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BERLIN The United States and its NATO allies are moving to bulk up their military commitments in the Baltics and Eastern Europe as the standoff with Russia over Ukraine deepens.

Denmark is sending fighter jets to Lithuania and a frigate to the Baltic Sea. France has offered to send troops to Romania. Spain is sending a frigate to the Black Sea. President Biden has put thousands of U.S. troops on high alert.

And then there is Germany. In recent days Germany Europes largest and richest democracy, strategically situated at the crossroads between East and West has stood out more for what it will not do than for what it is doing.

No European country matters more to European unity and the Western alliance. But as Germany struggles to overcome its post-World War II reluctance to lead on security matters in Europe and set aside its instinct to accommodate rather than confront Russia, Europes most pivotal country has waffled in the first crucial test for the new government of Chancellor Olaf Scholz.

Germanys evident hesitation to take forceful measures has fueled doubts about its reliability as an ally reversing the dynamic with the United States in recent years and added to concerns that Moscow could use German wavering as a wedge to divide a united European response to any Russian aggression.

President Biden held a video call with European leaders on Monday night, saying it went very, very, very well, and beforehand Chancellor Scholz reiterated that Russia would suffer high costs in case of a military intervention. But Germanys allies have still been left to wonder what cost it is prepared to bear to confront possible Russian aggression.

Within the European Union Germany is crucial to achieve unity, said Norbert Rttgen, a senior conservative lawmaker and advocate of a more muscular German foreign policy. Putins goal is to split the Europeans, and then split Europe and the U.S. If the impression prevails that Germany is not fully committed to a strong NATO response, he will have succeeded in paralyzing Europe and dividing the alliance.

As Russia held military drills near the Ukrainian border on Tuesday, Mr. Scholz met with President Emmanuel Macron of France in Berlin, warning Moscow that a military aggression calling into question the territorial integrity of Ukraine would have grave consequences.

But the German government has not only ruled out any arms exports to Ukraine it is also holding up a shipment of nine Communist-era howitzers from Estonia to Ukraine.

Mr. Scholz and other senior Social Democrats in his government and party have been vague about whether shuttering the controversial Nord Stream 2 undersea gas pipeline from Russia to Germany would be part of an arsenal of possible sanctions against Russia, insisting it was a private -sector project and one separate from Ukraine.

Friedrich Merz, the designated new leader of Angela Merkels opposition conservative party, meanwhile, has warned against excluding Russian banks from the Swift payment transactions network, which handles global financial transfers, because it would harm Germanys economic interests.

Germanys muddled stance has been especially unsettling to Ukraine and some of Germanys eastern neighbors. The Ukrainian foreign minister, Dmytro Kuleba, accused Berlin of effectively encouraging Russian aggression. Other were no less scathing.

Berlin is making a big strategic mistake and putting its reputation at risk, Laurynas Kasinas, chairman of the national security committee of the Lithuanian Parliament told the public broadcaster LRT.

Artis Pabriks, Latvias defense minister, said these days German deterrence was not sending weapons to Ukraine, but a field hospital.

The strain in the alliance came to a head last weekend when the chief of the German Navy said that President Vladimir V. Putin of Russia deserved respect and that Crimea would never be returned to Ukraine. Vice Adm. Kay-Achim Schnbach, resigned, but the backlash was swift and emotional.

This patronizing attitude subconsciously also reminds Ukrainians of the horrors of the Nazi occupation, when Ukrainians were treated as subhuman, said Andriy Melnyk, Ukraines ambassador to Germany.

Washington has been at pains to publicly stress its trust in Berlin, while privately lobbying Mr. Scholz to take a harder line.

President Biden sent several emissaries to Berlin. William J. Burns, head of the C.I.A., presented the chancellor with the latest intelligence on Ukraine. Secretary of State Antony J. Blinken, who stopped in Berlin before meeting his Russian counterpart in Geneva last week, said on Sunday he had no doubts over Germanys determination to stand up to Russia.

It is telling that the U.S. has to publicly reaffirm its trust in Germany, Jana Puglierin of the Berlin-based European Council on Foreign Relations said. That used to be a given.

The wrenching debate over where precisely German loyalties lie is not new. Russian-German relations have been shaped by centuries of trade and cultural exchange but also two World Wars. The Cold War added yet another layer of complexity: West Germany became firmly embedded in the Western alliance while East Germany lived under Soviet occupation.

Why do we see Russia differently from the Americans? History, said Matthias Platzeck, chairman of the Russian-German Forum and a former chair of Mr. Scholz Social Democrats. Germany and Russia have been linked for a thousand years. The biggest Russian czarina was Catherine the Great, a German, who incidentally made Crimea part of Russia.

We attacked Russia twice, and the second time it was a genocidal war, he added. Twenty-seven million Soviets died, 15 million Russians among them.

Ominous warnings. Russia called the strike a destabilizing act that violated the cease-fire agreement, raising fears of a new intervention in Ukraine that could draw the United States and Europe into a new phase of the conflict.

The Kremlins position. President Vladimir V. Putin of Russia, who has increasingly portrayed NATOs eastward expansion as an existential threat to his country, said that Moscows military buildupwas a response to Ukraines deepening partnership with the alliance.

That does not mean that Germany has failed to stand up to Russia in recent years. Germany commands a multinational NATO battle unit in Lithuania and helps monitor Baltic airspace for Russian interference. It is planning to send fighter jets to Romania next month to do the same there. (And yes, it is also sending a field hospital to Kyiv next month.)

In 2014, when Mr. Putin invaded Ukraine and annexed Crimea, it was Ms. Merkel who rallied neighboring countries in East and West to back tough sanctions on Russia.

But the change of German leadership after 16 years of Ms. Merkel has put in place a government that is divided on how hard a line to draw with Russia.

Mr. Scholzs Social Democrats have traditionally favored a policy of working with the Russians. In the 1970s, Chancellor Willy Brandt engineered the policy of rapprochement with Moscow during the Cold War, while the last Social Democratic chancellor, Gerhard Schrder, is not just a close friend of Mr. Putin (he celebrated his 70th birthday with him) but has been on the payroll of Russian energy companies since 2005.

The new Green Party foreign minister, Annalena Baerbock, has been more outspoken on being tougher on Russia. But even she has drawn a line on sending German arms to Ukraine, citing history.

The arms-export policy in many ways embodies the modern German paradox of a nation that knows it has to assume more leadership responsibility in the world but is not quite ready to act that way.

The idea that Germany delivers weapons that could then be used to kill Russians is very difficult to stomach for many Germans, said Marcel Dirsus, a political analyst and nonresident fellow at the Institute for Security Policy at Kiel University.

The government has been even more divided over Nord Stream 2, a gas pipeline owned by Gazprom, Russias state-owned energy company, that many fear will hand Mr. Putin an easy way to exert influence over Americas European allies.

Russia is Europes main supplier of natural gas. Once Nord Stream 2 is operational, Gazprom would be able to sell additional gas to European customers without paying transit fees to Ukraine.

Championed by Ms. Merkel in 2015, a year after Russia first invaded Ukraine, Nord Stream 2 has long inflamed Washington and European capitals alike.

While Ms. Baerbock, the Green Party foreign minister, has not been shy about expressing her hostility toward the project, Ms. Merkel and Mr. Scholz have defended it on economic and energy security grounds and long ruled out using it as leverage in talks about sanctions.

It was only last week, standing next to the NATO general secretary, that the chancellor shifted his language, saying that everything would be on the table in case of a Russian invasion.

Putin gave NATO a new reason to exist, said Mr. Dirsus of the Institute for Security Policy in Kiel. Who knows, maybe he can teach the Germans once and for all that the world has changed and they need to be prepared to pay to defend peace.

Christopher F. Schuetze contributed reporting from Berlin and Andrew Higgins from Warsaw.

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Where Is Germany in the Ukraine Standoff? Its Allies Wonder. - The New York Times

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the European Commission has approved KEYTRUDA, Mercks anti-PD-1 therapy, as monotherapy for the adjuvant treatment of adults with renal cell carcinoma (RCC) at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. This approval is based on results from the Phase 3 KEYNOTE-564 trial, in which KEYTRUDA demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) after a median follow-up of 23.9 months compared to placebo, in patients at increased risk of recurrence (defined in the clinical trial protocol as intermediate-high or high risk following nephrectomy and those with resected advanced disease).

KEYTRUDA addresses a critical unmet need for treatment options that help patients reduce their risk of cancer returning following surgery, said Dr. Thomas Powles, professor of Genitourinary Oncology and director of Barts Cancer Centre at St. Bartholomews Hospital. The European Commissions approval of KEYTRUDA brings certain patients with renal cell carcinoma a long-awaited therapy that has demonstrated a statistically significant reduction in the risk of disease recurrence or death by almost a third.

KEYTRUDA is the first adjuvant therapy approved for certain patients with renal cell carcinoma in Europe, providing the option of immunotherapy earlier in the course of their treatment, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. This approval demonstrates our progress in bringing KEYTRUDA to patients with earlier stages of cancer, with the goal of helping more patients around the globe prevent disease recurrence.

This approval allows marketing of KEYTRUDA monotherapy in all 27 European Union member states plus Iceland, Lichtenstein, Norway and Northern Ireland.

Merck has a broad clinical development program exploring KEYTRUDA, as monotherapy or in combination, as well as several other investigational and approved medicines across multiple settings and stages of RCC, including adjuvant and advanced or metastatic disease.

Data Supporting the European Approval

The approval was based on data from KEYNOTE-564 (NCT03142334), a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial that enrolled 994 patients with increased risk of recurrence of RCC defined as intermediate-high or high risk, or M1 with no evidence of disease (NED). Patients must have undergone a partial or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion[s] in M1 NED participants) with negative surgical margins for at least four weeks prior to the time of screening. Patients with active autoimmune disease or a medical condition that required immunosuppression were excluded from the study. The primary efficacy outcome measure was investigator-assessed DFS. The secondary efficacy outcome measure was overall survival (OS). Patients with RCC with clear cell component were randomized (1:1) to receive KEYTRUDA 200 mg administered intravenously every three weeks (n=496) or placebo (n=498) for up to one year until disease recurrence or unacceptable toxicity.

At a pre-specified interim analysis with a median follow-up time of 23.9 months, KEYTRUDA demonstrated a statistically significant improvement in DFS, reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared with placebo in patients with RCC at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. Updated efficacy results with a median follow-up time of 29.7 months demonstrated KEYTRUDA reduced the risk of disease recurrence or death by 37% (HR=0.63 [95% CI, 0.50-0.80]; p<0.0001) compared with placebo. Median DFS has not been reached for either group. The trial will continue to assess OS as a secondary outcome measure.

The safety of KEYTRUDA as monotherapy has been evaluated in 7,148 patients with advanced melanoma, resected stage III melanoma (adjuvant therapy), non-small cell lung cancer, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, colorectal cancer, endometrial, gastric, small intestine, biliary, pancreatic cancer or adjuvant therapy of RCC across four doses (2 mg/kg bodyweight [bw] every three weeks, 200 mg every three weeks, or 10 mg/kg bw every two or three weeks) in clinical studies. In this patient population, the most frequent adverse reactions with KEYTRUDA were fatigue (31%), diarrhea (22%) and nausea (21%). The majority of adverse reactions reported for KEYTRUDA monotherapy were of Grades 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions. The incidences of immune-related adverse reactions were 36.1% for all Grades and 8.9% for Grades 3-5 for KEYTRUDA monotherapy in the adjuvant setting (n=1,480) and 24.2% for all Grades and 6.4% for Grades 3-5 in the metastatic setting (n=5,375). No new immune-related adverse reactions were identified in the adjuvant setting.

About Renal Cell Carcinoma

Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In Europe, it is estimated there were more than 138,000 new cases of kidney cancer diagnosed and more than 54,000 deaths from the disease in 2020.

About Mercks Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,700 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB, IIC, or III melanoma following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [Tumor Proportion Score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [Combined Positive Score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy.

KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

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.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). 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.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. 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. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA With Axitinib

First-line treatment of advanced RCC in combination therapy with axitinib (KEYNOTE-426)

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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European Commission Approves Merck's KEYTRUDA (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following...

This Rapid Risk Assessment extends the assessment of the further emergence and potential impact of Omicron in the context of ongoing transmission of the Delta variant that was published on 15 December 2021, to include new epidemiological data on the spread of Omicron, new data on vaccine uptake, updated forecasts, and the latest evidence on Omicron transmissibility, severity, immune escape, vaccine effectiveness, post-COVID-19 condition, and non-pharmaceutical interventions.

The SARS-CoV-2 Omicron variant of concern (VOC) is rapidly replacing SARS-CoV-2 Delta in most European Union/European Economic Area (EU/EEA) countries, and is broadly following a west-to-east progression. As pointed out by earlier in vitro and in vivo studies, Omicron can to a degree evade the protective effects of antibodies elicited by vaccination or natural infection according to factors such as number of vaccinations or time since last vaccination, thus leaving large portions of the EU/EEA population susceptible to infection. This has resulted in sharp increases in the number of COVID-19 cases, reaching an unprecedented intensity of community transmission across the region.

In comparison with earlier circulating variants, Omicron infections appear less likely to lead to a severe clinical outcome that requires hospitalisation or ICU admission. Hence, although the current overall 14-day notification rate in the EU/EEA is 2 621 cases per 100 000 population, which is three times higher than the highest peak observed during the pandemic to date, hospitalisation rates and mortality are below the levels observed in earlier pandemic waves. However, the number of cases among older people has been increasing more recently in several EU/EEA countries, and this could result in a delayed increase of severe cases and deaths. Although the reduction in severity is partially due to inherent characteristics of the virus, results from vaccine effectiveness studies have shown that a significant role in preventing severe clinical outcomes from Omicron infection is played by vaccination, with effectiveness against severe illness increasing significantly among people having received three vaccine doses. Since vaccination uptake is variable across EU/EEA countries (country range: 28.482.9%, average 69.4%) and since the uptake of booster doses is still at suboptimal levels in the majority of EU/EEA countries (80% of EU/EEA countries with booster uptake among adults below 60% as of week 2-2022), the expected impact of Omicron will vary, but countries with lower vaccine uptake are expected to experience the highest disease burden. Furthermore, given the very high levels of community transmission observed regardless of overall vaccine uptake, leading to many people being sick at the same time, countries with very high vaccine uptake will also likely undergo a period of substantial pressure on their healthcare systems and on the functioning of the society as a whole (mainly through absence from work and education).

Mathematical modelling results demonstrate that there is a substantial proportion of the population that remains vulnerable to severe outcomes across all EU/EEA countries, especially in those with lower vaccination coverage. Static projections show hospitalisations and mortality are expected to have a proportionally greater impact among people 60 years and older but will also impact people younger than 60 years. In response to the high incidence of Omicron, protection against the risk of high hospitalisation burden can be accomplished by increasing overall vaccination uptake, including rapidly administering booster doses, especially in the older and at-risk population, will protect against the risk of high hospitalisation burden. Furthermore, the vaccines and boosters provide additional longer-term benefits for individuals and society (e.g. preventing absence from work or education and post-acute COVID-19 syndrome).

There are no data so far on the incidence of prolonged symptoms after COVID-19 due to Omicron, nor on whether this differs from the incidence of post-COVID syndrome brought about by previously circulating variants of SARS-CoV-2. It is plausible that the large number of cases of Omicron infection may be followed by a high incidence of post-COVID-19 condition, with a proportionally higher incidence among people who are unvaccinated.

While we expect to be moving towards a more sustainable situation with COVID-19 circulating at manageable levels, we currently remain in a public health emergency pandemic situation, and it is important to note that even in a post-pandemic phase SARS-CoV-2 could still periodically cause high levels of strain on healthcare systems and lead to large outbreaks. Thus, moving forward, multi-layered surveillance, preparedness, and response strategies for addressing COVID-19 will be essential.

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Assessment of the further spread and potential impact of the SARS-CoV-2 Omicron variant of concern in the EU/EEA, 19th update - EU News

It feels like a scene from the Cold War.

An unpredictable Russian president amassing thousands of troops on the border of a neighboring country, Ukraine. The threat of invasion. A possible bloody conflagration between East and West.

But what may seem like a perilous episode from a bygone era is now front and center in global diplomacy as the United States jockeys to deter a Russian incursion into Ukraine.

The situation intensified over the weekend as it emerged that President Biden was considering deploying several thousand U.S. troops, as well as warships and aircraft, to NATO allies in the Baltics and Eastern Europe. The move appeared to signal a shift from the Biden administration which has taken pains to avoid provoking Russia.

But with President Vladimir V. Putin of Russia ramping up his threats and talks between American and Russian officials failing to defuse the crisis, the administration appeared to be changing tack.

Russia has mobilized about 100,000 troops near its border with Ukraine. The United States has disclosed intelligence showing that Russia has a war plan envisioning an invasion force of 175,000 troops that Ukraines military, despite U.S.-provided equipment and training, would have little ability to stop.

Mr. Biden has said that an invasion would be the most consequential thing thats happened in the world in terms of war and peace since World War II. Current intelligence assessments described by White House officials conclude that Mr. Putin has not made a decision about whether to invade. And so far, none of the military options being considered include deploying additional American troops to Ukraine itself.

A potential military flare-up threatens to destabilize the already volatile post-Soviet region, buffeted by the popular revolt this month in Kazakhstan. It would also have serious consequences for the security structure that has governed Europe since the collapse of the Soviet Union three decades ago.

Russia has made a list of far-reaching demands, including that NATO pledge to halt further eastward expansion and agree not to admit Ukraine as a member. But the United States has called those positions unacceptable. Russian officials have repeatedly insisted that Moscow has no plans to invade Ukraine and that the massive troop buildup is just for exercises.

Essentially, Mr. Putin is seeking to redraw the post-Cold War boundaries of Europe, establishing a broad, Russian-dominated security zone and drawing Ukraine back into Moscows orbit by force, if necessary.

In the event of an invasion, the United States and its allies have threatened to impose a series of sanctions that would go far beyond those imposed in 2014, after the Russian annexation of Crimea. Mr. Putin has warned that imposing new sanctions could lead to a complete rupture in relations with Washington.

Tensions between Ukraine and Russia have been simmering since 2014. Thats when Ukraine ousted its pro-Russian president and the Russian military crossed into Ukrainian territory, annexing Crimea and fomenting a rebellion by separatists in eastern Ukraine. A tenuous cease-fire was reached in 2015, but peace has been elusive amid a grinding war that has killed more than 13,000 soldiers and civilians.

The Kremlins position toward its neighbor has been hardening, as Mr. Putin has grown more insistent that Ukraine is fundamentally a part of Russia, culturally and historically. Concerns were raised in late October, when Ukraine used an armed drone to attack a howitzer operated by Russian-backed separatists in eastern Ukraine. Russia called the strike a destabilizing act that violated the cease-fire agreement.

Now 69 years old and edging toward the twilight of his political career, Mr. Putin is determined to burnish his legacy and to correct what he has long viewed as a catastrophe of the 20th century: the disintegration of the former Soviet Union.

Asserting Moscows power over Ukraine, a country of 44 million people that was previously part of the Soviet bloc and shares a 1,200-mile border with Russia, is part of his aim of restoring what he views as Russias rightful place among the worlds great powers, along with the United States and China.

Mr. Putin has increasingly portrayed NATOs eastward expansion as an existential threat to his country, and insists that Moscows military buildup is a reaction to Ukraines intensifying ties with the alliance. He appears intent on winding back the clock 30 years, to just before the collapse of the Soviet Union.

The timing of Russias troop mobilization is perhaps no coincidence. Mr. Putin is seeking to energize nationalist support at home amid a raging pandemic and a stumbling economy. Last year, opposition groups held some of the largest anti-Putin protests in years.

But while some analysts have portrayed Mr. Putin as a wily chess player adroitly manipulating the West, his latest gambit could backfire. NATO could reinforce its military presence in member countries bordering Russia, like the Baltics. And an invasion would invite punishing sanctions that could diminish his support in a country weary of foreign adventures.

In Ukraine, meanwhile, Moscows aggressive posture has further inflamed nationalist passions, with citizen militias preparing for a drawn-out guerrilla campaign in the event of a Russian occupation. And if Mr. Putins aim is to reassert Russias sphere of influence, invading Ukraine would further destabilize the post-Soviet region, where Russian troops are helping restore order in Kazakhstan and Belarus is still smoldering after an uprising in 2020.

In early December, Mr. Biden made clear that his administration was not considering sending troops to Ukraine, since, among other reasons, Ukraine is not a member of the NATO alliance and does not come under its commitment to collective defense.

Instead, Mr. Biden has said that he would reinforce the American military presence in NATO countries that border Russia. And, referring to Mr. Putin, he has promised that there would be economic consequences like none hes ever seen.

The United States and NATO gave formal responses on Wednesday to Russias demands that NATO pull back forces from Eastern Europe and bar Ukraine from ever joining the alliance. While the United States has previously made clear that those demands are nonstarters, Secretary of State Antony J. Blinken said the U.S. written response set out a diplomatic path for Russia out of the crisis and outlined measures to increase confidence regarding military exercises and maneuvers in Europe, as well as nuclear arms control in Europe.

Ominous warnings. Russia called the strike a destabilizing act that violated the cease-fire agreement, raising fears of a new intervention in Ukraine that could draw the United States and Europe into a new phase of the conflict.

The Kremlins position. President Vladimir V. Putin of Russia, who has increasingly portrayed NATOs eastward expansion as an existential threat to his country, said that Moscows military buildupwas a response to Ukraines deepening partnership with the alliance.

The Biden administration has already made such proposals, so it is unclear whether the U.S. response will make a difference.

Mr. Biden is considering several options that would shift American military assets much closer to Mr. Putins doorstep. The options include sending 1,000 to 5,000 troops to Eastern European countries, with the potential to increase that number tenfold if the situation deteriorates.

Biden officials have also recently warned that the United States could throw its weight behind a Ukrainian insurgency should Mr. Putin invade Ukraine.

U.S. officials have hinted that Washington could be turning to its China playbook potentially instituting sanctions that could deprive Russians of their beloved next-generation phones, laptops and other gadgets, and the military from advanced equipment. There is also the option of cutting Russia off from the international banking system, though analysts have said that is unlikely.

An intensifying conflict in Ukraine would test the resolve of the Biden administration, which has been working to restore confidence in Americas global leadership following the recent messy withdrawal from Afghanistan and its retrenchment from foreign engagements under President Donald J. Trump.

How the United States handles Russia and Ukraine will affect its ongoing efforts at rebuilding frayed ties with NATO allies after the Trump presidency, during which Mr. Trump declared the alliance obsolete.

An escalating crisis in Ukraine also threatens to upend recent efforts by the United States and NATO to shift the alliances attention to the security challenge posed by China.

At stake for Europe is whether it can allow Mr. Putin to upend the security structure that has helped keep the peace on the continent since World War II. And with Europeans divided over how to respond to various forms of Russian aggression, the conflict has also laid bare the weakness of the European Union and its failure as a foreign policy force in international relations.

With the departure of Chancellor Angela Merkel, who grew up in the east, speaks fluent Russian, and had developed a good working relationship with Mr. Putin, Europe lost an invaluable interlocutor with Moscow.

Europe has important trade ties with Russia, and would stand to lose far more than the U.S. from sanctions imposed after a Russian invasion of Ukraine. It is also dependent on Russian gas supplies, a weakness that Mr. Putin has exploited in past disputes.

Steven Erlanger in Brussels contributed reporting.

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What Does Russia Want in Ukraine? The Tensions Explained - The New York Times

Christian Democrat Roberta Metsola of Malta delivers a speech at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

Christian Democrat Roberta Metsola of Malta arrives to deliver a speech at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

Christian Democrat Roberta Metsola of Malta hugs Swedish Alice Khunke, at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

Christian Democrat Roberta Metsola of Malta delivers a speech at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

Christian Democrat Roberta Metsola of Malta delivers a speech at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

Christian Democrat Roberta Metsola of Malta acknowledges applause after being elected president European Union's parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola is only the third woman elected to the post. Her birthday was Tuesday, and at age 43, she is the European Parliament's youngest president.

Christian Democrat Roberta Metsola of Malta delivers a speech at the European Parliament, in Strasbourg, eastern France, Tuesday, Jan 18, 2022. Metsola was elected president of the European Union's parliament Tuesday, taking over for a 2 -year term following the death of Socialist David Sassoli last week.

By RAF CASERT - Associated Press

BRUSSELS (AP) Roberta Metsola, a Christian Democratic politician from Malta, was elected president of the European Unions parliament Tuesday, taking over for a 2-year term following the death of Socialist David Sassoli last week.

Metsola is only the third woman elected to the post. Her birthday was Tuesday, and at age 43, she is the European Parliament's youngest president.

Sassoli, 65, had been sick for several months, and before his death the Italian politician declined to seek another term.

Metsola was the candidate of the parliaments biggest group, and she received 458 of the 616 votes cast Tuesday. She had already been acting president since Sassolis Jan. 11 death.

She will lead an EU institution which has become more powerful over the years and been instrumental in charting the course of the 27-nation bloc on issues such as the digital economy, climate change and Brexit.

The European Parliament represents the EUs 450 million citizens and refers to itself as the heart of European democracy.

Known as a committed bridge-builder between parties, Metsola said she would stick to Sassoli's style of work.

David fought hard to bring people around the same table. It is that commitment to holding the constructive forces in Europe together that I will build on, she said.

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Maltese legislator elected European Parliament president ...