On­col­o­gists lis­ten when the FDA speaks, even af­ter a drug hits the mar­ket

The FDA took off some of the guard rails in an ef­fort to speed in­no­va­tion. The ques­tion was if, once those were gone, there’d be some­one to pull the emer­gency stop when things went wrong.

A new study in JA­MA on on­col­o­gists and two im­munother­a­pies the FDA re­strict­ed af­ter ap­proval sug­gests the sec­ondary brakes do work. Re­searchers at the Uni­ver­si­ty of Penn­syl­va­nia tracked us­age rates for two blad­der can­cer im­munother­a­pies the FDA ap­proved in 2017 but re­strict­ed in 2018 af­ter da­ta showed that sur­vival rates were worse in the new ther­a­pies than in the stan­dard cis­platin-based chemother­a­py. They found that on­col­o­gists de­creased their us­age of the im­munother­a­py by over 20 per­cent­age points and in­creased their us­age of chemother­a­py by over 20 per­cent­age points, sug­gest­ing that doc­tors were close­ly mon­i­tor­ing FDA up­dates and ad­just­ing their treat­ments ac­cord­ing­ly.

The ther­a­pies were ap­proved through the FDA’s con­tro­ver­sial ac­cel­er­at­ed ap­proval pro­gram, based on sin­gle-arm Phase II clin­i­cal tri­als as op­posed to the full gold-stan­dard Phase III ran­dom­ized stud­ies. The FDA sub­se­quent­ly re­strict­ed the pro­gram to pa­tients not el­i­gi­ble for chemo.

Ronac Mam­tani Perel­man

“On­col­o­gy physi­cians re­spond­ed very quick­ly to an FDA warn­ing and la­bel change for two very pop­u­lar drugs,” lead au­thor Ravi Parikh told End­points News.  “What this means is that this is a vi­able strat­e­gy to re­spond to safe­ty con­cerns for drugs ob­tain­ing ac­cel­er­at­ed ap­proval in the fu­ture. “

Cru­cial­ly, though, the study does not probe in­to the costs, in health and dol­lars, for pa­tients who were giv­en the treat­ment in­stead of chemother­a­py be­fore the FDA re­stric­tion. Nor can it say how many doc­tors have ig­nored the FDA warn­ings or how many pa­tients are still get­ting the wrong treat­ment, as the da­ta on­ly look at the over­all rates of each treat­ment and the rate of PD-L1 test­ing. (The im­munother­a­pies ex­am­ined are PD1/L1 in­hibitors).

The re­searchers an­a­lyzed 1,965 pa­tients be­tween May 2018, one month be­fore the FDA rolled out re­stric­tions, and Jan­u­ary 2019. Over that time, the num­ber of pa­tients re­ceiv­ing im­munother­a­py fell from 51.9% to 30.3% and the rate of chemother­a­py in­creased from 37% to 60.6%. The rate of PD-L1 test­ing rose from 9.3% to 21.2%.

Near­ly 30 years af­ter its launch, the FDA’s ac­cel­er­at­ed ap­proval pro­gram re­mains con­tro­ver­sial, crit­i­cized both by those who say it is not fast enough and slows ac­cess to ex­per­i­men­tal treat­ments for pa­tients who might not live to see the drug hit mar­ket, and by those who say in­creas­ing­ly lax stan­dards and a re­liance on sur­ro­gate end­points is let­ting risky and in­ef­fec­tive drugs reach pa­tients.

Two re­views pub­lished ear­li­er this year took aim at the pro­gram. An­oth­er JA­MA study found can­cer drugs grant­ed ac­cel­er­at­ed ap­proval were okayed based on less ev­i­dence than those ap­proved through the reg­u­lar process, a BMJ study found stud­ies for sur­ro­gate end­points far more like­ly to be at risk of bias, and a third JA­MA study found on­ly one fifth of can­cer drugs ap­proved through AA were lat­er con­firmed to im­prove sur­vival rates.

“Pa­tients don’t need just any can­cer drugs, they need can­cer drugs that help them have a longer and-or bet­ter lives,” Bishal Gyawali, lead au­thor of the lat­ter study, told CNN at the time.

But there is ev­i­dence that pa­tients are will­ing to take the risk be­cause of the hope it pro­vides. A 2017 Val­ue in Health study found that while most physi­cians would choose a hy­po­thet­i­cal safer ther­a­py that of­fered a guar­an­teed 4 years of life, no-more-no-less, over a riski­er ther­a­py that gave a 20% chance of liv­ing more than 7 years but a 50% of not liv­ing past year one. Al­most 2/3 of pa­tients chose the riski­er op­tion.

The study pro­vides a boon to the FDA’s lat­est project: Fa­cil­i­tate. The project will help physi­cians sub­mit ex­pand­ed ac­cess re­quests for in­di­vid­ual can­cer pa­tients, giv­ing an op­por­tu­ni­ty for those un­able to en­roll in a clin­i­cal a teth­er to ex­per­i­men­tal treat­ments.

What Will it Take to Re­al­ize the Promise and Po­ten­tial of Im­mune Cell Ther­a­pies?

What does it take to get to the finish line with a new cancer therapy – fast? With approvals in place and hundreds of immune cell therapy candidates in the pipeline, the global industry is poised to create a fundamental shift in cancer treatments towards precision medicine. At the same time, unique challenges associated with cell and process complexity present manufacturing bottlenecks that delay speed to market and heighten cost of goods sold (COGS) — these hurdles must be overcome to make precision treatments an option for every cancer patient. This series of articles highlights some of the key manufacturing challenges associated with the production of cell-based cancer therapies as well as the solutions needed to transcend them. Automation, process knowledge, scalability, and assured supply of high-quality starting material and reagents are all critical to realizing the full potential of CAR-based therapies and sustaining the momentum achieved in recent years. The articles will highlight leading-edge technologies that incorporate these features to integrate across workflows, accelerate timelines and reduce COGS – along with how these approaches are enabling the biopharmaceutical industry to cross the finish line faster with new treatment options for patients in need.

The biggest ques­tions fac­ing gene ther­a­py, the XLMTM com­mu­ni­ty, and Astel­las af­ter fourth pa­tient death

After three patients died last year in an Astellas gene therapy trial, the company halted the study and began figuring out how to safely get the program back on track. They would, executives eventually explained, cut the dose by more than half and institute a battery of other measures to try to prevent the same thing from happening again.

Then tragically, Astellas announced this week that the first patient to receive the new regimen had died, just weeks after administration.

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Mi­rati's KRAS drug looks like the fa­vorite in colon can­cer with new da­ta, putting the pres­sure square on Am­gen

With Amgen already providing proof-of-concept for KRAS inhibitors with its sotorasib, Mirati Therapeutics is piecing together a follow-up effort in lung cancer with data it thinks are superior. But in colon cancer, where solo sotorasib has turned in a dud, Mirati may now have a strong case for superiority.

Mirati’s adagrasib, dosed solo or in combination with chemotherapy cetuximab, showed response rates grater than sotorasib solo  and as part of combination study in a similar patient population also revealed this week at #ESMO21. Mirati’s data were presented as part of a cohort update from the Phase II KRYSTAL-1 study testing adagrasib in a range of solid tumors harboring the KRAS-G12C mutation.

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Lat­est news: It’s a no on uni­ver­sal boost­ers; Pa­tient death stuns gene ther­a­py field; In­side Tril­li­um’s $2.3B turn­around; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Next week is shaping up to be a busy one, as our editor-in-chief John Carroll and managing editor Kyle Blankenship lead back-to-back discussions with a great group of experts to discuss the weekend news and trends. John will be spending 30 minutes with Jake Van Naarden, the CEO of Lilly Oncology, and Kyle has a brilliant panel lined up: Harvard’s Cigall Kadoch, Susan Galbraith, the new head of cancer R&D at AstraZeneca, Roy Baynes at Merck, and James Christensen at Mirati. Don’t miss out on the action — sign up here.

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The best of the rest: High­lights from the be­low-the-fold pre­sen­ta­tions at #ES­MO21

This year’s ESMO Congress has had a major focus on Big Pharma drugs — most notably candidates from Merck and AstraZeneca — but there have also been updates from smaller biotechs with data looking to challenge the big-name drugmakers.

Today, we’re highlighting some of the data releases that flew under the radar at #ESMO21 — whether from early-stage drugs looking to make a mark or older stalwarts with interesting follow-up data.

As­traZeneca, Dai­ichi Sanky­o's ADC En­her­tu blows away Roche's Kad­cy­la in sec­ond-line ad­vanced breast can­cer

AstraZeneca and Japanese drugmaker Daiichi Sankyo think they’ve struck gold with their next-gen ADC drug Enhertu, which has shown some striking data in late-stage breast cancer trials and early solid tumor tests. Getting into earlier patients is now the goal, starting with Enhertu’s complete walkover of a Roche drug in second-line breast cancer revealed Saturday.

Enhertu cut the risk of disease progression or death by a whopping 72% (p=<0.0001) compared with Roche’s ADC Kadcyla in second-line unresectable and/or metastatic HER2-positive breast cancer patients who had previously undergone treatment with a Herceptin-chemo combo, according to interim data from the Phase III DESTINY-Breast03 head-to-head study presented at this weekend’s #ESMO21.

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Merck Research Laboratories CMO Roy Baynes

Mer­ck­'s Keytru­da un­corks full da­ta on lat­est ad­ju­vant win — this time in melanoma — adding bricks to ear­ly can­cer wall

In recent months, the battle for PD-(L)1 dominance has spilled over into early cancer with Merck’s Keytruda and Bristol Myers Squibb’s Opdivo all alone on the front lines. Keytruda now has another shell in its bandolier, and it could spell a quick approval.

Keytruda cut the risk of relapse or death by 35% over placebo (p=0.00658) in high-risk, stage 2 melanoma patients who had previously undergone surgery to remove their tumors, according to full data from the Phase III KEYNOTE-716 presented Saturday at #ESMO21.

President Biden and Pfizer CEO Albert Bourla (Patrick Semansky/AP Images)

Chaot­ic ad­comm sees Pfiz­er/BioN­Tech boost­ers re­ject­ed for gen­er­al pop­u­la­tion, but rec­om­mend­ed for old­er and high-risk pop­u­la­tions

With just days before President Joe Biden’s Covid-19 booster rollout is set to go into effect, an FDA advisory committee appeared on the verge of not recommending boosters for anyone in the US before a last-minute change of wording laid the groundwork for older adults to have access to a third dose.

The FDA’s adcomm on Vaccines and Related Biological Products (VRBPAC) roundly rejected Pfizer/BioNTech booster shots for all individuals older than 16 by a 16-2 vote Friday afternoon. Soon after, however, the agency posed committee members a new question limiting booster use to the 65-and-older population and individuals at high risk of disease due to occupational exposure or comorbidities.

Mer­ck flesh­es out Keytru­da win in first-line cer­vi­cal can­cer, adding more fire­pow­er to its ear­ly can­cer push

Merck has worked hard to bring its I/O blockbuster Keytruda into earlier and earlier lines of therapy, and now the wonder drug appears poised to make a quick entry into early advanced cervical cancer.

A combination of Keytruda and chemotherapy with or without Roche’s Avastin cut the risk of death by 33% over chemo with or without Avastin (p=<0.001) in first-line patients with persistent, recurrent or metastatic cervical cancer, according to full data from the Phase III KEYNOTE-826 study presented Saturday at #ESMO21.