafinlar). The first and second doses of Tafinlar should be taken approximately 12 hours apart. Patients should take Tafinlar + Mekinist at least 1 hour before or 2 hours after a meal. Do not take a missed dose of Tafinlar within 6 hours of the next dose of Tafinlar. Do not open, crush, or break Tafinlar capsules. Do not take a missed dose of Mekinist within 12 hours of the next dose of Mekinist.

Please see full Prescribing Information for Tafinlar and Mekinist.

New Data Presented at European Society for Medical Oncology Meeting Demonstrate Antitumor Activity with IONIS-STAT3-2.5 Rx in Combination with Imfinzi

On September 11, 2017 Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) reported that new data from the clinical program for IONIS-STAT3-2.5Rx (AZD9150) were presented at the 2017 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress. The presentation included clinical and safety results from the Phase 1b/2 study evaluating the activity of IONIS-STAT3-2.5Rx in combination with Imfinzi (durvalumab), AstraZeneca’s programmed death ligand (PD-L1) blocking antibody, in patients with advanced solid tumors and recurrent metastatic head and neck cancer (Press release, Ionis Pharmaceuticals, SEP 11, 2017, View Source [SID1234520469]). In the study, the combination treatment resulted in encouraging antitumor activity with a safety and tolerability profile supportive of continued development.

"Today’s positive data with IONIS-STAT3-2.5Rx are exciting, demonstrating robust activity that is comparable to other promising late-stage checkpoint inhibitor combination therapies for cancer. We continue to be encouraged by the substantial antitumor activity of our Generation 2.5 antisense drugs. Our Generation 2.5 chemistry increases the potency of our antisense drugs, thereby creating opportunities for drugs like IONIS-STAT3-2.5Rx to be effective in targeting more diseases with high unmet need, such as cancers," said Brett Monia, Ph.D., senior vice president of drug discovery and franchise leader for oncology and rare diseases at Ionis Pharmaceuticals. "We are enthusiastic about the broad clinical program AstraZeneca is conducting to evaluate the potential of combining our antisense drugs with immunotherapy approaches to deliver potent and targeted treatment options to patients stricken with various cancers."

"We are encouraged by the anti-tumor activity and safety profile observed in patients with head and neck cancer with AZD9150 in combination with Imfinzi," said Susan Galbraith. M.B., B.Chir., Ph.D. senior vice president and head of oncology innovative medicines unit at AstraZeneca. "We believe this combination therapy supports further study in this group as well as patients with other cancers."

Results from the study were presented at the 2017 ESMO (Free ESMO Whitepaper) Annual Congress in an oral presentation titled, "Phase 1b/2 Study (SCORES) Assessing Safety, Tolerability, and Preliminary Anti-tumor Activity of Durvalumab Plus AZD9150 or AZD5069 in Patients With Advanced Solid Tumors and Refractory and Metastatic (R/M) Squamous Cell Carcinoma of the Head and Neck (R/M-SCCHN)." In the study, combination therapy with IONIS-STAT3-2.5Rx and Imfinzi in 28 PD-L1 treatment naïve patients with R/M-SCCHN resulted in encouraging antitumor activity and deep responses to treatment. The treatment combination demonstrated a 29% (8/28) objective response rate with four partial responses (PR) and four complete responses (CR), of which one was a CR in target lesions only. An additional eight patients on the treatment combination had stable disease (SD) at 12 weeks, resulting in an overall disease control rate of 57% (16/28). Importantly, a complete response was seen in a patient with R/M-SCCHN that was refractory to previous PD-L1 treatment. Combination therapy with IONIS-STAT3-2.5Rx and Imfinzi demonstrated a manageable safety profile. The most common drug-related adverse events occurred infrequently and were similar to those observed with other drugs targeting the JAK/STAT pathway, including mild liver enzyme increases, mild platelet count decreases and mild anemia.

The Phase 1b/2 study is currently ongoing and enrolling an additional treatment group. AstraZeneca is also currently evaluating IONIS-STAT3-2.5Rx in combination with Imfinzi in patients with diffuse large B cell lymphoma.

About IONIS-STAT3-2.5Rx
IONIS-STAT3-2.5Rx, also referred to as AZD9150, is a Generation 2.5 antisense drug designed to reduce the production of signal transducer and activator of transcription 3, or STAT3, for the treatment of patients with cancer. STAT3 is a protein involved in the translation of key factors critical for tumor cell growth and survival and is an important factor in immune cells of the tumor microenvironment where it contributes to the ability of tumors to evade the host immune system. STAT3 is over-active in a variety of cancers, including brain, lung, breast, bone, liver and multiple myeloma.

Ionis licensed IONIS-STAT3-2.5Rx to AstraZeneca for the treatment of cancer. AstraZeneca is currently evaluating IONIS-STAT3-2.5Rx in combination with Imfinzi, AstraZeneca’s programmed death ligand (PDL1) blocking antibody, in multiple Phase 2 studies, including in patients with head and neck cancer in patients with diffuse large B cell lymphoma.

OncoCyte to Present Data from its Liquid Biopsy Breast Cancer Diagnostic Test at the San Antonio Breast Cancer Symposium

On September 11, 2017 OncoCyte Corporation (NYSE American:OCX), a developer of novel, non-invasive liquid biopsy tests for the early detection of cancer, reported that data from its most recent breast cancer diagnostic study has been selected for presentation in a poster session at the 2017 San Antonio Breast Cancer Symposium (SABCS) (Press release, BioTime, SEP 11, 2017, View Source [SID1234520468]). The SABCS will take place at the Henry B. Gonzalez Convention Center in San Antonio, Texas, from December 5-9, 2017.

The data to be presented are from the Company’s NICE-BC (Non-Invasive Confirmatory dEtection (of) Breast Cancer follow-on study. The data confirm the findings from OncoCyte’s previous breast cancer study, which were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2016. In the earlier study, the 15-marker model resulted in an area under the curve (AUC) of 0.92 with a sensitivity of 90% and specificity of 76%. Given this level of accuracy, and subject to successful completion of further R&D and clinical studies, OncoCyte’s novel panel of serum protein biomarkers may become the foundation of a highly accurate, non-invasive breast cancer diagnostic test.

The AUC of a test is a measure that combines sensitivity and specificity to express its total accuracy, with 1.0 being perfect accuracy and 0.50 being a random result. Sensitivity and specificity are statistical measures of test performance, with sensitivity measuring the percentage of malignant lumps or masses that are identified correctly by the test and specificity measuring the percentage of benign lumps or masses correctly identified.

"The presentation of data from our ongoing breast cancer diagnostic studies is another important step in the development of our non-invasive breast cancer diagnostic test," said William Annett, President and Chief Executive Officer. "There is a significant unmet need for a confirmatory breast cancer test that would reduce the number of unnecessary invasive biopsies and lower the financial burden to the healthcare system. We look forward to continued development of this important program."

The data from the NICE-BC study will be presented at SABCS 2017 by Philip McQuary, Ph.D., Director of Product Development at OncoCyte.

Abstract Title: Assessment of an immune response panel of serum protein biomarkers for the non-invasive detection of breast cancer
Poster Session: 4
Session Title: Detection/Diagnosis: Circulating Markers
Session Date: December 7, 2017
Session Time: 7:00 am CT – 9:00 am CT

The current standard of care for breast cancer diagnosis – annual or biannual mammogram screenings – does not meet the needs of large populations of women for whom mammography alone is not sufficient. These populations include women with dense breast tissue, genetic mutations (BRCA), a family history of breast cancer, or those who have suspicious mammogram screening results (BIRADs 3 or 4). The Company’s non-invasive liquid biopsy breast cancer diagnostic is intended to be a confirmatory, post-mammogram test that would address the needs of some of these populations, thereby reducing the number of patients subjected to invasive procedures.

According to published reports, there are about 39 million mammograms performed annually in the U.S., resulting in 1.6 million breast biopsies per year. Of these, only 260,000 (16%) result in a cancer diagnosis. The large number of suspicious findings in diagnostic mammograms leads to a significant amount of unnecessary invasive follow-up procedures. The financial burden to the healthcare system imposed by the follow-up testing of false-positive mammograms and breast cancer over-diagnosis is estimated to be $4 billion a year.

About Breast Cancer

Breast cancer is the second most common cancer among US women. Current screening guidelines set forth by the American Cancer Society recommend screening mammography for the early detection of breast cancer in women at average risk. Specifically, guidelines call for annual mammography for asymptomatic women age 45 to 54 and once every two years for women age 55 and older. Suspicious screening mammograms are generally followed up with a diagnostic mammogram and sometimes by an MRI (Magnetic Resonance Image) or an ultrasound. Ultimately, suspicious findings unresolved by imaging typically result in the recommendation of a breast biopsy.

Inovio’s Cancer Immunotherapy (INO-5150) Slowed PSA Rise and Significantly Increased PSA Doubling Times In Patients with Recurrent Prostate Cancer

On September 11, 2017 Inovio Pharmaceuticals, Inc. (NASDAQ:INO), reported that an interim data analysis showed that its INO-5150 cancer immunotherapy product generated antigen-specific CD8+ killer T cell responses measured in peripheral blood from subjects with biochemically recurrent prostate cancer (Press release, Inovio, SEP 11, 2017, View Source;In-Patients-with-Recurrent-Prostate-Cancer/default.aspx [SID1234520467]). The immunology results demonstrate that INO-5150 treatment as a monotherapy generated prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) specific T cell responses in peripheral blood in 60% (35/58) of the subjects. Moreover, patients with specific CD8+ T cell responses experienced dampening in the rise of PSA and significant increases in PSA Doubling Times (PSADT). PSA is a prostate cancer associated biomarker and positive changes on PSA levels could signal INO-5150’s potential positive impact on the treatment of prostate cancer.

These results were presented as a poster discussion on September 10th at the 2017 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) meeting in Madrid, Spain.

Dr. Neil Shore, MD, Medical Oncologist at Urologic Associates of North Carolina, and the principal investigator of this study said, "Immunotherapy is an exciting new approach being evaluated for the treatment of many cancers including prostate cancer, where a small subset of patients have been shown to demonstrate clinical benefit from such therapy in the form of checkpoint inhibitors. Our study provides encouraging immunologic and clinical data that Inovio’s immunotherapy product can generate antigen-specific CD8+ killer T cell responses in the blood and link such responses to PSA changes in prostate cancer patients. Our results suggest that further evaluation of this product in prostate cancer patients should be explored."

Dr. J. Joseph Kim, Inovio’s President and CEO, said, "As a leader in active immunotherapy for cancer with its lead program in phase 3, Inovio is pleased to report on promising phase 1b clinical trial data of our prostate cancer therapy INO-5150. The immunotherapy’s ability to generate anti-prostate cancer CD8+ T cell responses in patients dosed is truly exciting. Perhaps even more importantly, we also observed that the treated patients with better T cell responses saw a slower rise of PSA levels compared to those without the T cell responses.

We believe the new clinical data positions INO-5150 as an attractive T cell generating immunotherapy component of a potential combination regimen. In this regard, Inovio already has one the most extensive and dynamic T cell immunotherapy combo portfolio in our field, with three different PD-1/PDL-1 immuno-oncology combo efficacy studies with 3 different collaborators – MedImmune, Regeneron, and Genentech for MEDI0457 and INO-5401."

INO-5150, an active immunotherapy targeting both PSA and PSMA antigens which are present in the majority of prostate cancer cells, is administered with and without INO-9012, Inovio’s DNA-based IL-12 immune activator. INO-5150 is designed to activate patients’ immune responses and to specifically target prostate cancers expressing PSA and PSMA. This open label phase 1b study has fully enrolled 62 subjects with biochemically recurrent (rising PSA) prostate cancer and is intended to assess the safety, tolerability, dosing and immunogenicity of INO-5150 alone or in combination with INO-9012. This multi-centered study is also evaluating changes in PSA levels and kinetics, as PSA is an important biomarker in prostate cancer.

INO-5150 was generated using Inovio’s proprietary technology process to enable significant production of PSA and PSMA antigens with genetic sequences differentiated from native human PSA and PSMA sequences. This patented approach is designed to help the body’s immune system overcome its "self-tolerance" to prostate cancer cells and mount a strong targeted CD8+ killer T cell response to eliminate the cancerous cells displaying these antigens. PSMA is also one of 3 antigens comprising INO-5401, which is being tested as an immunotherapy to treat glioblastoma multiforme and metastatic bladder cancer in combination with Regeneron and Genentech’s checkpoint inhibitors, respectively.

This poster presentation provided immune response and clinical correlation across all four cohorts. In addition to immune responses, clinical correlative analyses evaluating PSA kinetics showed that patients with specific CD8+ T cell responses experienced dampening in the rise of PSA and significant increases in PSADT. Additional prostate cancer tissue analyses are ongoing to further investigate immunological correlation.

About Prostate Cancer and Biochemically Recurrent Prostate Cancer (BRPC)

Prostate cancer is the second most frequently diagnosed cancer in men. Nearly three-quarters of the registered cases occur in developed countries. Accounting for nearly 300,000 deaths each year, prostate cancer is the sixth leading cause of death from cancer in men. There are about 60,000 patients each year in the US that develop biochemically recurrent prostate cancer (BRPC). The development of a new treatment for prostate cancer would be a significant medical advance given that current standard-of-care treatment options (surgery, radiation and hormone deprivation), while somewhat effective, all carry deleterious side effects and are often not a long-term cure.