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"I suspect that for other combinations going forward Keytruda is going to be the control arm for those trials as it is such an important part of standard-of-care for many tumors."
Keytruda is the gift that keeps on giving for Merck, and here’s what’s next for the cancer juggernaut
Michael Gibney
Sitting at the crest of the wave of checkpoint inhibitors that changed the game in oncology and made Merck & Co. the pharma behemoth it is today, Keytruda has come a long way in its more than eight years on the market.
Dr. Gregory Lubiniecki, VP of oncology clinical research, Merck
Permission granted by Merck / Gregory Lubiniecki
The cancer immunotherapy — which works by priming tumors to be eliminated by a patient's immune system — has had a storied history of treating more than a million patients with many different kinds of cancers, Merck vice president of oncology clinical research Dr. Gregory Lubiniecki, said in an interview. It's also the bestselling cancer drug in the world a few years running and is set to become the bestselling drug overall next year.
One of the reasons the drug is so successful is how versatile it is, winning approval after approval for different types of cancers, including some of the trickiest out there. Another is its longevity, as demonstrated most recently by five-year survival studies in patients with non-small cell lung cancer, the company presented at this year's European Society for Medical Oncology (ESMO) annual meeting in September. In the two trials, a regimen of Keytruda with chemotherapy resulted in almost 20% of patients with the deadly disease living for five years.
Here, Lubiniecki talks about Keytruda's successes as it approaches a decade on the market, what the long-term benefit of the drug means for patients and the oncology community, and the future of combinations and newer treatments.
This interview has been edited for style and brevity.
PHARMAVOICE: How would you characterize Keytruda's trajectory over time since its very first approval in 2014 to the place it currently holds in the oncology arena today?
DR. GREGORY LUBINIECKI: Keytruda has had an amazing trajectory. I can say that we've treated over a million patients commercially, and there have been over 40 indications across over 20 different tumor types. And that includes pan-tumor indications covering microsatellite instability and tumor mutation burden-high indications, and these have been transformative in patient care. A number of these have been based off a demonstration of an improved survival benefit for patients, and what we saw at ESMO this year are long-term outcomes for lung cancer, head and neck cancer and melanoma.
These long-term studies are really game-changing. Did you think back at the beginning of the journey that these results would eventually be realized?
This is certainly very surprising and inspiring. When the journey began, it was clear that Keytruda's mechanism of action had a role to play in patients with melanoma, kidney cancer and non-small cell lung cancer — and so being data driven, initially it seemed as though it may have just been very limited, but as we began to explore other opportunities, we found other indications where the monotherapy could have benefit. We found a biomarker that could help with patient selection to identify the patients most likely to benefit, and then we also opened ourselves up to the possibility of combination therapy in an agnostic fashion.
"I suspect that for other combinations going forward Keytruda is going to be the control arm for those trials as it is such an important part of standard-of-care for many tumors."
Dr. Gregory Lubiniecki
Vice president of oncology research, Merck
In some cases, we combined Keytruda with chemotherapy. And you would think, well, some of the chemotherapy perhaps will kill off the immune cells that have been activated around the tumor site, as well as other ways they might not work together. But still, you're having the benefit of two different therapies on board, and in a number of instances, it's been demonstrated that the chemotherapy is not working at odds against the checkpoint inhibitor and the two drugs are able to produce their desired effect in the patients and result in overall benefit for the majority of patients treated.
It's exciting to see all the trickier cancers you're able to target now with drug combinations. How do you approach finding a good combination candidate?
Merck opted to take an agnostic approach to the development of combination work with Keytruda — this philosophy has been led by Dr. Roy Baynes, who's no longer at Merck, and Eric Rubin and Emmett Schmidt. We have been willing to partner with other companies so they can test their products with Keytruda, and when we see that there is greater activity with the combination over what one might expect with a single agent, then we've thought, OK, this looks like it's something worth taking forward.
What are the unique qualities that Merck brings to a partnership, and then qualities that a company like Eisai or AstraZeneca, for example, might contribute to make it successful overall?
The partnerships are a very special aspect of the development program at Merck. And certainly two heads addressing a problem are better than one. So it's good to have the input from people at both companies working on trying to solve this problem of cancer drug development and trying to improve the lives of patients with cancer. Often, each company will agree to provide their drug and it's decided which company can run a protocol. And you have the people from development at both companies contributing to the design of that study and any plans for next steps thereafter. I think it's a benefit for patients and for science to have this joint approach to trying to tackle the problem.
What do you see as the shining light for Keytruda moving forward? Long-term survival, more indications, drug combinations — what drives Keytruda into its next phase?
When it became apparent how broad Keytruda's benefit is for patient care, an effort was made to demonstrate the value through clinical trials. It's at the point now where Keytruda is foundational in the care of many patients early on in a first-line setting and in some cases a second-line or greater setting. And we're looking at a number of studies in earlier stages of disease, both locally advanced and resectable, so it's expected that the ability of Keytruda to play a role in the care of patients at any stage of their disease is being explored. There are a little over 80 opportunities left for studies yet to be read out to demonstrate this benefit, and I suspect that for other combinations going forward Keytruda is going to be the control arm for those trials as it is such an important part of standard-of-care for many tumors.
What are you excited about in the field of oncology? Are there trends you see as most promising to the landscape going forward?
I'm very excited to see more of these trials in the earliest stages of cancer with checkpoint inhibitors like Keytruda reading out, because there's an opportunity to make yet another impact on the lives of patients with cancer. We've seen in a few of the studies that have read out so far that there is a progression- or relapse-free survival benefit in some of these studies — but I'm very interested and excited to see if we can identify a benefit in overall survival, which can be very challenging. Even in the era when chemotherapy was the predominant therapeutic option, it took a long time for these adjuvant studies to demonstrate survival benefit. Now with the advent of immunotherapy as a next line of therapy for when patients relapse, it may take even longer for us to see the benefit of immunotherapy in an adjuvant setting to show us an overall survival benefit.
And we're on the cusp of seeing more data from antibody-drug conjugates, and it will be interesting to see how these change the landscape in cancer care, as we're now able to try and deliver chemotherapy in a more targeted setting, right to the tumor cells, ideally speaking.
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Sitting at the crest of the wave of checkpoint inhibitors that changed the game in oncology and made Merck & Co. the pharma behemoth it is today, Keytruda has come a long way in its more than eight years on the market.
Dr. Gregory Lubiniecki, VP of oncology clinical research, Merck
Permission granted by Merck / Gregory Lubiniecki
The cancer immunotherapy — which works by priming tumors to be eliminated by a patient's immune system — has had a storied history of treating more than a million patients with many different kinds of cancers, Merck vice president of oncology clinical research Dr. Gregory Lubiniecki, said in an interview. It's also the bestselling cancer drug in the world a few years running and is set to become the bestselling drug overall next year.
One of the reasons the drug is so successful is how versatile it is, winning approval after approval for different types of cancers, including some of the trickiest out there. Another is its longevity, as demonstrated most recently by five-year survival studies in patients with non-small cell lung cancer, the company presented at this year's European Society for Medical Oncology (ESMO) annual meeting in September. In the two trials, a regimen of Keytruda with chemotherapy resulted in almost 20% of patients with the deadly disease living for five years.
Here, Lubiniecki talks about Keytruda's successes as it approaches a decade on the market, what the long-term benefit of the drug means for patients and the oncology community, and the future of combinations and newer treatments.
This interview has been edited for style and brevity.
PHARMAVOICE: How would you characterize Keytruda's trajectory over time since its very first approval in 2014 to the place it currently holds in the oncology arena today?
DR. GREGORY LUBINIECKI: Keytruda has had an amazing trajectory. I can say that we've treated over a million patients commercially, and there have been over 40 indications across over 20 different tumor types. And that includes pan-tumor indications covering microsatellite instability and tumor mutation burden-high indications, and these have been transformative in patient care. A number of these have been based off a demonstration of an improved survival benefit for patients, and what we saw at ESMO this year are long-term outcomes for lung cancer, head and neck cancer and melanoma.
These long-term studies are really game-changing. Did you think back at the beginning of the journey that these results would eventually be realized?
This is certainly very surprising and inspiring. When the journey began, it was clear that Keytruda's mechanism of action had a role to play in patients with melanoma, kidney cancer and non-small cell lung cancer — and so being data driven, initially it seemed as though it may have just been very limited, but as we began to explore other opportunities, we found other indications where the monotherapy could have benefit. We found a biomarker that could help with patient selection to identify the patients most likely to benefit, and then we also opened ourselves up to the possibility of combination therapy in an agnostic fashion.
"I suspect that for other combinations going forward Keytruda is going to be the control arm for those trials as it is such an important part of standard-of-care for many tumors."
Dr. Gregory Lubiniecki
Vice president of oncology research, Merck
In some cases, we combined Keytruda with chemotherapy. And you would think, well, some of the chemotherapy perhaps will kill off the immune cells that have been activated around the tumor site, as well as other ways they might not work together. But still, you're having the benefit of two different therapies on board, and in a number of instances, it's been demonstrated that the chemotherapy is not working at odds against the checkpoint inhibitor and the two drugs are able to produce their desired effect in the patients and result in overall benefit for the majority of patients treated.
It's exciting to see all the trickier cancers you're able to target now with drug combinations. How do you approach finding a good combination candidate?
Merck opted to take an agnostic approach to the development of combination work with Keytruda — this philosophy has been led by Dr. Roy Baynes, who's no longer at Merck, and Eric Rubin and Emmett Schmidt. We have been willing to partner with other companies so they can test their products with Keytruda, and when we see that there is greater activity with the combination over what one might expect with a single agent, then we've thought, OK, this looks like it's something worth taking forward.
What are the unique qualities that Merck brings to a partnership, and then qualities that a company like Eisai or AstraZeneca, for example, might contribute to make it successful overall?
The partnerships are a very special aspect of the development program at Merck. And certainly two heads addressing a problem are better than one. So it's good to have the input from people at both companies working on trying to solve this problem of cancer drug development and trying to improve the lives of patients with cancer. Often, each company will agree to provide their drug and it's decided which company can run a protocol. And you have the people from development at both companies contributing to the design of that study and any plans for next steps thereafter. I think it's a benefit for patients and for science to have this joint approach to trying to tackle the problem.
What do you see as the shining light for Keytruda moving forward? Long-term survival, more indications, drug combinations — what drives Keytruda into its next phase?
When it became apparent how broad Keytruda's benefit is for patient care, an effort was made to demonstrate the value through clinical trials. It's at the point now where Keytruda is foundational in the care of many patients early on in a first-line setting and in some cases a second-line or greater setting. And we're looking at a number of studies in earlier stages of disease, both locally advanced and resectable, so it's expected that the ability of Keytruda to play a role in the care of patients at any stage of their disease is being explored. There are a little over 80 opportunities left for studies yet to be read out to demonstrate this benefit, and I suspect that for other combinations going forward Keytruda is going to be the control arm for those trials as it is such an important part of standard-of-care for many tumors.
What are you excited about in the field of oncology? Are there trends you see as most promising to the landscape going forward?
I'm very excited to see more of these trials in the earliest stages of cancer with checkpoint inhibitors like Keytruda reading out, because there's an opportunity to make yet another impact on the lives of patients with cancer. We've seen in a few of the studies that have read out so far that there is a progression- or relapse-free survival benefit in some of these studies — but I'm very interested and excited to see if we can identify a benefit in overall survival, which can be very challenging. Even in the era when chemotherapy was the predominant therapeutic option, it took a long time for these adjuvant studies to demonstrate survival benefit. Now with the advent of immunotherapy as a next line of therapy for when patients relapse, it may take even longer for us to see the benefit of immunotherapy in an adjuvant setting to show us an overall survival benefit.
And we're on the cusp of seeing more data from antibody-drug conjugates, and it will be interesting to see how these change the landscape in cancer care, as we're now able to try and deliver chemotherapy in a more targeted setting, right to the tumor cells, ideally speaking.
Copyright © 2022 Industry Dive. All rights reserved. Provided by SyndiGate Media Inc. (Syndigate.info). -0- Oct/03/2022 12:06 GMT
Yes please tryn2 ...
Share for share could have maybe a bump or more to deal with than an all cash offer during the close period and would certainly not change my strategy of selling 100% in the next trading session.
..i’ve replied to SM
..well our price would move to reflect the cash value of the shares we are being swapped for …. so basically its the same .
ie ….if the shares value of Merck shares we are being given is say $14bn , our pps would be in the $9.50 - $9.80 range the next morning .
Yes , what happens is lets say they announce an offer or $10 a share , the next day it will trade somewhere between $9.50 and $10 and remain there till the deal closes which could be months , and whilst it would certainly would be likely to close , a bird in the hand .. and all that .
Correct. That’s normal ‘ Close ‘ would be some time after the announcement and the PPS would open within a few percent of the initial offer the next morning and I’ll be hitting that bid
and happy to let someone else have the percent or so.
( BTW I specialise in special sits / risk arb)
and 10 year market cap +1000% ...
you have completely and utterly missed the point ..
... you`ll no doubt remember Phase V..... now remind me , where were they based again ...
See any parallels ...
Lars Windhorst hired corporate spies that targeted football club boss, lawsuit says
Israeli company mounted operation to oust Hertha Berlin president, according to court documents
Lars Windhorst vowed to lift Hertha Berlin’s fortunes and transform it into a ‘big city club’ but the team’s performances have continued to be poor © David Swanson/Reuters
Cynthia O’Murchu and Robert Smith in London 5 HOURS AGO
German financier Lars Windhorst hired an Israeli private intelligence company that orchestrated a clandestine campaign aimed at ousting the then-president of Hertha Berlin, the Bundesliga football club, according to a lawsuit.
The plot against Werner Gegenbauer is detailed in Israeli court documents filed this month, which reveal that Tel Aviv-based Shibumi Strategy Limited ran a year-long covert operation to push him out of the club, where Windhorst is the majority owner.
Gegenbauer ultimately stepped down in May after 14 years at the helm, which Shibumi claimed was evidence that “the project was successfully accomplished”. The corporate intelligence firm is now suing Windhorst in an Israeli court, alleging that a unit of the financier’s company Tennor has breached a contract under which it owes Shibumi €1mn for eight months’ work, as well as a €4mn success fee allegedly agreed orally.
Windhorst had hired Shibumi to “plan and develop a strategy” that would “enhance” his reputation, according to a service agreement between the parties included in the court filings.
Asked to comment on the case, Ori Gur-Ari, chief executive of Shibumi Strategy, said: “We do not know anything about this alleged case and you must have made a mistake.” Gegenbauer could not be reached. Windhorst described it as “nonsense” and did not accept the reliability of the filed documents. He said he had not talked to Gur-Ari “for a long time”.
The Financial Times obtained the court papers, filed three weeks ago at a district court in Tel Aviv, with the assistance of the Times of Israel.
In a June 2022 report summarising the campaign, codenamed “Euro 2020”, Shibumi explained how its 20-strong team of operatives approached Gegenbauer’s supporters, opponents and family members online and in person, often going “undercover” to obtain information or promote their influence campaign against the German football executive, the court filings show.
Shibumi then set up online profiles of purported fans criticising Gegenbauer and paid a caricaturist to create unflattering images of the 72-year-old for use in social media posts. These cartoons included images that depicted Gegenbauer as the grim reaper and the devil.
It also created a website to lobby for the Hertha president’s removal called “Gegenbauer Raus” — “Gegenbauer Out” — and a channel on messaging service Telegram to “raise awareness” of the campaign, according to documents disclosed in the lawsuit.
Shibumi established a blog called “Sportfreax” where it published negative articles to “influence Hertha members about Hertha’s internal chaos”, while “identifying journalists that could be approached undercover” to promote the campaign.
Werner Gegenbauer stepped down in May after 14 years at the helm, which Shibumi claimed was evidence that ‘the project was successfully accomplished’ © dpa picture alliance/Alamy
The Israeli company planned to hold a “large-scale event” campaigning for the dismissal of Gegenbauer, at which its operatives would hand out customised “Gegenbauer Raus” merchandise to fans. The event did not go ahead, however, as Hertha’s general assembly in November 2021 was cancelled.
Windhorst and his company are yet to file a defence in the civil lawsuit, which Shibumi has brought against Windhorst and a Switzerland-based unit of the financier’s investment firm Tennor Holding. But according to email and text conversations disclosed in the case, Windhorst complained about having paid “huge amounts” of money to Shibumi for years with little to show for it.
“The problem here is that there has been and still is a huge discrepancy between your perception on what value your bring [sic] or brought in the past and the reality of how things turned out,” Windhorst — who also publicly called for Gegenbauer’s resignation — wrote in a May 2022 email to Gur-Ari.
In the same email, Windhorst acknowledged that Shibumi had successfully uncovered the person behind a Twitter account called “Wundersplat”, which posted derogatory messages about the 45-year-old financier, riffing on the “Wunderkind” nickname he earned as a teenage entrepreneur in the 1990s.
In messages back to the financier, Gur-Ari claimed that during a June 2021 meeting aboard a yacht, Windhorst said Shibumi stood to make “millions of euros” if the campaign was successful, but in the end the Israeli company “worked days and nights for eight months without getting paid”.
Windhorst’s investment in Hertha has proved controversial. The financier, who is famous in his native Germany for enduring a bruising downfall in the 2000s that culminated in personal bankruptcy and a criminal conviction, first bought a minority stake in the struggling club in 2019.
While Windhorst promised to improve Hertha Berlin’s fortunes and transform it into a “big city club”, the team’s continued poor performance on the pitch led some fans to chant “Windhorst Raus” at the club’s general meeting this year.
While the financier has a majority stake after pouring €374mn into the club, under Bundesliga rules aimed at protecting fans’ interests his voting rights are capped at 49.9 per cent. This restricted Windhorst’s ability to remove Gegenbauer directly, despite escalating tensions between the club’s owner and its president that spilled into public view.
Windhorst is separately facing numerous lawsuits from aggrieved creditors over alleged unpaid debts. Last month, he pledged that he would repay €550mn in “weeks” to his largest creditor H2O Asset Management, a European investment company that is under regulatory investigation for heavily investing in bonds linked to Windhorst.
and the funny thing is that`s all true ...
Well I`m hoping its simply NWBO now awaiting the ` good to go ` from a large pharma to release the journal with Merck`s name all over it ...
Because any suitor from the field will 100% want the PR as part of the deal ..
Correct
Somethings going on that none of us are aware of that`s most definitely the case . Maybe a deals done.. that would certainly explain just about everything from the start stop publication to the ultra late ASM.
Maybe Senti, would like to comment I believe it was she that protested the strange trial end date that didn't relate to anything any of us were aware of was used simply because they had to put some arbitrary future date on the .CT form ... or something to that effect anyway .(Apols of it wasn't Senti but I think it may have been )
duplicate
Yep - first time I`ve seen it though... and therein evidence there was a submittance and it was pulled as many have suggested recently .... Hopefully for good reason
BBC This morning :
Cancer-killing virus shows promise in patients
https://www.bbc.co.uk/news/health-62833581
FLIPPER ,
What dya reckon …
https://jitc.bmj.com/content/jitc/8/Suppl_3/A471.1.full.pdf
I was just shopping in Mayfair and whilst walking back along Piccadilly toward Piccadilly Circus which is 100 metres from my office I was stopped by a morbidly obese American lady . ' ...is there a pharmacy nearby ? she asked ..I replied sure just continue walking 100 yards along there`s a huge pharmacy called Boots just on your left on the Piccadilly Circus roundabout , you really cant miss it `
She turned to what I assume was her eating partner of some years and said ` just along here ` ...
Off they waddled , not a please or thankyou to be heard ...
Well that's certainly the rumour as you well know .
A partnership via C shares will take away all of the noise..
..its of significant importance if we don`t partner and of course if we sell its of no importance at all , but unless we reverse split then we will not meet the criteria for at least a few months after the stock is trading well above $5 .
FDA Approves Lilly's Retevmo® (selpercatinib), the First and Only RET Inhibitor for Adults with Advanced or Metastatic Solid Tumors with a RET Gene Fusion, Regardless of Type
PR Newswire
INDIANAPOLIS, Sept. 21, 2022
Tumor-agnostic data supporting approval demonstrated an overall response rate (ORR) of 44% across multiple tumor types
FDA simultaneously grants traditional approval in adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a RET gene fusion, as detected by an FDA-approved test
INDIANAPOLIS, Sept. 21, 2022 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced the U.S. Food and Drug Administration (FDA) has granted approval to Retevmo® (selpercatinib, 40 mg & 80 mg capsules) for adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on ORR and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
"In the LIBRETTO-001 trial, selpercatinib demonstrated clinically meaningful and durable responses across a variety of tumor types in patients with RET-driven cancers, including pancreatic, colon and other cancers in need of new treatment options," said Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center and co-investigator for LIBRETTO-001. "These data and FDA approval of the tumor-agnostic indication underscore the importance of routine, comprehensive genomic testing for patients across a wide variety of tumor types."
In addition to the tumor-agnostic approval, the FDA has granted traditional approval for Retevmo in adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a RET gene fusion, as detected by an FDA-approved test. This FDA action broadens the Retevmo label to include patients with locally advanced disease and converts the May 2020 accelerated approval for NSCLC to a traditional approval.
The labeling for Retevmo contains warnings and precautions for hepatotoxicity (evidence of liver dysfunction), interstitial lung disease (ILD)/pneumonitis, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, tumor lysis syndrome, risk of impaired wound healing, hypothyroidism, and embryo-fetal toxicity.
"Since its initial accelerated approval, Retevmo has shifted the treatment paradigm for patients with RET-altered cancers," said David Hyman, M.D., chief medical officer, Loxo@Lilly. "Retevmo is the first and only RET inhibitor to receive both tumor-agnostic accelerated approval and traditional approval in NSCLC, further supporting its ability to deliver meaningful clinical benefit for patients across diverse tumor types."
The two approvals are supported by data from the pivotal LIBRETTO-001 trial, which is the largest clinical trial of patients with RET-driven cancers treated with a RET inhibitor. The multicenter, open-label, multi-cohort study enrolled patients with locally advanced or metastatic RET-driven solid tumors, including NSCLC. Major efficacy outcomes were ORR and DOR, assessed by a blinded independent review committee (BIRC). Prespecified secondary endpoints included central nervous system (CNS) ORR and CNS DOR.
RET Fusion-Positive Solid Tumors
Among the 41 patients in the tumor-agnostic data set, the most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%), and unknown primary (7%). Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). Efficacy results are summarized below:
Headline News .... even though it only works for 2% of those with the disease... so extrapolate that ...
https://www.bbc.co.uk/news/health-62851186
1. Journal with global PR Campaign
2. UK MAA application
3. C Share completed placement announcement ( hopefully large pharma but real money / long only fund will do )
4.... and of course there`s a chance having had data in hand for ages LP's`s got a JV or a sale done.
Delays here have been a day maybe two no more ..
HRH Queen Elizabeth II worked till 2 days before she died at 96 and its been a common theme here that she would have wanted work to continue as smoothly and quickly as possible upon her passing.
The British Medical Journal is highly credible also Btw …
Nice thought but nope , remember he told the world he wasn’t going to invade Ukraine , pulled back from the border and invaded the next day .
He’s playing games and this is no more than a cynical attempt to slow the Ukrainian offensive whilst he regroups.
Amgen's new cancer drug faces questions about competition
(MarketWatch) -- Jaimy Lee
'This is a pretty shocking fall from grace for one of the more exciting innovations in targeted oncology this decade,' Baird's Brian Skorney told investors
Amgen Inc.'s (AMGN) Lumakras, which already has a type of conditional approval to treat lung cancer, produced mixed results in a closely watched clinical trial comparing the drug to docetaxel, a commonly used chemotherapy.
The news, announced in a news release on Sunday and in a presentation at the European Society for Medical Oncology meeting in Paris on Monday, hit Amgen's stock, which closed Monday at $237.62, a 10% drop over Friday's closing price of $247.69. The stock trended further down this week, closing at $228.12 on Wednesday.
A series of analyst notes that followed the clinical data underscore Wall Street's questions about the potential blockbuster status of the oral pill.
I guess nothings done till the ink is dry , the C shares at this stage to my knowledge are no more than a provision with only minimal amounts of them sold to accredited sophisticated investors.
Also a block sale of C shares could easily be part of a buy out structure and is in no way prohibitive for M&A possibilities .
Flipper , as Woj says very well in a later post, the embargoed journal story is well past its sell by date.
They are on the eve of reg approval and yet still only 19 people in the company ... nope this is a buy out scenario ...
As Woj says if any of us old timers could be objective ( which of course we cant ) this smacks of a company that are posturing not to be around in January 2023 ...
Logically I totally agree , but whilst LG continues to spout verbal diarrhoea to our latest iterations of Chris LeCoursier , Turtle and the California Kid ( that ones for those that have bene in over 9 years) there just cant be anything that progressed .
Hope I`m wrong ...
Merck & Co.'s Keytruda Wins Canadian Nod As Adjuvant Therapy For
(MT Newswires)
Merck & Co. (MRK.PA) said Tuesday that it received Health Canada's approval for Keytruda's use as an adjuvant treatment for adults and children, aged 12 and above, with stage 2B or 2C melanoma after complete resection.
Melanoma is the least common type of all skin cancers but the most serious due to its high risk of spreading into any organ. In Canada, there are around 9,000 individuals diagnosed with melanoma in 2022.
The approval is based on the results of the late-stage Keynote-716 trial, in which the anticancer drug significantly improved recurrence-free survival. At the time of a 14.3 months follow-up, about 11% of patients treated with Keytruda had a recurrence or died versus 17% in placebo.
Medicenna to Collaborate with Merck to Evaluate MDNA11 in Combination with Keytruda in ABILITY Trial
(MT Newswires)
Medicenna Therapeutics (MDNA.TO) on Tuesday said it has entered into a clinical trial collaboration and supply agreement with Merck (MSD) to evaluate MDNA11, Medicenna's "beta-only" long-acting IL-2 super-agonist in combination with Keytruda (pembrolizumab), Merck's anti-PD-1 (programmed death receptor-1) therapy, in the Phase 1/2 ABILITY Study.
The ABILITY Study is a Phase 1/2 trial designed to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of MDNA11 as a monotherapy and in combination with Keytruda) in patients with advanced/metastatic solid tumors. Under the terms of the clinical trial supply and collaboration agreement, Medicenna will sponsor the study and Merck will supply Keytruda. The two companies will establish a Joint Development Committee to advance the study's combination arm.
"Entering into this agreement with Merck provides us with an opportunity to work with the world's leading immuno-oncology company," said Fahar Merchant, PhD, President and CEO of Medicenna. "Although we believe that MDNA11 has great potential as a single agent, combining it with Keytruda may significantly enhance therapeutic benefit in different types of cancer, potentially maximizing the value of MDNA11."
Astellas, Seagen and Merck Announce Results of Clinical Trial Investigating PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) and PADCEV as Monotherapy in First-Line Advanced Urothelial Cancer
PR Newswire
TOKYO and BOTHELL, Wash. and RAHWAY, N.J., Sept. 12, 2022
– Results demonstrated a 64.5% confirmed objective response rate in patients treated with investigational combination of enfortumab vedotin and pembrolizumab –
– Data highlighted in late-breaking presentation at the European Society for Medical Oncology (ESMO) Congress 2022 –
TOKYO and BOTHELL, Wash. and RAHWAY, N.J., Sept. 12, 2022 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas"), Seagen Inc. (Nasdaq:SGEN) and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced results from the phase 1b/2 EV-103 clinical trial (also known as KEYNOTE-869) Cohort K investigating PADCEV® (enfortumab vedotin-ejfv) in combination with Merck's anti-PD-1 therapy KEYTRUDA® (pembrolizumab) and PADCEV alone as first-line treatment in patients with unresectable locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible to receive cisplatin-based chemotherapy. The findings were presented today at the European Society for Medical Oncology (ESMO) Congress as part of a late-breaking abstract presentation (Abstract #LBA73).
In patients treated with enfortumab vedotin and pembrolizumab (n=76), results demonstrated a 64.5% confirmed objective response rate (ORR) (95% CI: 52.7 to 75.1) per RECIST v1.1 by blinded independent central review (BICR), the primary endpoint of Cohort K, with 10.5% of patients experiencing a complete response and 53.9% of patients experiencing a partial response. The median duration of response (DOR) per BICR was not reached (95% CI: 10.25 months to NR). All-grade treatment-related adverse events (TRAEs) of special interest for enfortumab vedotin in combination with pembrolizumab were skin reactions (67.1%), peripheral neuropathy (60.5%), ocular disorders (dry eye, blurred vision, and corneal disorders) (26.3%), hyperglycemia (14.5%), and infusion-related reactions (3.9%). Pembrolizumab adverse events of special interest were consistent with previously observed safety data from monotherapy with the exception of severe skin reactions. Overall, the results were generally consistent with previously reported efficacy and safety results of the EV-103/KEYNOTE-869 dose-escalation cohort and expansion Cohort A.1
Please see Important Safety Information at the end of this press release for both drugs, including BOXED WARNING for enfortumab vedotin and immune-mediated adverse reactions for pembrolizumab.
Cohort K also included a monotherapy arm in which patients were treated with enfortumab vedotin alone (n=73), though this study was not designed to support a formal comparison between the two arms. Results showed a 45.2% confirmed ORR (95% CI: 33.5 to 57.3) per RECIST v1.1 by BICR, with 4.1% of patients experiencing a complete response and 41.1% of patients experiencing a partial response. The median DOR was 13.2 months (95% CI: 6.14 to 15.97) per RECIST v1.1 by BICR. All-grade TRAEs of special interest for enfortumab vedotin were peripheral neuropathy (54.8%), skin reactions (45.2%), ocular disorders (dry eye, blurred vision, and corneal disorders) (28.8%), hyperglycemia (11.0%), and infusion-related reactions (5.5%).
Additional secondary endpoints in the EV-103 Cohort K trial included progression-free survival (PFS) and overall survival (OS). Among patients treated with enfortumab vedotin and pembrolizumab, median PFS was not reached (95% CI: 8.31 months to NR). Median OS was 22.3 months (95% CI: 19.09 to NR). Among patients treated with enfortumab vedotin, median PFS was 8.0 months (95% CI: 6.05 to 10.35) and median OS was 21.7 months (95% CI: 15.21 to NR).
TRAEs of any grade that occurred in more than 20% of patients treated with enfortumab vedotin alone or in combination with pembrolizumab were fatigue, peripheral sensory neuropathy, alopecia, rash maculo-papular, pruritus, dysgeusia, weight decreased, diarrhea, decreased appetite, nausea, and dry eye.
"Results from EV-103/KEYNOTE-869 Cohort K support the ongoing investigation of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who are in need of treatment options, and this combination may be an important therapeutic option for these patients," said Jonathan E. Rosenberg, M.D., Chief, Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair, Memorial Sloan Kettering Cancer Center and EV-103/KEYNOTE-869 Cohort K primary investigator. Dr. Rosenberg has consulting relationships with Astellas, Seagen and Merck.
"We're encouraged by these positive findings from the combination of enfortumab vedotin and pembrolizumab in people with advanced urothelial cancer who historically have had limited treatment options in the first-line setting, and we intend to discuss these results with regulatory authorities," said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas.
"Nearly sixty-five percent of patients who were treated with enfortumab vedotin and pembrolizumab responded to the combination, with almost eleven percent showing no detectable cancer following treatment. These study results represent an encouraging finding for people with advanced urothelial cancer who are not eligible for cisplatin treatment," said Marjorie Green, Senior Vice President and Head of Late Stage Development, Seagen.
"We're pleased that this combination provided a meaningful benefit to this group of advanced bladder cancer patients in this study, and we will continue to investigate enfortumab vedotin plus pembrolizumab through our collaboration," said Dr. Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, Merck Research Laboratories.
In February 2020, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab for patients with unresectable la/mUC who are ineligible to receive cisplatin-based chemotherapy in the first-line setting. The designation is based on results from the dose-escalation cohort and expansion Cohort A of the phase 1b/2 trial, EV-103/KEYNOTE-869 (NCT03288545), evaluating patients with la/mUC who are ineligible to receive cisplatin-based chemotherapy treated in the first-line setting with enfortumab vedotin in combination with pembrolizumab.
Astellas, Seagen and Merck are further investigating enfortumab vedotin plus pembrolizumab in Phase 3 studies, including EV-302/KEYNOTE-A39 (NCT04223856), which is intended to confirm these results for the investigational treatment combination in previously untreated la/mUC and in muscle-invasive bladder cancer in EV-304/KEYNOTE-B15 (NCT04700124) and EV-303/KEYNOTE-905 (NCT03924895).
About Bladder and Urothelial Cancer
It is estimated that approximately 83,730 people in the U.S. were diagnosed with bladder cancer in 2021.2 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.3 Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.4
About the EV-103/KEYNOTE-869 Trial (Cohort K)
The EV-103 trial (NCT03288545)?is?an ongoing, multi-cohort, open-label, multicenter phase 1b/2 trial of?enfortumab?vedotin?alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with locally advanced or metastatic urothelial cancer (la/mUC) and in patients with muscle-invasive bladder cancer.
Cohort K of the EV-103/KEYNOTE-869 trial is a randomized 1:1 cohort investigating enfortumab vedotin alone (n=73) or in combination with pembrolizumab (n=76) in adult patients with unresectable la/mUC who are ineligible for cisplatin-based chemotherapy and have received no prior treatment for la/mUC. The enfortumab vedotin monotherapy study arm is intended to characterize the activity of enfortumab vedotin alone in this patient population. The key outcome measure of EV-103/KEYNOTE-869 Cohort K is objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1. Secondary endpoints include ORR per investigator assessment; duration of response (DOR), disease control rate (DCR) and progression-free survival (PFS) per BICR and investigator assessment; overall survival (OS); and assessment of safety.
About PADCEV
PADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.5 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).6
PADCEV (enfortumab vedotin-ejfv) U.S. Indication & Important Safety Information
BOXED WARNING: SERIOUS SKIN REACTIONS
PADCEV can cause severe and fatal cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), which occurred predominantly during the first cycle of treatment, but may occur later.
Closely monitor patients for skin reactions.
Immediately withhold PADCEV and consider referral for specialized care for suspected SJS or TEN or severe skin reactions.
Permanently discontinue PADCEV in patients with confirmed SJS or TEN; or Grade 4 or recurrent Grade 3 skin reactions.
Indication
PADCEV® is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:
have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.6
Important Safety Information
Warnings and Precautions
Skin reactions Severe cutaneous adverse reactions, including fatal cases of SJS or TEN, occurred in patients treated with PADCEV. SJS and TEN occurred predominantly during the first cycle of treatment but may occur later. Skin reactions occurred in 55% of the 680 patients treated with PADCEV in clinical trials. Twenty-three percent (23%) of patients had maculo-papular rash and 33% had pruritus. Grade 3-4 skin reactions occurred in 13% of patients, including maculo-papular rash, rash erythematous, rash or drug eruption, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), dermatitis bullous, dermatitis exfoliative, and palmar-plantar erythrodysesthesia. In clinical trials, the median time to onset of severe skin reactions was 0.6 months (range: 0.1 to 6.4). Among patients experiencing a skin reaction leading to dose interruption who then restarted PADCEV (n=59), 24% of patients restarting at the same dose and 16% of patients restarting at a reduced dose experienced recurrent severe skin reactions. Skin reactions led to discontinuation of PADCEV in 2.6% of patients. Monitor patients closely throughout treatment for skin reactions. Consider topical corticosteroids and antihistamines, as clinically indicated. Withhold PADCEV and refer for specialized care for suspected SJS or TEN or for severe (Grade 3) skin reactions. Permanently discontinue PADCEV in patients with confirmed SJS or TEN, or for Grade 4 or recurrent Grade 3 skin reactions.
Hyperglycemia and diabetic ketoacidosis (DKA), including fatal events, occurred in patients with and without pre-existing diabetes mellitus, treated with PADCEV. Patients with baseline hemoglobin A1C ≥8% were excluded from clinical trials. In clinical trials, 14% of the 680 patients treated with PADCEV developed hyperglycemia; 7% of patients developed Grade 3-4 hyperglycemia. The incidence of Grade 3-4 hyperglycemia increased consistently in patients with higher body mass index and in patients with higher baseline A1C. Five percent (5%) of patients required initiation of insulin therapy for treatment of hyperglycemia. The median time to onset of hyperglycemia was 0.6 months (range: 0.1 to 20.3). Hyperglycemia led to discontinuation of PADCEV in 0.6% of patients. Closely monitor blood glucose levels in patients with, or at risk for, diabetes mellitus or hyperglycemia. If blood glucose is elevated (>250 mg/dL), withhold PADCEV.
Pneumonitis Severe, life-threatening or fatal pneumonitis occurred in patients treated with PADCEV. In clinical trials, 3.1% of the 680 patients treated with PADCEV had pneumonitis of any grade and 0.7% had Grade 3-4. In clinical trials, the median time to onset of pneumonitis was 2.9 months (range: 0.6 to 6). Monitor patients for signs and symptoms indicative of pneumonitis, such as hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Evaluate and exclude infectious, neoplastic and other causes for such signs and symptoms through appropriate investigations. Withhold PADCEV for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue PADCEV in all patients with Grade 3 or 4 pneumonitis.
Peripheral neuropathy (PN) occurred in 52% of the 680 patients treated with PADCEV in clinical trials, including 39% with sensory neuropathy, 7% with muscular weakness and 6% with motor neuropathy; 4% experienced Grade 3-4 reactions. PN occurred in patients treated with PADCEV with or without pre-existing PN. The median time to onset of Grade ≥2 PN was 4.6 months (range: 0.1 to 15.8 months). Neuropathy led to treatment discontinuation in 5% of patients. Monitor patients for symptoms of new or worsening peripheral neuropathy and consider dose interruption or dose reduction of PADCEV when PN occurs. Permanently discontinue PADCEV in patients who develop Grade ≥3 PN.
Ocular disorders were reported in 40% of the 384 patients treated with PADCEV in clinical trials in which ophthalmologic exams were scheduled. The majority of these events involved the cornea and included events associated with dry eye such as keratitis, blurred vision, increased lacrimation, conjunctivitis, limbal stem cell deficiency, and keratopathy. Dry eye symptoms occurred in 34% of patients, and blurred vision occurred in 13% of patients, during treatment with PADCEV. The median time to onset to symptomatic ocular disorder was 1.6 months (range: 0 to 19.1 months). Monitor patients for ocular disorders. Consider artificial tears for prophylaxis of dry eyes and ophthalmologic evaluation if ocular symptoms occur or do not resolve. Consider treatment with ophthalmic topical steroids, if indicated after an ophthalmic exam. Consider dose interruption or dose reduction of PADCEV for symptomatic ocular disorders.
Infusion site extravasation Skin and soft tissue reactions secondary to extravasation have been observed after administration of PADCEV. Of the 680 patients, 1.6% of patients experienced skin and soft tissue reactions, including 0.3% who experienced Grade 3-4 reactions. Reactions may be delayed. Erythema, swelling, increased temperature, and pain worsened until 2-7 days after extravasation and resolved within 1-4 weeks of peak. Two patients (0.3%) developed extravasation reactions with secondary cellulitis, bullae, or exfoliation. Ensure adequate venous access prior to starting PADCEV and monitor for possible extravasation during administration. If extravasation occurs, stop the infusion and monitor for adverse reactions.
Embryo-fetal toxicity PADCEV can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during PADCEV treatment and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with PADCEV and for 4 months after the last dose.
Adverse Reactions
Most Common Adverse Reactions, Including Laboratory Abnormalities (≥20%)
Rash, aspartate aminotransferase (AST) increased, glucose increased, creatinine increased, fatigue, PN, lymphocytes decreased, alopecia, decreased appetite, hemoglobin decreased, diarrhea, sodium decreased, nausea, pruritus, phosphate decreased, dysgeusia, alanine aminotransferase (ALT) increased, anemia, albumin decreased, neutrophils decreased, urate increased, lipase increased, platelets decreased, weight decreased and dry skin.
EV-301 Study: 296 patients previously treated with a PD-1/L1 inhibitor and platinum-based chemotherapy.
Serious adverse reactions occurred in 47% of patients treated with PADCEV; the most common (≥2%) were urinary tract infection, acute kidney injury (7% each) and pneumonia (5%). Fatal adverse reactions occurred in 3% of patients, including multiorgan dysfunction (1.0%), hepatic dysfunction, septic shock, hyperglycemia, pneumonitis and pelvic abscess (0.3% each). Adverse reactions leading to discontinuation occurred in 17% of patients; the most common (≥2%) were PN (5%) and rash (4%). Adverse reactions leading to dose interruption occurred in 61% of patients; the most common (≥4%) were PN (23%), rash (11%) and fatigue (9%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common (≥2%) were PN (10%), rash (8%), decreased appetite and fatigue (3% each). Clinically relevant adverse reactions (<15%) include vomiting (14%), AST increased (12%), hyperglycemia (10%), ALT increased (9%), pneumonitis (3%) and infusion site extravasation (0.7%).
EV-201, Cohort 2 Study: 89 patients previously treated with a PD-1/L1 inhibitor and not eligible for platinum-based chemotherapy.
Serious adverse reactions occurred in 39% of patients treated with PADCEV; the most common (≥3%) were pneumonia, sepsis and diarrhea (5% each). Fatal adverse reactions occurred in 8% of patients, including acute kidney injury (2.2%), metabolic acidosis, sepsis, multiorgan dysfunction, pneumonia and pneumonitis (1.1% each). Adverse reactions leading to discontinuation occurred in 20% of patients; the most common (≥2%) was PN (7%). Adverse reactions leading to dose interruption occurred in 60% of patients; the most common (≥3%) were PN (19%), rash (9%), fatigue (8%), diarrhea (5%), AST increased and hyperglycemia (3% each). Adverse reactions leading to dose reduction occurred in 49% of patients; the most common (≥3%) were PN (19%), rash (11%) and fatigue (7%). Clinically relevant adverse reactions (<15%) include vomiting (13%), AST increased (12%), lipase increased (11%), ALT increased (10%), pneumonitis (4%) and infusion site extravasation (1%).
Drug Interactions
Effects of other drugs on PADCEV (Dual P-gp and Strong CYP3A4 Inhibitors)
Concomitant use with a dual P-gp and strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E exposure, which may increase the incidence or severity of PADCEV toxicities. Closely monitor patients for signs of toxicity when PADCEV is given concomitantly with dual P-gp and strong CYP3A4 inhibitors.
Specific Populations
Lactation Advise lactating women not to breastfeed during treatment with PADCEV and for at least 3 weeks after the last dose.
Hepatic impairment Avoid the use of PADCEV in patients with moderate or severe hepatic impairment.
For more information, please see the full Prescribing Information including BOXED WARNING for PADCEV here.
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 body's 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 industry's largest immuno-oncology clinical research program. There are currently more than 1,600 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.
Urothelial Carcinoma
KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):
who are not eligible for any platinum-containing chemotherapy, or
who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Non-muscle Invasive Bladder Cancer
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.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
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 anti–PD-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
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 anti–PD-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 anti–PD-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-Barré 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)
Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatments. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.
Increased Mortality in Patients With Multiple Myeloma
In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.
Embryofetal Toxicity
Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.
Adverse Reactions
In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, when KEYTRUDA was administered as a single agent to patients with stage III melanoma, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%). In KEYNOTE-716, when KEYTRUDA was administered as a single agent to patients with stage IIB or IIC melanoma, adverse reactions occurring in patients with stage IIB or IIC melanoma were similar to those occurring in 1011 patients with stage III melanoma from KEYNOTE-054.
In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).
In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.
In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).
In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).
In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).
In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).
In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.
In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).
In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).
In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).
In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or mUC. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).
In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or mUC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).
In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).
Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-811, when KEYTRUDA was administered in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma. The most common adverse reaction resulting in permanent discontinuation was pneumonitis (1.4%). In the KEYTRUDA arm versus placebo, there was a difference of ≥5% incidence between patients treated with KEYTRUDA versus standard of care for diarrhea (53% vs 44%) and nausea (49% vs 44%).
The most common adverse reactions (reported in ≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia.
In KEYNOTE-590, when KEYTRUDA was administered with cisplatin and fluorouracil to patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation, KEYTRUDA was discontinued due to adverse reactions in 15% of 370 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%), and pneumonia (1.1%). The most common adverse reactions (≥20%) with KEYTRUDA in combination with chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).
Adverse reactions occurring in patients with esophageal cancer who received KEYTRUDA as a monotherapy were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or paclitaxel and carboplatin, with or without bevacizumab (n=307), to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except when used concurrently as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases each of sepsis and due to unknown causes, and 1 case each of acute myocardial infarction, autoimmune encephalitis, cardiac arrest, cerebrovascular accident, femur fracture with perioperative pulmonary embolus, intestinal perforation, and pelvic infection. Serious adverse reactions occurred in 50% of patients receiving KEYTRUDA in combination with chemotherapy with or without bevacizumab; those ≥3% were febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and acute kidney injury and sepsis (3.3% each).
KEYTRUDA was discontinued in 15% of patients due to adverse reactions. The most common adverse reaction resulting in permanent discontinuation (≥1%) was colitis (1%).
For patients treated with KEYTRUDA, chemotherapy, and bevacizumab (n=196), the most common adverse reactions (≥20%) were peripheral neuropathy (62%), alopecia (58%), anemia (55%), fatigue/asthenia (53%), nausea and neutropenia (41% each), diarrhea (39%), hypertension and thrombocytopenia (35% each), constipation and arthralgia (31% each), vomiting (30%), urinary tract infection (27%), rash (26%), leukopenia (24%), hypothyroidism (22%), and decreased appetite (21%).
For patients treated with KEYTRUDA in combination with chemotherapy with or without bevacizumab, the most common adverse reactions (≥20%) were peripheral neuropathy (58%), alopecia (56%), fatigue (47%), nausea (40%), diarrhea (36%), constipation (28%), arthralgia (27%), vomiting (26%), hypertension and urinary tract infection (24% each), and rash (22%).
In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with previously treated recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).
Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).
Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).
In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).
In KEYNOTE-564, when KEYTRUDA was administered as a single agent for the adjuvant treatment of renal cell carcinoma, serious adverse reactions occurred in 20% of patients receiving KEYTRUDA; the serious adverse reactions (≥1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis, and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% including 1 case of pneumonia. Discontinuation of KEYTRUDA due to adverse reactions occurred in 21% of 488 patients; the most common (≥1%) were increased ALT (1.6%), colitis (1%), and adrenal insufficiency (1%). The most common adverse reactions (≥20%) were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%), and hypothyroidism (21%).
Adverse reactions occurring in patients with MSI-H or dMMR endometrial carcinoma who received KEYTRUDA as a single agent were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.
Adverse reactions occurring in patients with recurrent or metastatic cSCC or locally advanced cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.
In KEYNOTE-522, when KEYTRUDA was administered with neoadjuvant chemotherapy (carboplatin and paclitaxel followed by doxorubicin or epirubicin and cyclophosphamide) followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent (n=778) to patients with newly diagnosed, previously untreated, high-risk early-stage TNBC, fatal adverse reactions occurred in 0.9% of patients, including 1 each of adrenal crisis, autoimmune encephalitis, hepatitis, pneumonia, pneumonitis, pulmonary embolism, and sepsis in association with multiple organ dysfunction syndrome and myocardial infarction. Serious adverse reactions occurred in 44% of patients receiving KEYTRUDA; those ≥2% were febrile neutropenia (15%), pyrexia (3.7%), anemia (2.6%), and neutropenia (2.2%). KEYTRUDA was discontinued in 20% of patients due to adverse reactions. The most common reactions (≥1%) resulting in permanent discontinuation were increased ALT (2.7%), increased AST (1.5%), and rash (1%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA were fatigue (70%), nausea (67%), alopecia (61%), rash (52%), constipation (42%), diarrhea and peripheral neuropathy (41% each), stomatitis (34%), vomiting (31%), headache (30%), arthralgia (29%), pyrexia (28%), cough (26%), abdominal pain (24%), decreased appetite (23%), insomnia (21%), and myalgia (20%).
In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC who had not been previously treated with chemotherapy in the metastatic setting (n=596), fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy; the serious reactions in ≥2% were pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).
Lactation
Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.
Pediatric Use
In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).
Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).
Additional Indications for KEYTRUDA 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:
stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
metastatic.
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.
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, 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 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) as determined by an FDA-approved test.
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 gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:
in combination with platinum- and fluoropyrimidine-based chemotherapy, or
as a single agent after one or more prior lines of systemic therapy for patients with tumors of squamous cell histology that express PD-L1 (CPS ≥10) as determined by an FDA-approved test.
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.
Endometrial Carcinoma
KEYTRUDA, as a single agent, is indicated for the treatment of patients with advanced endometrial carcinoma that is MSI-H or dMMR, as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
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.
Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.
About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at?https://www.astellas.com/en.
About Seagen
Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on the company's marketed products and robust pipeline, visit www.seagen.com and follow @SeagenGlobal on Twitter.
Merck's focus on cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose, and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.
Today will be a big risk on day for Dow & NASDQ lets see if we can follow suit .
AstraZeneca Can Raise Its Dominance of Oncology Given ESMO Data
Data at ESMO 2022 for MEDI5752 show AstraZeneca has the scope to be a significant lung-cancer player, menacing Merck's Keytruda crown, though it's still early days. We also note data on Roche and Sanofi's novel breast-cancer drugs (oral SERD inhibitors) suggest Astra may have shot at winning with camizestrant over the next two years. The potential of neither of these drugs is meaningfully reflected in consensus.