Boeing workers stage protest near Seattle over U.S. vaccine mandate

 

Waving signs like "coercion is not consent," and "stop the mandate," some 200 Boeing Co employees and others staged a protest on Friday over the planemaker's COVID-19 vaccine requirement for U.S. workers.

Boeing said on Tuesday it will require https://www.reuters.com/business/aerospace-defense/boeing-will-require-its-125000-us-employees-be-vaccinated-against-covid-19-2021-10-12 its 125,000 U.S. employees to be vaccinated by Dec. 8 under an executive order issued by President Joe Biden for federal contractors.

As the pandemic has continued to rage, Biden announced the requirement in September because a large swath of Americans have resisted vaccination even though the shots are free, widely available and declared safe by regulators.

"It's my choice and it's my body," one avionics engineer said, his voice nearly drowned out by anti-Biden chants and trucks honking to show support along the busy street outside Boeing's factory in Everett, north of Seattle.

"It's an experimental drug given under a pseudo-emergency," he added.

Another worker, an assembly mechanic, said: "This is America. We don't just do what we're told because one person says to."

Earlier this week, Boeing said employees must either show proof of vaccination or have an approved reasonable accommodation based on a disability or sincerely held religious belief by Dec. 8.

"Boeing is committed to maintaining a safe working environment for our employees," a spokesperson said. "Advancing the health and safety of our global workforce is fundamental to our values and a core priority every day."

Major U.S. airlines including American Airlines have said they will also meet the deadline imposed on federal contractors, as has aircraft parts manufacturer Spirit AeroSystems.

"Now that he has issued the Executive Order, it is our responsibility to comply with that order," Spirit Chief Executive Officer Tom Gentile wrote in a memo to employees and seen by Reuters on Friday.

Spirit was calling back former employees as it prepares for what Gentile characterized as "one of the fastest increases in production rates in the history of our industry."

Boeing has said its mandate does not apply immediately to its sites in Texas, where Republican Governor Greg Abbott issued an executive order on Monday barring COVID-19 vaccine mandates by any entity, including private employers.

https://www.marketscreener.com/news/latest/Boeing-workers-stage-protest-near-Seattle-over-U-S-vaccine-mandate--36696621/

NIH study finds mixing COVID-19 boosters increases immune response

 

• People vaccinated with one of the three coronavirus shots authorized in the U.S. could benefit from receiving a different booster dose than their first, a study run by the National Institutes of Health and published online Wednesday found, offering important new data for public health officials and regulators.
• In the study, which enrolled about 450 people who had been vaccinated with either Pfizer's, Moderna's or Johnson & Johnson's vaccine, an additional dose of any of the three shots spurred many times higher immune responses. While there are major limitations, including the study's size and follow-up, the data suggest a more flexible approach to booster doses may be possible.
• Results come one day before advisers to the Food and Drug Administration begin a two-day meeting to debate whether to recommend authorization of booster doses of Moderna's and J&J's vaccines. The FDA cleared a booster of Pfizer's for many Americans on Sept. 22.

Scientists at the FDA and Centers for Disease Control and Prevention have been grappling with the question of who needs an additional vaccine dose, and when, for weeks now.

The authorization of a third dose of Pfizer and BioNTech's vaccine for certain groups in late September left without guidance tens of millions of Americans who received either Moderna's or J&J's shot for their initial vaccination. CDC data shows that nearly 9 million Americans have received a booster shot to date, although it does not distinguish whether they were part of groups authorized to receive one. Reports indicate Americans across the country are seeking out boosters even if one is not yet recommended for them.

In the NIH study, 458 volunteers who had been fully immunized with either Pfizer's, Moderna's or J&J's shot were given a booster four to six months after completing their initial vaccine regimen. They were divided into groups based on the vaccine they first received, then given either a matching booster from the same developer or a shot from one of the other two.

In all cases, the additional dose increased antibody levels against the coronavirus, a change that's generally associated with greater protection from COVID-19.

But results suggested a boost from the mRNA vaccines from Moderna and Pfizer spiked antibody levels by much higher than did J&J's. This was particularly the case for people who received J&J's vaccine initially and had lower levels to begin with. Volunteers who got Moderna or Pfizer's two-dose regimen and received either of those two for an additional dose had more closely comparable antibody levels afterwards.

Notably, however, the Moderna dose used in the study was the 100 microgram dose currently authorized, rather than the 50 microgram dose the company has requested be cleared as a booster shot.

There were other limitations, too. Participants were not randomized, nor segmented based on the time from last vaccination. Researchers further noted that the follow-up period was too short to detect rarer or late-emerging side effects from booster doses. It's also not yet clear for how long an increase in antibody levels might drive higher protection following a third dose.

"These data suggest that if a vaccine is approved or authorized as a booster, an immune response will be generated regardless of the primary Covid-19 vaccination regimen," the researchers wrote. Their work has not yet been peer-reviewed and was made available online on the "pre-print" server medRxiv.

A third dose of Pfizer's vaccine is currently authorized six months after the first two for adults over 65, younger adults with underlying medical conditions and individuals older than 18 whose "frequent institutional or occupational exposure" puts them at higher risk of contracting severe COVID-19. Immunocompromised people are also eligible for a third dose of either Pfizer or Moderna's vaccine, although in that case the extra shot is because they are less likely to have had a sufficient immune response with two.

On Thursday and Friday, the FDA's advisory committee will discuss authorizing boosters for Moderna and J&J vaccine recipients more widely. Moderna requested a clearance that matches what's been authorized for Pfizer's shot, while J&J is asking for booster authorization for people over 18 years old.

The committee will hear from the NIH about the results of boosting study on Friday, though at that point, they will have already voted on their recommendations, according to the meeting schedule.

https://www.biopharmadive.com/news/nih-coronavirus-vaccine-booster-mix-match/608199/

Personality traits linked to hallmarks of Alzheimer’s

 New research from the Florida State University College of Medicine found that changes in the brain associated with Alzheimer's disease are often visible early on in individuals with personality traits associated with the condition.

The study focused on two traits previously linked to the risk of dementia: neuroticism, which measures a predisposition for negative emotions, and conscientiousness, which measures the tendency to be careful, organized, goal-directed and responsible.

"We have done studies showing who's at risk of developing dementia, but those other studies were looking at the clinical diagnosis," said Antonio Terracciano, professor of geriatrics at the College of Medicine. "Here, we are looking at the neuropathology; that is, the lesions in the brain that tell us about the underlying pathological change. This study shows that even before clinical dementia, personality predicts the accumulation of pathology associated with dementia."

The findings, published as an article-in-press online with Biological Psychiatry and also available through FSU's open access research repository, combine data from the Baltimore Longitudinal Study of Aging (BLSA) and previously published work in a meta-analysis that summarized 12 studies on personality and Alzheimer's neuropathology. The studies combined included more than 3,000 participants. Combining results across studies provides more robust estimates of the associations between personality and neuropathology than a single individual study can typically provide.

In both the BLSA and meta-analysis, the researchers found more amyloid and tau deposits (the proteins responsible for the plaques and tangles that characterize Alzheimer's disease) in participants who scored higher in neuroticism and lower in conscientiousness.

The team also found associations to be stronger in studies of cognitively normal people compared to studies that included people with cognitive problems.

The findings suggest that personality can help protect against Alzheimer's and other neurological diseases by delaying or preventing the emergence of neuropathology for those strong in conscientiousness and low in neuroticism.

"Such protection against neuropathology may derive from a lifetime difference in people's emotions and behaviors," Terracciano said. "For example, past research has shown that low neuroticism helps with managing stress and reduces the risk of common mental health disorders. Similarly, high conscientiousness is consistently related to healthy lifestyles, like physical activity. Over time, more adaptive personality traits can better support metabolic and immunological functions, and ultimately prevent or delay the neurodegeneration process."

The BLSA is a scientific study of human aging conducted by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), that began in 1958. Personality was measured using a five-factor personality test, the most common personality assessment tool. At the time of their enrollment in the BLSA neuroimaging sub-study, all participants were free of dementia or other severe medical conditions.

Advances in brain scan technology used to assess in vivo amyloid and tau neuropathology made it possible for researchers to complete this work.

"Until recently, researchers measured amyloid and tau in the brain through autopsy -- after people died," Terracciano said. "In recent years, advances in medical imaging have made it possible to assess neuropathology when people are still alive, even before they show any symptoms."

Story Source:

Materials provided by Florida State University. Original written by Doug Carlson. Note: Content may be edited for style and length.

---

Journal Reference:

1. Antonio Terracciano, Murat Bilgel, Damaris Aschwanden, Martina Luchetti, Yannick Stephan, Abhay R. Moghekar, Dean F. Wong, Luigi Ferrucci, Angelina R. Sutin, Susan M. Resnick. Personality associations with amyloid and tau: Results from the Baltimore Longitudinal Study of Aging and meta-analysis.. Biological Psychiatry, 2021; DOI: 10.1016/j.biopsych.2021.08.021

https://www.sciencedaily.com/releases/2021/10/211012185709.htm

Bone-loss discovery points to new treatment for osteoporosis

 A new discovery about osteoporosis suggests a potential treatment target for that brittle-bone disease and for bone loss from rheumatoid arthritis.

The findings from University of Virginia School of Medicine researchers and their collaborators help explain why specialized bone cells called osteoclasts begin to break down more bone than the body replaces. With more research, scientists one day may be able to target that underlying cause to prevent or treat bone loss.

The discovery also suggests an answer for why some previous attempts to develop osteoporosis treatments produced disappointing results.

"Bone degradation and subsequent repair are fine-tuned through complex interactions between the cells that degrade the bone, osteoclasts, and those that produce new bone matrix. Simple elimination of osteoclasts is, therefore, not always the best approach to treat pathologic bone loss. Instead, we found a 'signaling node' in osteoclasts that regulates their function in degrading the bone but doesn't reduce osteoclast numbers," said researcher Sanja Arandjelovic, PhD, of UVA's Department of Medicine and UVA's Carter Immunology Center.

Researcher Kodi Ravichandran, PhD, chairman of UVA's Department of Microbiology, Immunology and Cancer Biology and director of UVA's Center for Cell Clearance, noted the potential of the findings to inform efforts to develop better treatments for osteoporosis: "In this study," he said, "we identified previously unappreciated factors that contribute to osteoclast function that is truly exciting and opens up new avenues to pursue."

Understanding Bone Loss

Osteoporosis affects more than 200 million people around the world, and it causes bone fractures in 1 in 3 women and 1 in 5 men over age 50. Bone loss is also seen in rheumatoid arthritis, a painful inflammatory condition that affects up to 1% of people, including more than 1.3 million Americans.

Scientists are eager to understand what causes this bone loss, and to develop new ways to treat and prevent it. Arandjelovic, Ravichandran and their collaborators have found an important contributor, a cellular protein called ELMO1. This protein, they found, promotes the activity of the bone-removing osteoclasts. While osteoclasts may seem like 'bad guys' because they remove bone, they are critical for bone health, as they normally remove just enough to stimulate new bone growth. The problem arises when the osteoclasts become too aggressive and remove more bone than the body makes. Then bone density suffers and bones grow weaker.

This excessive bone degradation is likely influenced by genetic factors, the researchers say. They note that many of the genes and proteins linked to ELMO1 have been previously associated with bone disorders and osteoclast function.

Treating Osteoporosis and Rheumatoid Arthritis

Encouragingly, the researchers were able to prevent bone loss in lab mice by blocking ELMO1, including in two different models of rheumatoid arthritis. That suggests clinicians may be able to target the protein in people as a way to treat or prevent bone loss caused by osteoporosis and RA, the researchers say.

They note that prior efforts to treat osteoporosis by targeting osteoclasts have had only mixed success, and they offer a potential explanation for why: Osteoclasts not only remove bone but play a role in calling in other cells to do bone replacement. As such, targeting ELMO1 may offer a better option than simply waging war on the osteoclasts.

"We used a peptide to target ELMO1 activity and were able to inhibit degradation of the bone matrix in cultured osteoclasts without affecting their numbers," Ravichandran said. "We hope that these new osteoclast regulators identified in our study can be developed into future treatments for conditions of excessive bone loss such as osteoporosis and arthritis."

Story Source:

Materials provided by University of Virginia Health System. Note: Content may be edited for style and length.

---

Journal Reference:

1. Sanja Arandjelovic, Justin S. A. Perry, Ming Zhou, Adam Ceroi, Igor Smirnov, Scott F. Walk, Laura S. Shankman, Isabelle Cambré, Suna Onengut-Gumuscu, Dirk Elewaut, Thomas P. Conrads, Kodi S. Ravichandran. ELMO1 signaling is a promoter of osteoclast function and bone loss. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-25239-6

https://www.sciencedaily.com/releases/2021/10/211014100223.htm

Flu and heart disease: Surprising connection should convince you to schedule your shot

 If you have heart disease or risk factors for heart disease, you already know about the increased risk of heart attack and stroke. But did you know that coming down with the flu can substantially increase the risk of a serious or even fatal cardiac event? Or that getting the influenza vaccine can substantially reduce that risk, even if you do wind up contracting the seasonal virus?

Probably not, if annual influenza vaccination rates are any indication, especially if you're under the age of 65. According to a Houston Methodist review published in the Journal of the American Heart Association, Americans with heart disease continue to have low vaccination rates every year despite higher rates of death and complications from influenza.

The flu vaccination rate for American adults who are less than 65 years of age and have heart disease is less than 50%, compared to 80% in older adults with heart disease.

"It seems that younger Americans with high-risk conditions have not gotten the same memo that their older counterparts have received about the importance of getting the influenza vaccine," says Dr. Priyanka Bhugra, internal medicine specialist at Houston Methodist and lead author of the JAHA article. "That's dangerous, considering people with heart conditions are particularly vulnerable to influenza-related heart complications, whether they've reached retirement age or not."

It's well-known that the flu can lead to significant respiratory symptoms such as pneumonia, bronchitis and bacterial infection of the lungs. The virus' effects on the heart have historically been harder to parse out, in part because many patients already have a known predisposition to cardiac events and in part because the cardiac event often occurs weeks after the onset of the flu.

But here's what recent research has shown:

• Cardiovascular deaths and influenza epidemics spike around the same time.
• Patients are six times more likely to experience a heart attack the week after influenza infection than they are at any point during the year prior or the year after the infection.
• In one study looking at 336,000 hospital admissions for flu, 11.5% experienced a serious cardiac event.
• Another study looking at 90,000 lab-confirmed influenza infections showed a strikingly similar rate of 11.7% experiencing an acute cardiovascular event.
• One in eight patients, or 12.5%, admitted to the hospital with influenza experienced a cardiovascular event, with 31% of those requiring intensive care and 7% dying as a result of the event, another study found.

The reason influenza stresses the heart and vascular system so much has to do with the body's inflammatory response to the infection.

Inflammation occurs when your body's "first responders" -- white blood cells and what they produce in order to protect you -- convene in an area and get to work fighting an infection, bacteria or virus. When you're sick, you can typically feel the effects of these "combat zones" in the swelling, tenderness, pain, weakness and sometimes redness and increased temperature of your joints, muscles and lymph nodes.

The increased activity can also cause a traffic jam of sorts, leading to blood clots, elevated blood pressure and even swelling or scarring within the heart. The added stressors make plaque within your arteries more vulnerable to rupture, causing a blockage that cuts off oxygen to the heart or brain and results in heart attacks or strokes, respectively.

Additionally, non-cardiac complications from the viral illness, including pneumonia and respiratory failure, can make heart failure symptoms or heart arrhythmia much worse.

In short, the added stress on the cardiovascular system could be overwhelming to an already weakened heart muscle.

Because influenza viruses are constantly mutating, scientists alter the vaccine each year to match the likely prevalent strands. On average, it's effective at preventing infection 40% of the time. While that might not sound great -- especially in comparison to the highly effective mRNA COVID-19 vaccines -- it's enough to significantly lower the risk of severe illness in most people.

Lately, studies have been able to show that not only is the vaccine effective at protecting the general population and the most vulnerable age groups (over 65 and under 2) from severe cases of the flu, but it's also protective against cardiovascular mortality as well, especially among the high-risk population.

Some of the recent findings:

• Adults who received the vaccine were 37% less likely to be hospitalized for the flu and 82% less likely to be admitted to the ICU because of it. Among people admitted to the hospital with the flu, those vaccinated were 59% less likely to be admitted to the ICU. Vaccinated patients admitted to the ICU spent four fewer days in the ICU than unvaccinated patients.
• Vaccination was associated with a lower risk of cardiovascular events (2.9% vs 4.7%) if the patient got the flu. Among the highest-risk patients with more active coronary disease, vaccination was associated with considerably better outcomes.
• Patients admitted to the hospital with acute coronary syndrome were randomly assigned to either receive a flu vaccine or not before discharge. Major cardiovascular events occurred less frequently in the vaccine group than the control group (9.5% vs. 19%).

As a result of the demonstrated benefits conferred by influenza vaccination and the risks posed by flu infection among those with cardiovascular disease, the CDC and numerous other international societies strongly recommend annual influenza vaccination in patients with cardiovascular disease.

Clinicians should ensure high rates of influenza vaccination, especially in those with underlying chronic conditions, to protect against acute cardiovascular events associated with influenza.

Unfortunately, many heart patients visit their cardiologist more frequently than their primary care providers, and cardiology practices typically do not provide flu vaccinations, though proposed recommendations may change in the future. Until then, it is incumbent upon both the cardiology provider and the primary care provider to communicate the increased risk to their patients and the importance of getting vaccinated.

For patients with heart conditions, there are two important steps you can take to reduce your risk:

• Make sure you do obtain your influenza vaccine from your local pharmacy or primary care provider. The earlier you get it, the better it is at protecting you, as you never know when the virus may begin to spread.
• Make sure you are taking your medications and following your recommended diet, exercise and stress reduction plans. If your heart condition is stable and you end up with the flu, chances are you'll experience fewer, less severe complications than if your heart condition is poorly managed.

---

Story Source:

Materials provided by Houston Methodist. Original written by Eden McCleskey. Note: Content may be edited for style and length.

---

Journal Reference:

1. Priyanka Bhugra, Gowtham R. Grandhi, Reed Mszar, Priyanka Satish, Rahul Singh, Michael Blaha, Ron Blankstein, Salim S. Virani, Miguel Cainzos‐Achirica, Khurram Nasir. Determinants of Influenza Vaccine Uptake in Patients With Cardiovascular Disease and Strategies for Improvement. Journal of the American Heart Association, 2021; 10 (15) DOI: 10.1161/JAHA.120.019671

https://www.sciencedaily.com/releases/2021/10/211015184212.htm

FDA delays decision on Moderna's COVID-19 vaccine for adolescents

 The U.S. health regulator is delaying its decision on authorizing Moderna Inc’s COVID-19 vaccine for adolescents to check if the shot could increase the risk of a rare inflammatory heart condition, the Wall Street Journal reported on Friday.

The U.S. Food and Drug Administration (FDA) has been inspecting the risk of the condition, myocarditis, among younger men vaccinated with Moderna's shot, especially versus Pfizer's vaccine, after certain Nordic countries limited use of the shot, the report on.wsj.com/3p3P5Zp said, citing people familiar with the matter.

The agency has not yet determined whether there is heightened risk, and the delay could be several weeks, though the timing was unclear, the report said.

In June, Moderna filed for U.S. authorization of its vaccine among adolescents aged 12 through 17. The FDA authorized rival Pfizer’s vaccine for use in children as young as 12 in May.

The U.S. FDA’s review of Moderna’s application is ongoing, an FDA spokesperson told Reuters, adding that while the agency cannot predict how long the process may take, it is evaluating the data as expeditiously as possible.

Europe’s drug regulator found in July that such inflammatory conditions could occur in very rare cases following vaccination with Moderna’s vaccine or Pfizer/BioNTech’s shot, more often in younger men after the second dose.

However, the regulator stressed that the benefits of the shots outweighed any risks.

Earlier this month, Finland, Sweden and Denmark paused the use of Moderna’s shot for younger males due to reports of myocarditis, though the Danish Health Agency later said the vaccine was available to under-18s.

Moderna’s two-shot vaccine has U.S. authorization for emergency use in people aged 18 and above.

The FDA in June added a warning to the literature accompanying Pfizer/BioNTech and Moderna COVID-19 shots to indicate the rare risk of heart inflammation.

https://www.reuters.com/article/health-coronavirus-fda-moderna/update-3-u-s-fda-delays-decision-on-modernas-covid-19-vaccine-for-adolescents-wsj-idUSL4N2RB39B

Treme climbs a new mountain

 Astrazeneca’s long-delayed Himalaya study in front-line liver cancer has apparently come up trumps. After Poseidon this is the second trial to suggest that tremelimumab might not, after all, be a write-off, and its success probably owes something to a novel dosing regimen that could avoid treme’s toxicities.

Still, with Roche’s Tecentriq plus Avastin already available, first-line liver cancer is no longer the immuno-oncology white space it once was. And several upcoming phase 3 readouts for Astra’s rivals might make it harder still for the UK company to make a significant dent in this market.

The next relevant readout should come later this year from a Chinese study of Juangsu Hengrui’s camrelizumab, though the big threats in terms of Western datasets are Beigene’s Rationale-301 trial of tislelizumab, and Merck & Co/Eisai’s Leap-002 study of Keytruda plus Lenvima. Both have primary completion dates next May.

Bristol Myers Squibb’s Checkmate-9DW trial of Opdivo plus Yervoy is highly relevant, testing the same anti-PD-1/CTLA-4 mechanism as Himalaya, though it might not yield data until 2023. Notably, however, Opdivo has already failed in first-line liver cancer, as monotherapy in Checkmate-459 – a result that prompted this year’s withdrawal of Opdivo’s second-line label; a Yervoy combo remains available second line.

But Astra can celebrate the fact that, pending full data release from Himalaya, it looks like Imfinzi plus tremelimumab might be approvable in first-line liver cancer. Until the combo’s unexpected success in the NSCLC study Poseidon, which also included chemo, tremelimumab had run up a dismal record of failures, and Astra seemed largely to have deprioritised it.

Selected pivotal studies containing tremelimumab
Trial	Cancer type	Treatment cohort(s)	Enrolment	Result/data due
Arctic	3rd-line NSCLC	Imfinzi +/- tremelimumab	597	Fail
Eagle	2nd-line head & neck	Imfinzi +/- tremelimumab	736	Fail
Mystic	1st-line NSCLC	Imfinzi +/- tremelimumab	1,118	Fail
Poseidon	1st-line NSCLC	Imfinzi + chemo +/- tremelimumab	1,000	Tremelimumab combo arm positive for OS; Imfinzi arm negative for OS (both positive for PFS)
Neptune	TMB-high, 1st-line NSCLC	Imfinzi + tremelimumab	953	Fail
Danube	1st-line urothelial	Imfinzi +/- tremelimumab	1,126	Fail
Caspian	1st-line SCLC	Imfinzi + chemo +/- tremelimumab	988	Imfinzi arm positive for OS, tremelimumab combo arm negative for OS
Kestrel	1st-line head & neck	Imfinzi +/- tremelimumab	823	Fail
Himalaya	1st-line hepatocellular	Imfinzi +/- tremelimumab	1,504	Tremelimumab combo arm positive for OS; Imfinzi arm non-inferior for OS
Adriatic	SCLC maintenance	Imfinzi +/- tremelimumab	600	H2 2022
Strong	Various	Imfinzi +/- tremelimumab	1,200	2022 or beyond
Nile	1st-line urothelial	Imfinzi + chemo +/- tremelimumab	1,215	2022 or beyond
Source: clinicaltrials.gov & EvaluatePharma.

Himalaya also included an Imfinzi-only cohort, but this did not appear to have performed as well, only meeting overall survival non-inferiority, as opposed to the combo’s stated OS benefit, versus Nexavar. This is important, suggesting – as in Poseidon – that the anti-CTLA-4 MAb has an additive benefit, and that the success is not just down to Imfinzi.

Cracking the treme puzzle might be thanks to Himalaya’s use of what Astra calls the Stride regimen, comprising just a single 300mg priming dose of treme together with Imfinzi, followed by Imfinzi alone. Still, this had not been employed in Poseidon.

But data at Asco in 2020 had already suggested the potential of Stride, in Study 22, comprising a mixture of first and second-line liver cancer subjects. This was said to read out positively, and though it had no control cohort it provided a way of handicapping the Himalaya result.

At present the front-line immuno-oncology space has only one US contender, Roche’s Tecentriq plus Avastin having been approved last year on the basis of Imbrave-150; more recently a Tecentriq combo with Exelixis’s Cabometyx failed the Cosmic-312 trial, however.

In China Innovent’s Tyvyt is approved in combination with an Avastin biosimilar called Bevasda.

Keytruda, meanwhile, got a US complete response letter because, after Avastin’s approval, the uncontrolled Keynote-524 trial no longer gave sufficient front-line backing. It retains a second-line label, having failed the potentially confirmatory Keynote-240 trial but succeeded in Keynote-394, a study in Asian patients.

For now Astra can celebrate tapping into treme’s efficacy while avoiding its toxicity; this in itself is a big surprise.

Selected phase 3 studies of anti-PD-(L)1 projects in first-line liver cancer
Project	Company	Design	Study	Result
Opdivo	Bristol Myers Squibb	Vs Nexavar	Checkmate-459	Fail
Tecentriq	Roche	Avastin combo vs Nexavar	Imbrave-150	Success; US approval
Tecentriq	Roche/Exelixis	Cabometyx combo vs Nexavar	Cosmic-312	Fail
Tyvyt	Innovent	Bevasda (Avastin biosimilar) combo vs Nexavar	Orient-32	Success; China approval
Imfinzi	Astrazeneca	+/- tremelimumab vs Nexavar	Himalaya	Success
Camrelizumab	Jiangsu Hengrui	Apatinib combo vs Nexavar	NCT03764293	Ends Dec 2021
Tislelizumab	Beigene	Vs Nexavar	Rationale-301	Ends May 2022
Keytruda	Merck & Co/Eisai	Lenvima combo vs Lenvima	Leap-002	Ends May 2022
Toripalimab	Shanghai Junshi	Lenvima combo vs Lenvima	NCT04523493	Ends Aug 2023
Opdivo	Bristol Myers Squibb	Yervoy combo vs Nexavar or Lenvima	Checkmate-9DW	Ends Sep 2023
HLX10	Shanghai Henlius/Fosun	HLX04 (Avastin biosimilar) combo vs Nexavar	NCT04465734	Ends Oct 2023
Source: clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/trial-results/treme-climbs-new-mountain