AstraZeneca to Withdraw Imfinzi Indication in Advanced Bladder Cancer in the US


  • The company reported the voluntary withdrawal of the Imfinzi (durvalumab) indication in the US for prior treated adult patients with LA or metastatic bladder cancer. The withdrawal was made in consultation with the US FDA
  • The withdrawal is aligned with FDA guidance for evaluating indications with accelerated approvals that did not meet post-marketing requirements
  • In May’2017, Imfinzi has received accelerated approval in the US based on Study 1108 while the continued approval was contingent on results from the P-III DANUBE study in the 1L metastatic bladder cancer setting, which did not meet its 1EPs in 2020

Click here ­to­ read full press release/ article | Ref: AstraZeneca | Image: Healthline

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AZ withdraws Imfinzi in US bladder cancer use after trial failure

AstraZeneca has suffered a setback after it voluntarily withdrew its cancer immunotherapy Imfinzi (durvalumab) in a bladder cancer indication in the US.

AZ’s share price ticked downwards after the announcement that it will stop marketing Imfinzi, a PD-L1 class immunotherapy, for previously treated adult patients with advanced or metastatic bladder cancer.

It’s news that will likely hand market share to Roche and Pfizer/Merck KGaA, whose respective immunotherapies Tecentriq and Bavencio have bladder cancer indications.

In a statement, the big UK pharma said it had made the decision in consultation with the FDA, which was running the rule over results from the phase 3 DANUBE trial.

Following an accelerated approval in 2017 based on earlier clinical data DANUBE was supposed to supply the confirmatory survival data for Imfinzi’s first line bladder cancer indication.

But in March last year AZ announced that DANUBE had failed to meet its overall survival endpoints compared with standard care in advanced bladder cancer patients with high levels of the PD-1 biomarker, or patients regardless of their PD-1 status.

The trial tested Imfinzi as monotherapy and as part of a combination with AZ’s CTLA-4 immunotherapy and neither showed an improvement over standard care.

AZ said that the withdrawal is aligned with FDA post-approval guidance, where trial data did not meet post-approval requirements.

The news will come as a blow for AZ, where Imfinzi has been an important component of the company’s cancer portfolio.

In full year 2020 results the drug generated over $2 billion, with US sales of just under $1.2 billion.

AZ did not provide sales by indication but Imfinzi is also approved in unresectable stage III non-small cell lung cancer after chemoradiation therapy in the US and other markets, based on data from the PACIFIC phase 3 trial.

It is also approved in extensive stage small cell cancer in the US and other markets based on findings from the CASPIAN phase 3 trial.

It is also being tested in a range of other cancers, including in combination with tremelimumab, liver cancer, biliary tract cancer, oesophageal cancer, ovarian cancer and other solid tumours.

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Astellas/Seagen prepare full US filing of bladder cancer drug Padcev

Astellas and Seagen have the data they need for a full licence for their bladder cancer drug Padcev in the US, based on trial results announced over the weekend.

To recap, Padcev (enfortumab vedotin) was quickly okayed by the FDA in December 2019 in advanced urothelial cancer on the basis of phase 2 response data that made it a rising star at that year’s American Society of Clinical Oncology (ASCO) conference.

But although the response rate data was eye-catching, the FDA could only grant a faster accelerated approval that needed to be confirmed with further data.

That is now available from the trial data announced at this year’s ASCO genitourinary cancer specialist conference (ASCO GU), from a second cohort from the phase 2 EV-201 trial.

The first cohort formed the basis for the accelerated approval and the second cohort from the single-arm trial showed an objective response of 52% and a median duration of response was 10.9 months.

In Seagen’s Q4 results statement, the company said that the new EV-201 data will support a filing for a full licence in the US.

Meanwhile the data from the phase 3 EV-301 data will support filings with regulators outside of the US, Seagen said.

The late stage data showed Padcev significantly improved overall survival compared with chemotherapy in a group of patients previously treated with platinum chemo and and a PD-1/L1 inhibitor.

An interim analysis from EV-301 showed a median overall survival of 12.9 months in patients treated with Padcev compared with nine months in those treated with chemotherapy.

For patients in the Padcev arm of the trial, maculopapular rash, fatigue and decreased neutrophil count were the most frequent Grade 3 or greater treatment-related adverse events (TRAEs) occurring in more than 5% of patients.

Median progression-free survival was 5.6 months in the Padcev group compared with 3.7 months in the chemotherapy group.

Overall response rate, the percentage of patients with either complete or partial response, was 40.6% vs. 17.9% of patients in the chemotherapy arm.

Disease control rate – the percentage of patients who have achieved complete response, partial response or had stable disease, was 71.9% for Padcev and 53.4% for chemotherapy.

In an interview with pharmaphorum, Andy Krivoshik, senior vice president and Oncology Therapeutic Area head at Astellas, said the data could be used to confirm a full US licence as well as negotiations with payers.

In the UK, cost-effectiveness body NICE requires overall survival data for regular NHS reimbursement and Krivoshik said the overall survival data could help with discussions with other reimbursement authorities.

He said that the endpoints are “meaningful for payer systems”, because of the implications they have for patients.

Moving forward, Astellas and Seagen will be looking to develop the drug for other cancers with high expression of NECTIN-4, including triple-negative breast cancer, non-small cell lung cancer, head and neck and certain types of gastro-oesophageal cancer.

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Merck, Pfizer get EU nod for Bavencio as bladder cancer maintenance

Pfizer and partner Merck KGaA now have approval on both sides of the Atlantic for their checkpoint inhibitor Bavencio as a first-line maintenance therapy for bladder cancer, stealing a march on rival drugs in a highly competitive market.

The European Commission has cleared Bavencio (avelumab) for locally advanced or metastatic urothelial carcinoma (UC) – the most common form of bladder cancer – in cases where cancer hasn’t progressed after platinum-containing chemotherapy. The green light in Europe comes six months after the FDA backed the same use for the drug in the US.

The EU decision is based on results from the phase 3 JAVELIN Bladder 100 study, which showed a 31% improvement in overall survival for Bavencio plus supportive care as first-line maintenance treatment following induction chemotherapy, compared to supportive care alone.

Bavencio has previously been approved in Europe and the US as a second-line treatment for bladder cancer after platinum-based chemotherapy.

That is a crowded indication however, and the drug has to jostle for market share with Merck & Co’s Keytruda (pembrolizumab), Roche’s Tecentriq (atezolizumab), AstraZeneca’s Imfinzi (durvalumab), and Bristol-Myers Squibb’s Opdivo (nivolumab).

For now, Pfizer and Merck’s drug is the only checkpoint inhibitor cleared for the first-line maintenance after induction chemotherapy.

That allows anti-tumour treatment to continue for longer, as most patients can’t tolerate more than six cycles of chemo because of toxicity, and crucially gives Pfizer and Merck’s drug a chance to grow without competition.

Tecentriq can be used as a first-line alternative to chemotherapy in locally advanced or metastatic UC in the US, while Imfinzi and Keytruda have also been given conditional approvals by the FDA for first-line use in some patients.

However, AZ’s drug flunked a confirmatory trial last year, while Keytruda also missed the mark as a monotherapy as well as in combination with chemo in newly diagnosed UC, which could put those approvals in jeopardy.

Most UC patients see their disease worsen within nine months of induction chemo, and only 5% of patients diagnosed with metastatic bladder cancer will live longer than five years, so Bavencio’s new indication has been hailed as a significant advance in treatment.

It is now approved for the maintenance use in 38 countries, with 13 others reviewing the application, including Japan. Analysts at Credit Suisse have suggested it could drive peak sales of the drug towards $800 million.

Merck – the only one of the two companies that breaks out Bavencio sales – said that the drug recorded sales of €105 million ($127 million) in the first nine months of 2020.

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Arsenic in Infant Rice Cereal

When it comes to rice and rice-based products, pediatric nutrition authorities have recommended that arsenic intake should be as low as possible.

“The US Food and Drug Administration (FDA) has been monitoring the arsenic content in foods” for decades, yet despite the “well-established science describing the health risks associated with arsenic exposure, no standards have been set limiting the amount of arsenic allowable in foods” in the United States. In 2001, the EPA “adopted a new stricter standard for arsenic in drinking water,” and in 2013, the FDA proposed a legal limit for apple juice. “There are still no standards for arsenic in food products despite the fact that food sources are our main source of exposure.”

Unlike the United States, China has standards. As of 2014, China set a maximum threshold of inorganic arsenic at 150 parts per billion, stricter than the World Health Organization’s limit of 200 ppb. In the United States, a 200 ppb limit wouldn’t change the cancer risk much. If we had China’s safety limits of 150 ppb, though, cancer risk would be reduced up to 23 percent and a maximum threshold of 100 ppb would lower cancer risk up to 47 percent—but that could seriously affect the rice industry. In other words, U.S. rice is so contaminated with arsenic that if a safety standard that really cut down on cancer risk were set, it “would wipe out the U.S. rice market.” However, with no limits, what’s the incentive for the rice industry to change its practices? Setting arsenic limits would not only directly protect consumers but also encourage the industry to stop planting rice paddies on arsenic-contaminated land.

Those cancer estimates are based on arsenic-contaminated water studies. Might the arsenic in rice somehow have a different effect? You don’t know…until you put it to the test. We know rice has a lot of toxic arsenic that urine studies have shown we absorb into our body, but there hadn’t been any studies demonstrating “deleterious health impacts” specific to rice arsenic—until now. Since arsenic causes bladder cancer, the researchers figured they would see what kind of DNA mutations the urine of rice eaters can have on human bladder cells growing in a petri dish. And, indeed, they clearly demonstrated that eating a lot of arsenic-contaminated rice every day can “give rise to significant amounts of genetic damage,” the kind that‘s associated with cancer. Yes, but the study used pretty contaminated rice. However, only about 10 percent of the rice in certain parts of Asia might ever reach those levels of contamination, though a quarter of rice in parts of Europe might and more half in the United States, making for considerable public health implications.

So, “there remains little mystery surrounding the health risks associated with arsenic levels in rice. The remaining mystery is why long-overdue standards for arsenic levels in rice have not been set by the FDA” in the United States, but that may be changing. In 2016, the FDA proposed setting a limit on toxic arsenic—at least in infant rice cereal, which I discuss in my video Arsenic in Infant Rice Cereal.

As you can see at 3:24 in my video, infants and children under four years of age average the highest rice intake, in part because they eat about three times the amount of food in relation to their body size, so there’s an especially “urgent need for regulatory limits” on toxic arsenic in baby food.

Pediatric nutrition authorities have recommended that when it comes to rice and rice-based products, “arsenic intake should be as low as possible,” but how about as early as possible? Approximately 90 percent of pregnant women eat rice, which may end up having “adverse health effects” on the baby.

You can estimate how much rice the mother ate while pregnant by analyzing arsenic levels in the infant’s toenail clippings. “Specifically, an increase of 1/4 cup of rice per day was associated with a 16.9% increase in infants toenail [arsenic] concentration,” which indicates that arsenic in rice can be passed along to the fetus. What might that arsenic do? A quarter cup of rice worth of arsenic has been associated with low birth weight, increased respiratory infections, and, above that, a 5- to 6-point reduction in IQ, among other issues. So, “based on the FDA’s findings, it would be prudent for pregnant women to consume a variety of foods, including varied grains (such as wheat, oats, and barley),” which is code for cut down on rice. Saying eat less of anything, after all, is bad for business.

Once the baby is weaning, “what’s a parent to do?” Asks Consumer Reports, “To reduce arsenic risks, we recommend that babies eat no more than 1 serving of infant rice cereal per day on average. And their diets should include cereals made of wheat, oatmeal, or corn grits, which contain significantly lower levels of arsenic”—that is, rely on other grains, which are much less contaminated than rice. As the American Academy of Pediatrics has emphasized, “there is no demonstrated benefit of rice cereal over those made with other grains such as oat, barley, and multigrain cereals, all of which have lower arsenic levels than rice cereal.” As you can see at 5:28 in my video, reducing consumption of infant rice cereal to just two servings per week could have an even more dramatic effect on reducing risk.

 The proposed limit on toxic arsenic in infant rice cereals would end up removing about half of the products off the shelves. The FDA analyzed more than 500 infant and toddler foods, and the highest levels of toxic arsenic were found in organic brown rice cereals and “Toddler Puffs.” Based on the wording in the report, these puffs appear to be from the Happy Baby brand. Not-so-happy baby if they suffer brain damage or grow up to get cancer. A single serving could expose infants to twice the tolerable arsenic intake set by the EPA for water. I contacted the Happy Baby company and was told they “are not able to provide any comments” on the FDA’s results.

“Eliminating all rice and rice products from the diets of infants and small children up to 6 years old could reduce the lifetime cancer risk from inorganic arsenic in rice and rice products by 6% and 23% respectively.” That is, there would be a 6 percent lower chance of developing lung or bladder cancer later in life if infants stopped, and a 23 percent lower chance if young kids stopped. However, switching to other grains is a move described as “drastic and dramatic,” creating “a huge crisis”—for the rice industry, presumably—and therefore “not feasible at all.”

I was hoping Happy Baby, upon learning of the concerning FDA arsenic toddler puffs data (regardless of whether the data were about its brand or not) would have kicked its own testing and potential remediation into high gear like Lundberg did (see Which Brands and Sources of Rice Have the Least Arsenic?). But, unfortunately, in my email correspondence with the company, I got no sense that it did.

For more videos on this topic, see:

And here are five more:

In health,

Michael Greger, M.D.

PS: If you haven’t yet, you can subscribe to my free videos here and watch my live presentations:

AstraZeneca’s Imfinzi (durvalumab) Receives the US FDA’s Priority Review for Less Frequent Fixed-Dose Use in NSCLC and Bladder Cancer


  • The US FDA has accepted sBLA and granted PR to Imfinzi (1500mg) for a new 4wks. FD regimen to treat patients with unresectable Stage III NSCLC after CT and prior treated advanced bladder cancer, consistent with the approved dosing in ES-SCLC
  • The company anticipates the PDUFA date in Q4’20. The sBLA is based on multiple clinical trials, including results of P-III CASPIAN trial in ES-SCLC which used the 4wks., FD regimen during maintenance
  • If approved, the new dosing will be available as an alternative to the approved weight-based dosing of 10mg/kg q2w

Click here ­to­ read full press release/ article | Ref: AstraZeneca | Image: Fierce Pharma

Related News: AstraZeneca Reports Results of Imfinzi + Tremelimumab in P-III CASPIAN Study as 1L Treatment for Extensive-Stage Small Cell Lung Cancer

AZ aims to cut cancer clinic visits with new Imfinzi regimen

The FDA is to review data supporting AstraZeneca’s Imfinzi (durvalumab) cancer immunotherapy in a new four-week regimen that will halve the number of required clinic visits for patients with lung and bladder cancer.

The regulator has granted a faster six-month Priority Review for the fixed dose regimen, based on data from several Imfinzi clinical trials, including results from the phase III CASPIAN trial in extensive stage small-cell lung cancer (ES-SCLC) which used the four-week, fixed-dose regimen during maintenance.

AZ hopes that the new dosing regimen will be able to offer patients and doctors an alternative to the existing fortnightly regimen, allowing the drug to gain traction and taking pressure off clinics during the COVID-19 pandemic.

The strategy is similar to one employed by Merck & Co, which has extended the length of the dosing regimen for its rival immunotherapy Keytruda from three to six weeks in certain indications.

The FDA grants Priority Review to applications for medicines that offer significant advances over available options for serious diseases in terms of safety, efficacy preventing serious conditions, or patient compliance.

Cutting the number of visits to clinics is an important factor in getting patients to comply with regimens, saving on travel costs and reducing the impact on patients’ lives.

A regulatory decision is due during the fourth quarter of 2020.

Dave Fredrickson, executive vice president at AstraZeneca’s oncology unit, said: “The new less-frequent dosing option for non-small cell lung cancer and bladder cancer will simplify and improve treatment by enabling continuity of care while minimising the risk of exposure to infection in the healthcare setting.

“This takes on particular urgency during the current pandemic, as doctors care for patients at high risk of COVID-19 complications.”

Imfinzi is approved in the curative-intent setting of unresectable, stage III NSCLC after chemoradiation therapy in the US, Japan, China, across the EU and in many other countries, based on the phase 3 PACIFIC trial.

Imfinzi is also approved for previously treated patients with advanced bladder cancer in the US and several other countries.

It is also approved in the US and under review in Japan and other countries for ES-SCLC. Imfinzi was also recently recommended for marketing authorisation in the EU for this indication.

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